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Background In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. Patients and methods Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. Conclusions Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Purpose Osimertinib has proven efficacy in EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) patients; however, its benefits have not been evaluated in a real-world setting. Methods ASTRIS is a single-arm, open-label, multinational study to evaluate the efficacy and safety of osimertinib for the treatment of EGFR T790M mutation-positive NSCLC. We present the study design and preliminary cut-off analysis results (as of October 2017) describing the baseline characteristics and methodology for T790M mutation detection in the Spanish cohort. Results The Spanish cohort included 131 patients from a total 3014 patients. Forty patients (28.1%) were still undergoing therapy at the time of cut-off; 68.7% were women and 97.7% were Caucasian, with a mean age of 64.8 (SD 11.7) years. The most common type of sample for evaluating T790M mutations was tissue (55.0%), and samples were obtained from the primary tumor in 61.1% of cases. Mutation analysis was performed by the local laboratory in 60.3% of cases and using the Roche Cobas® EGFR assay in 43.5% of cases. Conclusions ASTRIS is expected to confirm the benefits of osimertinib in a real-world setting. Data on real-world practices for the detection of the EGFR T790M mutation may provide additional information for the designing of guidelines for best practices.

PURPOSE In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680 ). METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p &lt, 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

To evaluate the evolution of disease-related symptoms and its relationship with the control of the disease in first-line treatment in patients with metastatic non-small cell lung cancer (NSCLC). This was an observational, prospective, national and multicentre study with two visits in which the following were collected: (1) baseline visit: sociodemographic and clinical variables (2) visit after completing the 4–6 chemotherapy cycles: criteria for ending treatment, control of the disease and clinical variables. Ad hoc questionnaires were collected to assess the frequency of symptoms (evaluated by the patient), and quality-of-life questionnaires to assess the intensity of symptoms (using the Lung Cancer Symptom Scale, LCSS), and interference in the patient’s daily life, assessed by the patient and by the investigator. A total of 155 patients were included. Patients predominantly described tiredness (24.1%) and pain (23.9%) as the symptoms that appeared “frequently or continuously”. A statistically significant decrease in scores for symptoms of cough (15.4 points), dyspnoea (8.5 points), pain (9.5 points) and discomfort related to their illness (9 points) was observed between visits. Patients who achieved a complete or partial response showed a statistically significant reduction in the cough, dyspnoea, pain and disconfort frequency. Regarding the intensity, cough was the only symptom that showed a statistically significant decrease for both the patient and the investigator. Tiredness/asthenia and pain were the symptoms with the greatest interference in daily life at baseline according to the patient; however, according to the investigator, they were mood and quality/quantity of sleep, although none of them were significant. But changes in the score of the interference questionnaire between visits were not statistically significantly related to the control of the disease. However, average score according to both investigator and patients showed a significant correlation with ECOG status. The first-line treatment of NSCLC is correlated with an improvement in the symptomatic evolution of advanced NSCLC patients. Roche.

Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with ≥50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.

TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.

e24098 Background: Patient reported outcomes measures (PROMs) represent a tool to objectively assess the health of cancer patients. PROMs may complement oncological evaluations by adding patients’ perspectives on their care priorities. Aim: to address more accurately the management of tumor related symptoms or drug related toxicities to bring he therapies more accurately to bring patients the best quality of life possible. Methods: Data was collected from our electronic registry after proper authorization and corresponding anonymization. Patients were systematically asked for symptoms as fever, diarrhea, dyspnea, vomiting and nausea. These symptoms were graded according to their severity using the Common Toxicity Criteria v5.0. Results: 49 patients admitted to Medical Oncology Hospitalization were included from July of 2020 to January 2021, 80% in advanced disease. Median age 63yo, 32% above 70 yo. Baseline data showed that 27% patients (19% stage IV) had fever at admission, decreasing at 48h to 4%. Patients who had vomiting at admission were 33% (28% stage IV) median grade 2 becoming 20% and grade 1 at 48h. Nausea was present in 49% patients (35% stage IV) at the time of admission with a median grade 1.5, and it decreased to 16% at 48h with a median grade 2. Diarrhea was reported in 12% patients (6% stage IV) median grade 2 at baseline and it was reduced to 10% median grade 1 at 48h. The median severity of diarrhea at admission was 2 and only 1 at 48h. At admission, 33% (all stage IV) of patients presented dyspnea with a median grade 3, while at 48h it was present in 26% of patients and reduced to median grade 2. Conclusions: By systematically measuring symptoms, patients achieved better control of diarrhea, dyspnea, vomiting and nausea after admission. It should be noted that nausea was the variable that decreased the most at 48h, followed by fever, vomiting, dyspnea and diarrhea. All patients with stage IV disease had dyspnea and most of them had nausea and vomiting. These results reflect that these symptoms are more usual in patients with advanced disease compared to those with localized disease. PROMS also help us educate patients by teaching them how to manage treatments, thus improving therapeutic adherence.

8567 Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]

4576 Background: TITAN-RCC uses a tailored immunotherapy approach in renal cell carcinoma (RCC), starting with nivolumab (nivo) induction followed by nivo + ipilimumab (ipi) as immunotherapeutic “boost” in non-responders. Patients with initial partial or complete response (PR/CR) continued with nivo maintenance but received later “boosts” for progressive disease (PD). Here we report updated results focusing on the efficacy of nivo+ipi in patients with initial PD vs. initial responders with later PD. Methods: Patients with IMDC intermediate and poor risk advanced clear cell RCC were recruited between OCT 2016 and DEC 2018. Patients started with nivo 240 mg Q2W induction. Patients with early significant PD (week 8) or non-responders at week 16 received 2-4 nivo+ipi “boost” cycles. Responders (PR/CR) to nivo monotherapy continued with maintenance but could receive nivo+ipi for later PD. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST in first line (1L) and second line (2L). Secondary endpoints included activity of nivo monotherapy, remission rate with nivo+ipi “boost”, safety and overall survival (OS). Results: 109 1L and 98 2L (after TKI) patients were analyzed for efficacy. Median age was 65 years (range 20-87). 71 % were intermediate and 25 % poor risk. Confirmed ORR with nivo monotherapy was 28 % for 1L and 17 % for 2L. After a median follow-up of 12.8 months best overall response after nivo induction ± nivo+ipi was 36 % in 1L and 30 % in 2L. Of all patients, 38 received nivo+ipi for stable disease (SD) up to week 16, with 1 (3 %), 4 (11 %) and 26 (68 %) achieving CR, PR and SD, respectively. 28 patients in 1L and 43 in 2L were boosted with nivo+ipi for initial PD. Of these, 3 (11 %) and 8 (29 %) achieved PR and SD, respectively, in 1L, whereas 3 (7.0 %) achieved CR, 6 (14 %) PR and 13 (30 %) SD in 2L. 16 and 10 patients received “boosts” later than week 16 for PD during nivo maintenance in 1L and 2L, respectively. Thereof, 3 (19 %) achieved PR and 5 (31 %) SD in 1L, whereas 2 (20 %) achieved PR and 3 (30 %) SD in 2L. Progression-free survival was 6.3 months (95 % CI 3.7 – 10.1) and 3.7 months (95 % CI 2.0 - 4.5) in 1L and 2L, respectively. OS was 27.2 months (95 % CI 19.9 – not estimable (NE)) in 1L and 20.2 months (95 % CI 15.6 – NE) in 2L. Treatment-related adverse events will be presented. Conclusions: Our tailored approach with nivo+ipi “boosts” results in improved response rates compared to nivo monotherapy. Our updated analysis suggests that almost half of the patients receiving “boosts” for PD improve to either PR/CR (18 %) or SD (30 %), irrespective of initial or later progression with nivo. Clinical trial information: NCT02917772. [Table: see text]

Cancer prevalence in Latin America (LATAM) is increasing and represents a major cause of morbidity and mortality. Managing cancer patients—who live longer than ever before—requires appropriate management of cancer pain, described by the World Health Organization (WHO) in 1988 with its now famous “pain ladder,” the rungs of which represented nonopioids, weak opioids, and strong opioids as pain relievers. Yet even today much cancer pain is undertreated. Cancer pain can be multimechanistic with a neuropathic component which may complicate pain control. Acute pain should be treated aggressively to avoid the potential transition to chronic pain, a maladaptive form of pain that can be particularly challenging to treat. Although opioids have been recognized by WHO in 1988 and since then as a safe, effective form for treating moderate to severe cancer pain, opioid consumption in LATAM nations is very low. LATAM countries make up about 9% of the world’s population but represent only about 1% of global opioid consumption. Better education about pain control in cancer and opioid therapy is needed by both healthcare providers and patients to better treat cancer pain in LATAM. But opioid-associated side effects and the risk of abuse and diversion are important risks of opioid therapy that are to be fully understood by both healthcare providers and patients before commencing therapy. Opioid risk management plans balance the need for access to opioids for appropriate patients with the mitigation of opioid-related risks of abuse and addiction. Risks as well as benefits should be clearly understood in order to consider opioid therapy. Combining education, prescription drug monitoring plans, and other risk mitigation strategies may be useful tools. Abuse-deterrent formulations, such as fixed-dose combination products of an opioid with naloxone, have been designed to resist abuse. LATAM may benefit from such new products in efforts to bring better pain control to cancer patients in a rational and responsible manner.

Updated information published up to 2016 regarding major advances in renal cancer, bladder cancer, and prostate cancer is here presented. Based on an ever better understanding of the genetic and molecular alterations that govern the initial pathogenic mechanisms of tumor oncogenesis, an improvement in the characterization and treatment of urologic tumors has been achieved in the past year. According to the Cancer Genome Atlas (ATLAS) project, alterations in the MET pathway are characteristics of type 1 papillary renal cell carcinomas, and activation of NRF2-ARE pathway is associated with the biologically distinct type 2. While sunitinib and pazopanib continue to be the standard first-line treatment in metastatic renal cell carcinoma of clear cell histology, nivolumab and cabozantinib are now the agents of choice in the second-line setting. In relation to urothelial bladder carcinoma, new potential molecular targets such as FGFR3, PI3K/AKT, RTK/RAS, CDKN2A, ARIDIA, ERBB2 have been identified. Response to adjuvant cisplatin-based chemotherapy appears to be related to basal, luminal, and p53-like intrinsic subtypes. A phase II study with eribulin and a maintenance phase II trial with vinflunine have shown promising results. Similarly, the use of the check point inhibitors in advanced disease is likely to revolutionize the management of patients who have progressed after cisplatin-based chemotherapy. In prostate cancer, seven mutually exclusive molecular subtypes have been identified by the TCGA project. Chemotherapy has been consolidated as a key treatment for castration-sensitive metastatic prostate cancer, and abiraterone, enzalutamide, cabazitaxel, and radium-223 remain standard therapeutic options for men with metastatic castration-resistant prostate cancer. All this progress will undoubtedly contribute to the development of new treatments and therapeutic strategies that will improve the survival and quality of life of our patients.

Background High-dose chemotherapy (HDCT) has been studied in several clinical scenarios in advanced germ cell cancer (GCC). Objective To establish a clinical practice guideline for HDCT use in the treatment of GCC patients. Design, setting, and participants An expert panel reviewed information available from the literature. The panel addressed relevant issues concerning and related to HDCT. The guideline was externally reviewed by two international experts. Results and limitations The efficacy of HDCT has been demonstrated in selected GCC patients. The most conclusive evidence comes from retrospective analyses that need to be interpreted with caution. HDCT can cure a significant proportion of heavily treated GCC patients. When indicated, sequential HDCT with regimens containing carboplatin and etoposide, as well as peripheral stem-cell support, is recommended. There is no conclusive evidence to recommend HDCT as first-line therapy. According to a multinational retrospective pooled analysis, HDCT might be superior to conventional CT as first salvage treatment in selected patients. There is an urgent need for prospective clinical trials addressing the value of HDCT in GCC patients who experience failure on first-line cisplatin-based CT. In patients who progress on conventional-dose salvage CT, HDCT should be considered. Treatment of these patients at experienced centers is strongly recommended. Conclusions It has been demonstrated that HDCT cures selected GCC patients who experience disease progression on conventional rescue regimens. The panel recommends the inclusion of GCC patients in randomized clinical trials including HDCT. Patient summary This consensus establishes clinical practice guidelines for the use and study of high-dose chemotherapy in patients with germ cell cancer.

Bone metastasis is the most common cause of cancer-related pain, and metastatic bone pain (MBP) is not only severe but also progressive in many patients. The aim of this study was to investigate the association between pain management and performance status in patients with metastatic bone cancer in the Spanish clinical setting. A 3-month follow-up prospective, epidemiologic, multicenter study was conducted in 579 patients to assess the evolution of their performance, the impact of pain control on sleep and functionality, and the degree of pain control according to analgesic treatment. In patients with MBP, Eastern Cooperative Oncology Group (ECOG) status (1.5 ± 0.7–1.3 ± 0.7 and 1.3 ± 0.8; p

Background KRAS mutations are observed in ∼25% of lung adenocarcinomas, with some studies suggesting it is a prognostic factor in NSCLC. We assessed the prevalence of KRAS mutations and their association with efficacy in an exploratory analysis of the KEYNOTE-189 study of pembrolizumab plus pemetrexed and platinum chemotherapy vs placebo plus chemotherapy as first-line therapy for metastatic non-squamous NSCLC (NCT02578680). Methods Whole-exome sequencing (WES) was used to assess KRAS status and tumor mutational burden (TMB) in participants (pts) who had available tumor and matched-normal tissue. Descriptive analyses of the association of KRAS and KRAS G12C status with efficacy were included as part of this exploratory analysis, as was correlation between KRAS mutational status and shifts in TMB and PD-L1 expression distributions. Results 289 (47%) of 616 pts had evaluable WES data from both tumor and normal DNA. 89 (31%) of 289 pts had KRAS mutation, including 37 (13%) G12C carriers. Pts with vs without KRAS mutations tended to have higher PD-L1 TPS (median [IQR] 30% [1-71] vs 5% [0-60]) and higher TMB (median [IQR] 204 [137-276] vs 141 [85-252] mut/exome). Outcomes of pembrolizumab plus chemotherapy and of placebo plus chemotherapy in pts with and without KRAS mutation and in KRAS G12C carriers are summarized in the table. 95% CIs were wide given the modest frequency of KRAS mutation, particularly KRAS G12C, and the 2:1 randomization that resulted in small populations for placebo plus chemotherapy.TableLBA5TableWith Any KRAS MutationWith KRAS G12C MutationWithout Any KRAS MutationPembro + Chemo (N = 59)Placebo + Chemo (N = 30)Pembro + Chemo (N = 26)Placebo + Chemo (N = 11)Pembro + Chemo (N = 145)Placebo + Chemo (N = 55)ORR, % (95% CI)40.726.750.018.247.610.9(28.1-54.3)(12.3-45.9)(29.9-70.1)(2.3-51.8)(39.2-56.0)(4.1-22.3)PFS, median, mo (95% CI)9 (7-14)5 (5-9)11 (6-18)5 (5-NR)9 (7-14)5 (4-5)PFS, HR (95% CI)0.47 (0.29-0.77)0.48 (0.22-1.06)0.40 (0.29-0.57)OS, median, mo (95% CI)21 (16-NR)14 (8-NR)18 (11-NR)25 (8-NR)23 (19-NR)9 (7-17)OS, HR (95% CI)0.79 (0.45-1.38)1.14 (0.45-2.92)0.55 (0.37-0.81) Conclusion Based on this descriptive exploratory analysis, pembrolizumab plus pemetrexed and a platinum should be a standard first-line treatment for pts with metastatic non-squamous NSCLC regardless of KRAS mutation status. Clinical trial identification KEYNOTE-189, NCT02578680. Editorial acknowledgement Joanne Tomassini and Melanie Leiby, both of Merck & Co., Inc., Kenilworth, NJ, USA, for writing support. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure S. Gadgeel: Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Xcovery; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novocure; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech/Roche; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Pharmamar. D. Rodriguez-Abreu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. E. Felip: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy: Abbvie; Honoraria (self), lecture fees: AstraZeneca; Honoraria (self), lecture fees: Bristol Myers Squibb; Honoraria (self), lecture fees: Novartis. E. Esteban: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): MSD. G. Speranza: Research grant / Funding (institution): MSD. M. Reck: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Merck ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Abbvie; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis. R. Hui: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Advisory / Consultancy: Eli Lilly. M. Boyer: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): MSD; Honoraria (institution): Roche; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Ascentage Pharma; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Janssen. E.B. Garon: Honoraria (self): Dracen; Honoraria (self), Research grant / Funding (institution): EMD Serono; Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Neon; Research grant / Funding (institution): MSD. H. Horinouchi: Honoraria (self), Advisory / Consultancy: Eli LIlly; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): ONO; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self): Kyowa-Kirin; Honoraria (self): Taiho; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Chugai/Roche; Research grant / Funding (institution): Genomic Health. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme. M.C. Garassino: Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Otsuka Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy: Takeda; Advisory / Consultancy: Inivata; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Tiziana Sciences; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution): Spectrum Pharmaceuticals.

Summary Background Pembrolizumab plus pemetrexed–platinum led to superior overall survival and progression-free survival, and a higher proportion of patients with a confirmed complete or partial response over placebo plus pemetrexed–platinum in the KEYNOTE-189 study. We aimed to evaluate prespecified exploratory patient-reported outcomes (PROs) in patients in KEYNOTE-189. Methods In the multicentre, double-blind, randomised, placebo-controlled, phase 3 KEYNOTE-189 study done at 126 cancer centres in 16 countries, eligible patients aged 18 years or older with histologically or cytologically confirmed metastatic non-squamous non-small-cell lung cancer without sensitising EGFR or ALK alterations, measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Patients were randomly assigned (2:1) to receive intravenous pembrolizumab (200 mg) or saline placebo every 3 weeks for up to 2 years (35 cycles); all patients received four cycles of intravenous pemetrexed (500 mg/m2) with carboplatin (5 mg/mL per min) or cisplatin (75 mg/m2; investigator's choice) every 3 weeks for four cycles, followed by pemetrexed maintenance therapy every 3 weeks. Permuted block randomisation (block size six) was done with an interactive voice-response system and stratified by PD-L1 expression, choice of platinum, and smoking status. Patients, investigators, and other study personnel were unaware of treatment assignment. The European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13) were administered at cycles 1–5, every three cycles thereafter during year 1, and every four cycles during years 2–3. The primary endpoints (overall survival and progression-free survival) have been published previously. Key PRO endpoints were change from baseline to week 12 (during chemotherapy) and week 21 (following chemotherapy) in QLQ-C30 global health status/quality of life (GHS/QOL) score, and time to deterioration in cough, chest pain, or dyspnoea. PROs were analysed in all randomly assigned patients who received at least one dose of study medication and who completed at least one PRO assessment, and the results are provided with two-sided, nominal p values. This ongoing study is registered with ClinicalTrials.gov , number NCT02578680 . Findings Between Feb 26, 2016, and March 6, 2017, 616 patients were enrolled; median follow-up was 10·5 months (range 0·2–20·4) as of data cutoff on Nov 8, 2017. 402 (99%) of 405 patients in the pembrolizumab plus pemetrexed–platinum group and 200 (99%) of 202 patients in the placebo plus pemetrexed–platinum-treated group completed at least one PRO assessment. At baseline, 359 (89%) of 402 patients in the pembrolizumab plus pemetrexed–platinum group and 180 (90%) of 200 in the placebo plus pemetrexed–platinum group were compliant with QLQ-C30; at week 12, 319 (90%) of 354 and 149 (89%) of 167 patients were compliant, respectively; and at week 21, 249 (76%) of 326 and 91 (64%) of 143 patients were compliant, respectively. From baseline to week 12, GHS/QOL scores were maintained with both pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·0 point [95% CI −1·3 to 3·2] increase) and placebo plus pemetrexed–platinum (−2·6 points [−5·8 to 0·5] decrease; between-group difference: 3·6 points [−0·1 to 7·2]; p=0·053). From baseline to week 21, GHS/QOL scores were better maintained with pembrolizumab plus pemetrexed–platinum (least-squares mean change: 1·3 points [95% CI −1·2 to 3·6] increase) than with placebo plus pemetrexed–platinum (−4·0 points [−7·7 to −0·3] decrease; between-group difference: 5·3 points [1·1 to 9·5]; p=0·014). Median time to deterioration in cough, chest pain, or dyspnoea was not reached (95% CI 10·2 months to not reached) with pembrolizumab plus pemetrexed–platinum, and was 7·0 months (4·8 months to not reached) with placebo plus pemetrexed–platinum (hazard ratio 0·81 [95% CI 0·60–1·09], p=0·16). Interpretation The addition of pembrolizumab to standard chemotherapy maintained GHS/QOL, with improved GHS/QOL scores at week 21 in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group. These data further support use of pembrolizumab plus pemetrexed–platinum as first-line therapy for patients with metastatic non-squamous non-small-cell lung cancer. Funding Merck Sharp & Dohme.

Summary Background Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. Findings Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9–48·4) in the MAGE-A3 group and 39·5 months (27·9–50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2–not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7–not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89–1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6–not reached) in those in the MAGE-A3 group and 56·9 months (44·4–not reached) in the placebo group (HR 0·97, 95% CI 0·80–1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). Interpretation Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. Funding GlaxoSmithKline Biologicals SA.

In the last 10 years, there has been a major change in the treatment of lung cancer (LC). The discovery of activating mutations in the epidermal growth factor receptor (EGFR) in some histological subtypes of LC and its sensitivity to tyrosine kinase inhibitors (TKI) has represented a substantial advance in the treatment of this entity. Until then, the only available option to treat this type of tumour was based on chemotherapy, with a small but significant benefit in terms of survival and quality of life. The arrival of new agents that act against activating EGFR mutations gave rise to the era of precision medicine with targeted therapies able to act on the origin of the tumour, thus providing a therapeutic benefit while minimizing adverse effects and delaying administration of chemotherapy. In addition, this has produced a change in the diagnostic paradigm of lung cancer (as well as in that of all tumours), with a shift from a purely histological diagnosis to a classification of tumours based on their mutational characteristics. This shift has been made possible by the development of technologies allowing complex DNA analysis. Together with the efforts of researchers from all over the world, these techniques allow continued discovery of genetic alterations that could be the target of new drugs as well as definition of the mechanisms of activity and resistance to treatments. This extraordinary development of targeted therapies cannot change the fact that metastatic lung cancer continues to be an incurable disease and, at the present time, only a few patients will benefit from targeted therapies. Ongoing research will shed new light on the molecular alterations that give rise to LC and will provide new treatment alternatives for this disease.

Background: Mutations in the tumor suppressor genes STK11 (also known as LKB1) and KEAP1 have been associated with poorer clinical outcomes in patients (pts) with NSCLC. In an exploratory analysis, we assessed the prevalence of STK11 and KEAP1 mutations and their association with efficacy in KEYNOTE-189 (NCT02578680). Methods: STK11 and KEAP1 status and tumor mutational burden (TMB) were assessed by whole-exome sequencing (WES) in pts who had available tumor and matched-normal tissue. PD-L1 was assessed by the PD-L1 IHC 22C3 pharmDx assay. The association of STK11 and KEAP1 status with efficacy and their correlation with TMB and PD-L1 expression distributions were evaluated descriptively. Results: WES data from both tumor and normal DNA were evaluable for 289 (47%) of 616 pts, of whom 54 (19%) had an STK11 mutation and 68 (24%) had a KEAP1 mutation; 29 (10%) had both STK11 and KEAP1 mutations. PD-L1 TPS tended to be lower in pts with vs without STK11 mutation (median [IQR] 0% [0-16] vs 15% [0-75]), whereas TMB score tended to be higher in pts with mutation (209 [132-265] vs 146 [89-264]). Similar patterns were seen for pts with vs without KEAP1 mutation (PD-L1 TPS: 1% [0-13] vs 20% [0-75]; TMB: 173 [124-267] vs 147 [89-263]). Although ORR of pembrolizumab plus chemotherapy was lower and PFS and OS shorter in pts with vs without STK11 and KEAP1 mutation, pembrolizumab plus chemotherapy was associated with numerically better outcomes than placebo plus chemotherapy regardless of mutation status (Table). 95% CIs were wide given the modest mutation frequency and the 2:1 randomization in favor of pembrolizumab plus chemotherapy. Conclusions: Data from this exploratory analysis support use of pembrolizumab plus pemetrexed and platinum as standard first-line therapy for pts with metastatic nonsquamous NSCLC regardless of STK11 or KEAP1 status. STK11KEAP1With MutationWithout MutationWith MutationWithout MutationPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + ChemoPembro + ChemoPlacebo + Chemo(n = 36)(n = 18)(n = 168)(n = 67)(n = 45)(n = 23)(n = 159)(n = 62)ORR, % (95% CI)31 (16-48)17 (4-41)49 (41-57)16 (8-27)36 (22-51)17 (5-39)48 (40-56)16 (8-28)PFS, median, mo (95% CI)6 (4-9)5 (5-9)10 (8-14)5 (5-5)5 (4-11)5 (5-9)10 (8-14)5 (5-5)PFS, HR (95% CI)0.81 (0.44-1.47)0.38 (0.27-0.52)0.65 (0.38-1.12)0.38 (0.28-0.53)OS, median, mo (95% CI)17 (5-NR)8 (7-NR)23 (20-NR)12 (8-25)13 (7-NR)9 (7-NR)24 (20-NR)12 (8-NR)OS, HR (95% CI)0.75 (0.37-1.50)0.59 (0.41-0.85)0.81 (0.44-1.49)0.57 (0.39-0.84) Citation Format: Shirish M. Gadgeel, Delvys Rodriguez-Abreu, Enriqueta Felip, Emilio Esteban, Giovanna Speranza, Martin Reck, Rina Hui, Michael Boyer, Edward B. Garon, Hidehito Horinouchi, Razvan Cristescu, Deepti Aurora-Garg, Andrey Loboda, Jared Lunceford, Julie Kobie, Mark Ayers, Bilal Piperdi, M. Catherine Pietanza, Marina C. Garassino. Pembrolizumab plus pemetrexed and platinum vs placebo plus pemetrexed and platinum as first-line therapy for metastatic nonsquamous NSCLC: analysis of KEYNOTE-189 by STK11 and KEAP1 status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-397.

9521 Background: In a previous analysis of KEYNOTE-189 (NCT02578680), we showed that tissue TMB (tTMB) assessed by whole-exome sequencing was not significantly associated with efficacy in either arm and that pembro + chemo improved outcomes vs placebo + chemo in both the tTMB ≥175 and tTMB < 175 mut/exome subgroups. Here, we explored the association of bTMB with efficacy in KEYNOTE-189. Methods: 616 patients (pts) were randomized 2:1 to pembro + chemo or placebo + chemo. bTMB was assessed in cfDNA using the Guardant Health Omni assay. Association of bTMB (continuous square root transformed) with outcomes in each arm was assessed using Cox proportional hazards models (OS, PFS) and logistic regression (ORR) adjusted for ECOG PS; statistical significance was determined at the 0.05 level without multiplicity adjustment. The clinical utility of bTMB on outcomes was assessed using the cutoff that most closely approximated the 175 mut/exome tTMB cutoff as determined by AUROC analysis. Data cutoff was 21 Sep 2018. Results: 235 (38%) treated pts had evaluable tTMB and bTMB: 160 in the pembro + chemo arm and 75 in the placebo + chemo arm. bTMB as a continuous variable was not significantly associated with OS or ORR for pembro + chemo (one-sided P = .229 and .051) or placebo + chemo (two-sided P = .641 and .069); bTMB was significantly associated with PFS in the pembro + chemo arm (one-sided P = .015) but not the placebo + chemo arm (two-sided P = .058). bTMB and tTMB scores were moderately correlated (r = .61). The bTMB cutoff that most closely approximated tTMB 175 mut/exome was 15 mut/Mb (AUROC 0.81, 95% CI 0.75-0.86). 178 (76%) pts had concordant bTMB and tTMB results—101 low and 77 high by both—whereas 57 (24%) had discordant results—21 high bTMB but low tTMB, 36 low bTMB but high tTMB. Pembro + chemo improved OS, PFS, and ORR vs placebo + chemo for bTMB ≥15 and < 15 mut/exome (Table). Conclusions: Similar to previous findings based on tTMB, bTMB has limited clinical utility in the setting of pembro with pemetrexed and platinum given as first-line therapy for metastatic nonsquamous NSCLC. Clinical trial information: NCT02578680 . [Table: see text]

e14034 Background: Cancer patients under cytotoxic treatment with fever used to have an average time of antibiotics administration of 11h (median 3h43min) when admitted and identified at the Emergency Room Service in the third level Central University Hospital of Asturias. International guidelines recommend antibiotic administration in the first hour: the so called “Golden Hour”. This delay implies an increase in patient morbidity as well as the cost of managing this complication. Methods: Data was collected from our electronic registry after proper authorization and corresponding anonymization. Pareto and fishbone diagrams were built to point out the possible causes and to stratify them in related subgroups. We measured: Number of visits to ER with fever and Number of inpatients with Febrile Neutropenia diagnosis, Time from the admission to antibiotic administration, Average stay of inpatients with Febrile Neutropenia diagnosis. A protocol associated to electronic tools and validated international scores was designed for patients at Febrile Neutropenia risk and launched on March 2019. Results: 66 patients were included since January 2018. Baseline data showed that the median time to antibiotics indication was 3h50min (average 4h38min) with a median delay of 18min to the administration (average 1h06min), a median of 3h54min (average 10h09min) time to antibiotic administration. When the protocol was activated, median time to antibiotic indication was 30min (average (1h08min) with a median 41min (average 40min) delay in administration, and a median of 1h30min (average 1h42min) time to antibiotic administration. Those with activation of the protocol had average length of stay of 1d13h40min vs. 5d11h18min in those to whom this protocol was not applied. Conclusions: A continuous evaluation effort and the design of appropriate protocols and interventions will increase the efficiency of the oncology patient care process with febrile neutropenia, by reducing unnecessary variability and costs.

5060 Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng's scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427 .

95 Background: Abiraterone acetate (AA) improves OS and rPFS in first line mCRPC patients (pts). After AA progression D is commonly used as standard second line therapy. However, the value of maintaining AA in combination with D despite progression has not been tested beyond small exploratory studies (Tagawa ST, Eur Urol 2016) ABIDO is a randomized-phase II trial that evaluates efficacy and safety of D + AA vs D after first-line AA progression in mCRPC. Methods: Asymptomatic or minimally symptomatic mCRPC pts with no visceral metastases, ECOG PS 0-1, and adequate organ functions were included. The study has two stages: In stage I pts receive AA (1000 mg/d + prednisone (P) 10 mg qd) until radiological or unequivocal clinical progression. In stage II pts were randomized to D 75 mg/m2 q3wk in combination with AA 1000 mg/d (arm A) or without AA (arm B) The primary endpoint was rPFS and the secondary endpoints radiological response (RR), OS, PSA-response, PSA-PFS and safety. Results: 88 pts were randomized, (46 arm A, 42 Arm B). Median age was 69 y/o, 43% had ECOG 0 and 91%/11%/5% had bone, liver and lung metastases. Median rPFS was 11.4 months (m) in arm A vs 10.5 m in ARM B; 12-m rPFS was 43% vs 45%; Median PSA PFS was 6.2 vs 5.5 m and median OS was 17.3 vs 16.9 m. Twenty four pts (52%) in arm A and 19 (46%) in arm B achieve ≥50% PSA response. RR was achieved in 15% vs 7% of pts and disease control rate in 74% in both arms. No statistically significant differences were found in efficacy parameters. Half of pts received 10 cycles of D (median 7 and 8). D median dose intensity was 86% and 90% for each arm and 91% for AA. Eleven pts discontinued treatment due to non-hematological toxicity, 5 in arm A and 6 in arm B. Most frequent G3-4 toxicities per arm (A/B) were: neutropenia (57%/29%; P=0.027), febrile neutropenia (17%/10%), diarrhea (9%/7%), and asthenia (11%/10%). Conclusions: ABIDO trial was unable to demonstrate the significant clinical benefit of maintenance AA approach + D after AA first-line therapy. No differences were observed in RR, PSA PFS, rPFS and OS. In AA + D cohort, more frequent and severe hematological toxicity (neutropenia and febrile neutropenia) were reported. Clinical trial information: NCT02036060.

Several agents have demonstrated an overall survival (OS) benefit in metastatic castration-resistant prostate cancer (mCRPC); however, optimal sequencing is unknown. Retrospective analysis of data from 574 mCRPC patients showed increasing OS with the number of therapies provided; a sequence including docetaxel, cabazitaxel (CABA), and an androgen receptor-targeted agent (ART) provided the greatest benefit. Prior administration of ART did not appear to influence CABA activity. These findings will help guide treatment decisions in daily practice. Background: Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor-targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC). Patients and Methods: Records of 574 consecutive patients treated (2012-2016) at 44 centers in 6 countries were retrospectively examined. Results: A total of 267 patients received ADT -> DOC -> CABA (group 1), 183 patients ADT -> DOC -> ART -> CABA (group 2), and 124 patients ADT -> DOC -> CABA -> ART (group 3), with respective median OS from diagnosis of mCRPC of 38.3, 44.45, and 53.9 months (P = .012 for group 3 vs. group 1). Multivariate analysis showed response to first ADT

[Abstract] Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients. Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice. Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered. Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05) Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.

[Abstract] Background: Several potential predictive markers of efficacy of targeted agents in patients with metastatic renal cell carcinoma (mRCC) have been identified. Interindividual heterogeneity warrants further investigation. Patients and methods: Multicenter, observational, retrospective study in patients with clear-cell mRCC treated with sunitinib. Patients were classified in two groups: long-term responders (LR) (progression-free survival (PFS)≥22 months and at least stable disease), and primary refractory (PR) (progressive disease within 3-months of sunitinib onset). Objectives were to compare baseline clinical factors in both populations and to correlate tumor expression of selected signaling pathways components with sunitinib PFS. Results: 123 patients were analyzed (97 LR, 26 PR). In the LR cohort, overall response rate was 79% and median duration of best response was 30 months. Median PFS and overall survival were 43.2 (95% confidence intervals[CI]:37.2-49.3) and 63.5 months (95%CI:55.1-71.9), respectively. At baseline PR patients had a significantly lower proportion of nephrectomies, higher lactate dehydrogenase and platelets levels, lower hemoglobin, shorter time to and higher presence of metastases, and increased Fuhrman grade. Higher levels of HEYL, HEY and HES1 were observed in LR, although only HEYL discriminated populations significantly (AUC[ROC]=0.704; cut-off=34.85). Increased levels of hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p were also associated with prolonged survival. No statistical significant associations between hsa-miR-23b or hsa-miR-27b and the expression of c-Met were found. Conclusions: Certain mRCC patients treated with sunitinib achieve extremely long-term responses. Favorable baseline hematology values and longer time to metastasis may predict longer PFS. HEYL, hsa-miR-27b, hsa-miR-23b and hsa-miR-628-5p could be potentially used as biomarkers of sunitinib response. PPfizer; SOGUG-2011-05 Ministerio de Economía, Industria y Competitividad; SAF2015-66015-R Ministerio de Economía, Industria y Competitividad; ISCIII-RETIC RD12/0036/0009 Ministerio de Economía, Industria y Competitividad; PIE 15/00076

Background Inguinal orchiectomy is curative in 70–80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT. Methods Fifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays. Results Classical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3–9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations. Conclusions Epididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1162-3) contains supplementary material, which is available to authorized users.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management., Supported by Pfizer.

Purpose This international phase III trial (Investigating Torisel As Second-Line Therapy [INTORSECT]) compared the efficacy of temsirolimus (mammalian target of rapamycin inhibitor) and sorafenib (vascular endothelial growth factor receptor [VEGFR] tyrosine kinase inhibitor) as second-line therapy in patients with metastatic renal cell carcinoma (mRCC) after disease progression on sunitinib. Patients and Methods In total, 512 patients were randomly assigned 1:1 to receive intravenous temsirolimus 25 mg once weekly (n = 259) or oral sorafenib 400 mg twice per day (n = 253), with stratification according to duration of prior sunitinib therapy (≤ or > 180 days), prognostic risk, histology (clear cell or non–clear cell), and nephrectomy status. The primary end point was progression-free survival (PFS) by independent review committee assessment. Safety, objective response rate (ORR), and overall survival (OS) were secondary end points. Results Primary analysis revealed no significant difference between treatment arms for PFS (stratified hazard ratio [HR], 0.87; 95% CI, 0.71 to 1.07; two-sided P = .19) or ORR. Median PFS in the temsirolimus and sorafenib arms were 4.3 and 3.9 months, respectively. There was a significant OS difference in favor of sorafenib (stratified HR, 1.31; 95% CI, 1.05 to 1.63; two-sided P = .01). Median OS in the temsirolimus and sorafenib arms was 12.3 and 16.6 months, respectively. Safety profiles of both agents were consistent with previous studies. Conclusion In patients with mRCC and progression on sunitinib, second-line temsirolimus did not demonstrate a PFS advantage compared with sorafenib. The longer OS observed with sorafenib suggests sequenced VEGFR inhibition may benefit patients with mRCC.

Summary Background An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9–14·6). Median PFS was 3·7 months (95% CI 3·5–3·9) in the dovitinib group and 3·6 months (3·5–3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72–1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding Novartis Pharmaceuticals Corporation.

Background Nivolumab (N) + ipilimumab (I) has been approved for the 1st line treatment of IMDC intermediate and poor risk advanced RCC. However, administration of N+I in a fixed regimen with 4 induction cycles may result in more treatment related adverse events (AEs) compared with N alone. It is hypothesized that a tailored approach starting treatment with N alone and using N+I as immunotherapeutic boost will improve efficacy outcomes as compared to N alone and reduce AEs. Methods This multicentric European study enrolled 258 1st and 2nd line (after TKI) pts with IMDC intermediate and poor risk, advanced clear cell RCC between Oct. 2016 and Dec. 2018. Pts started with N 240 mg Q2W induction. Pts with early significant PD (week 8) or either SD or PD at week 16 received 2-4 N+I boost cycles. Responders (PR/CR) to N monotherapy continued with maintenance with N+I boosts only for progression. The primary endpoint is confirmed investigator assessed objective response rate (ORR) per RECIST independent in 1st and 2nd line. Secondary endpoints include activity of N monotherapy, remission rate with N+I boosts, safety, overall survival and QoL. Results 108 1st and 99 2nd line pts were analyzed for efficacy. Median age was 65 y (range 20-87). 70 % were intermediate and 27 % poor risk. Confirmed ORR with 1st line N monotherapy was 28.7 % (95 % CI 20 - 38). Best overall response (BOR) after N induction ± N+I boosts was 37 % (95 % CI 28 - 47) and 28 % (95 % CI 20 - 38) in 1st and 2nd line, respectively. 102 pts received N+I boosts for either SD (n = 35) or PD (n = 67) until week16. Of these, 12 (12 %) and 54 (53%) had a PR/CR and SD, respectively. Two (6%) pts entering boosts for SD had PD afterwards compared to 51% with early PD. Treatment-related AEs will be presented. Table . LBA57 1st line (n = 108) 2nd line (n = 99) n (%) Nivo mono ORR N ± N+I BOR Nivo mono ORR N ± N+I BOR Complete response 2 (1.9) 2 (1.9) 0 4 (4.0) Partial response 29 (26.9) 38 (35.2) 18 (18.2) 24 (24.2) Stable disease 26 (24.1) 26 (24.1) 23 (23.2) 25 (25.3) Progressive disease 13 (12.0) 38 (35.2) 16 (16.2) 43 (43.4) Early PD/Boost W8 22 (20.4) 26 (26.3) Not evaluable * 16 (14.8) 4 (3.7) 16 (16.2) 3 (3.0) * Including patients with early end of study e.g. due to death or immune related AEs Conclusions TITAN–RCC is the first study to assess the impact of a tailored approach using N+I as an immunotherapeutic boost. In 1st line, this significantly improved ORR compared to N mono. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial identification EudraCT: 2016-002307-26. Legal entity responsible for the study AIO-Studien-gGmbH, Berlin, Germany. Funding Bristol-Myers Squibb GmbH & Co.KGaA. Disclosure M. Grimm: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Amgen; Honoraria (self): Apogepha; Honoraria (self): Astellas; Honoraria (self): AstraZeneca; Honoraria (self): Bayer HealthCare; Honoraria (self): Hexal; Honoraria (self), Advisory / Consultancy: Intuitive Surgical; Honoraria (self): Janssen Cilag; Honoraria (self): Ipsen Pharma; Honoraria (self): Medac; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: ONO Pharma; Honoraria (self): Pfizer; Honoraria (self): Sanofi Aventis. M. Schmidinger: Honoraria (self): Astellas; Honoraria (self): BMS; Honoraria (self): EISAI; Honoraria (self): Eusa Pharma; Honoraria (self): Exelexis; Honoraria (self): Ipsen; Honoraria (self): MSD; Honoraria (self): Pfizer; Honoraria (self): Roche. I. Duran Martinez: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Non-remunerated activity/ies: Ipsen; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche Genentech; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Pharmacyclyc; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD. G. Baretton: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer. P. Barthelemy: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Janssen Cilag; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Astellas. B. Melichar: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. L. Albiges: Honoraria (institution): Pfizer; Honoraria (institution): Novartis; Honoraria (institution): BMS; Honoraria (institution): Ipsen; Honoraria (institution): Roche; Honoraria (institution): MSD; Honoraria (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Post-operative platinum-based chemotherapy is the standard of care for resected NSCLC with nodal involvement. Expression of genes involved in DNA repair may have a prognostic role for the outcome. BRCA1 plays an important role in DNA repair pathways and could have a prognostic impact in this setting. The SCAT trial results found that for low BRCA1 levels subgroup Cis-Gem was superior to Cis-Doc and in high BRCA1 subgroup docetaxel single agent without platinum achieved similar survival to Cis-Doc. Risk of recurrence analysis according BRCA-1 levels has been performed. Methods From Jun/2007 to May/2013 591 patients were screened and 500 were included, 108 in the control arm treated with Cis-Docetaxel and 392 in the experimental arms treated with Cis-Gem, Cis-Doc or docetaxel alone according to terciles of BRCA1 expression level. With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence patterns were analysed for the whole group according BRCA1 levels in tumor tissue and comparison were made for risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and metastatic sites (liver, bone, brain). Results Cumulative recurrence was evaluable in 232/456 patients (50.8%), 182/354 patients treated in the experimental arm and in 50/102 patients treated in the control arm (RR 1.04; 0.83-1.30) (p = 0.672). The majority of recurrences 159/232 (68.5%) were single site intrathoracic recurrences in 121/232 (52%) while 111/232 were extrathoracic (47.8%). Overall recurrence was 56.5% (113/200 p) for low tercile BRCA1 vs 48.8% (63/129) for intermediate tercile vs 44% (56/127) for high tercile (p = 0.025). No differences were seen between tercile groups for single site (p = 0.35), multiple site (p = 0.26), intrathoracic (p = 0.36), or extrathoracic (p = 0.38). More frequent distant metastatic sites were: bone (42 patients), brain (38 patients) and liver (11 patients). RIsk reduction was seen for brain metastases in patients with higher tercile BRCA1 (p = 0.003). Conclusions For NSCLC resected patients with lymph node involvement risk of recurrence remains high with a cumulative rate > 50%. Relative risk of recurrence was lower for tumors with higher BRCA1 levels. Distant metastases were seen in 47.8% of patients. Brain metastases risk was significant lower for patients with low BRCA1 expression. BRCA1 levels acts as a prognostic factor in early stages NSCLC. Clinical trial identification EudraCT: 2007-000067-15; NCT 00478699. Legal entity responsible for the study Spanish Lung Cancer Group - Grupo Espanol Cancer de Pulmon. Funding Sanofi Aventis. Disclosure All authors have declared no conflicts of interest.

Background: KEYNOTE-189 is a randomized, placebo-controlled, Phase III study of pembro plus pemetrexed-platinum versus placebo plus pemetrexed-platinum among pts with metastatic nonsquamous NSCLC. At median follow-up of 10.5 months, pts in the pembro-combination arm had improved OS (HR, 0.49; 95% CI, 0.38-0.64; P Methods: Pts with untreated metastatic nonsquamous NSCLC, ECOG PS 0/1, and without EGFR/ALK alteration were randomized 2:1 to receive up to 35 Q3W cycles of pembro 200 mg or placebo plus 4 cycles of pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by maintenance pemetrexed. Randomization was stratified by PD-L1 TPS ( Results: 616 pts were randomized (pembro-combination, n=410; placebo-combination, n=206). At data cutoff, median follow-up was 18.7 months. At baseline, 19% of pts had liver metastases and 18% had brain metastases. HRs for OS and PFS favored the pembro-combination vs placebo-combination across all groups, and were similar for pts with/without liver or brain metastases (Table). Conclusion: Pembro plus pemetrexed-platinum provided superior outcomes vs chemotherapy alone irrespective of liver or brain metastases in pts with untreated metastatic nonsquamous NSCLC. Benefit was observed in pts with brain or liver metastases, for whom prognosis is historically poor. PFSOSN*Median, mo (95% CI)HR(95% CI)Median, mo (95% CI)HR(95% CI)Pts With Liver MetastasesPembro-combination666.1 (4.7-8.5)0.52 (0.34-0.81)12.6 (8.1-19.1)0.62 (0.39-0.98)Placebo-combination493.4 (2.8-4.7)6.6 (4.6-7.6)Pts Without Liver MetastasesPembro-combination3449.2 (8.8-11.0)0.48 (0.39-0.59)23.7 (20.1-25.9)0.58 (0.45-0.74)Placebo-combination1575.4 (4.9-6.7)13.2 (10.0-16.4)Pts With Brain MetastasesPembro-combination736.9 (5.4-11.0)0.42 (0.27-0.67)19.2 (15.0-25.9)0.41 (0.24-0.67)Placebo-combination354.7 (2.2-5.5)7.5 (4.6-10.0)Pts Without Brain MetastasesPembro-combination3379.2 (8.3-10.9)0.48 (0.39-0.59)22.4 (19.7-25.4)0.59 (0.46-0.75)Placebo-combination1714.9 (4.7-5.9)12.1 (9.1-15.0)*25 patients had both brain and liver metastases. 1 of 2 Citation Format: Marina C. Garassino, Shirish Gadgeel, Emilio Esteban, Enriqueta Felip, Giovanna Speranza, Flávia De Angelis, Manuel Domine, Philip Clingan, Maximilian J. Hochmair, Steven F. Powell, Susanna Y.-S. Cheng, Helge G. Bischoff, Nir Peled, Francesco Grossi, Ross R. Jennens, Martin Reck, Rina Hui, Edward B. Garon, Michael Boyer, Belén Rubio-Viqueira, Silvia Novello, Takayasu Kurata, Jhanelle E. Gray, Anna Cardellino, Jing Yang, M. Catherine Pietanza, Delvys Rodríguez-Abreu. Outcomes among patients (pts) with metastatic nonsquamous NSCLC with liver metastases or brain metastases treated with pembrolizumab (pembro) plus pemetrexed-platinum: Results from the KEYNOTE-189 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT043.

665 Background: It is widely known the causal relationship establised between tobacco use and the development of renal cancer is widely known. Nevertheless, the impact of smoking on the efficacy and safety of anti-angiogenic drugs is unclear. Sunitinib is a tyrosine kinase inhibitor with proven efficacy metastatic renal cell carcinoma (mRCC). Methods: A retrospective analysis was carried out including 194 mRCC patients (pts) who received Sunitinib in a single Institution (Hospital Universitario Central de Asturias) with a high incidence of this disease. The aim of this study is to explore the impact of the smoking habit on treatment response in terms of progression‐free survival (PFS) and overall survival (OS). Results: Most patients presented clear cell histology (92%). Smoking status: 42% (n=82) never‐smoker, and 39% (n=76) former‐smoker and 19% (n=36) current‐smoker. Male predominance 78% (n=145). Median age was 65 (range: 40‐84). Survival analysis favors patients with a history of tobacco use. There was no significant difference in PFS between never‐smoker vs ever-smoker groups: median PFS 8.13 months (95% IC: 4.75‐11.52), vs 12 months (95% IC: 9.97‐14.03) was found respectively (p=0,086). Fewer than 10% developed grade 3 toxicity. A significative improvement in OS in patients ever-smokers: median OS 16.23 months (95% IC: 12.22‐20.25) vs 26.46 months (95% IC: 16.21‐36.73) (p=0.044). The advantage observed in patients with any smoking history became more evident for poor prognosis cases. A median OS 5.03 months (95% IC: 0.84‐9.23) vs 14.03 months (95% IC: 7.81‐20.26). A median PFS 6.4 months (95% IC: 2.53‐10.27) vs 13.33 months (95% IC: 1.14‐26.19) p > 0.05. Conclusions: In this series, tobacco seems to play a role on the efficacy and safety of anti‐angiogenic agents in mRCC. However, additional prospective studies in well‐balanced populations are required to confirm this data.

Purpose The MAGE-A3 protein is expressed in approximately 35% of patients with resectable non–small-cell lung cancer (NSCLC). Several immunization approaches against the MAGE-A3 antigen have shown few, but often long-lasting, clinical responses in patients with metastatic melanoma. Patients and Methods A double-blind, randomized, placebo-controlled phase II study was performed assessing clinical activity, immunologic response, and safety following immunization with recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) in completely resected MAGE-A3–positive stage IB to II NSCLC. The primary end point was disease-free interval (DFI). Results Patients were randomly assigned to either MAGE-A3 immunotherapeutic (n = 122) or placebo (n = 60). After a median postresection period of 44 months, recurrence was observed in 35% of patients in the MAGE-A3 arm and 43% in the placebo arm. No statistically significant improvement in DFI (hazard ratio [HR], 0.75, 95% CI, 0.46 to 1.23; two-sided P = .254), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48 to 1.21; P = .248), or overall survival (HR, 0.81; 95% CI, 0.47 to 1.40; P = .454) was observed. Corresponding analysis after a median of 70 months of follow-up revealed a similar trend for DFI and DFS. All patients receiving the active treatment showed a humoral immune response to the MAGE-A3 antigen, although no correlation was observed with outcome. No significant toxicity was observed. Conclusion In this early development study with a limited number of patients, postoperative MAGE-A3 immunization proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.

Background: Owing to the limited validity of clinical data on the treatment of prostate cancer (PCa) and bone metastases, biochemical markers are a promising tool for predicting survival, disease progression and skeletal-related events (SREs) in these patients. The aim of this study was to evaluate the predictive capacity of biochemical markers of bone turnover for mortality risk, disease progression and SREs in patients with PCa and bone metastases undergoing treatment with zoledronic acid (ZA). Methods: This was an observational, prospective and multicenter study in which ninety-eight patients were included. Patients were treated with ZA (4mg every 4 weeks for 18 months). Data were collected at baseline and 3, 6, 9, 12, 15 and 18 months after the beginning of treatment. Serum levels of bone alkaline phosphtase (BALP), aminoterminal propeptide of procollagen type I (P1NP) and beta-isomer of carboxiterminal telopeptide of collagen I (beta-CTX) were analysed at all points in the study. Data on disease progression, SREs development and survival were recorded. Results: Cox regression models with clinical data and bone markers showed that the levels of the three markers studied were predictive of survival time, with beta-CTX being especially powerful, in which a lack of normalisation in visit 1 (3 months after the beginning of treatment) showed a 6.3-times more risk for death than in normalised patients. Levels of these markers were also predictive for SREs, although in this case BALP and P1NP proved to be better predictors. We did not find any relationship between bone markers and disease progression. Conclusion: In patients with PCa and bone metastases treated with ZA, beta-CTX and P1NP can be considered suitable predictors for mortality risk, while BALP and P1NP are appropriate for SREs. The levels of these biomarkers 3 months after the beginning of treatment are especially important., This study was supported by Novartis Oncology Spain. As this was a multicenter study, Adknoma Health Research (Barcelona, Spain) collected and ordered data throughout the study. We especially thank Margarida Garcia from Adknoma who followed carefully the development of the study. M. Martin-Fernandez was a fellow of the Conchita Rabago Foundation.

Sequential targeted therapies are the standard of care for patients with metastatic renal cell carcinoma (mRCC). Several drugs are available for patients whose disease progresses while they receive initial tyrosine kinase inhibitor (TKI) therapy; these include nivolumab (an inhibitor of PD-1 receptor), everolimus (an inhibitor of the mechanistic target of rapamycin) or additional TKIs. Until now, there has been no clinical evidence to support the use of one strategy versus another, so investigators and physicians rely on experience, judgement and findings from molecular analyses to select the appropriate treatment. However, with the arrival of nivolumab and cabozantinib that provide an overall survival higher than other alternative treatments, therapeutic strategies may have changed. Here, we discuss findings from preclinical and clinical studies that might help clinicians to choose the optimal treatment approach for patients with mRCC who progress to initial therapy.

The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10-9 to 3 × 10-3). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (P = 4.6 × 10-3, 6.5 × 10-3, and 3.4 × 10-2, respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85; P = 1.3 × 10-4) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10-8 and 7.8 × 10-7 for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.

Background Markers able to predict the response to antiangiogenics in metastatic clear cell renal cell carcinoma (ccRCC) are not available. The development of new treatment options like immunotherapy are reaching the clinic; therefore, predictors of benefit from these different available treatments are increasingly needed. Objective In this study, we prospectively assessed the association of circulating endothelial cells (CECs) in peripheral blood with long-term benefit from first-line treatment in ccRCC. Design, setting, and participants A prospective observational study was designed involving 13 institutions of the Spanish Oncology Genitourinary Group. Adult patients diagnosed with advanced ccRCC who had achieved response or disease stabilization after 3 mo on first-line therapy were eligible. Outcome measurements and statistical analysis CECs were isolated from peripheral blood, captured with ferrofluids coated with monoclonal antibodies directed against the CD146 antigen, and assessed centrally with an automated standardized system. CECs were defined as 4′,6-diamidino-2-phenylindole+, CD105+, and CD45–. Blood samples were systematically taken every 6 wk for 15 mo or until tumor progression, whichever occurred first. Clinical data were externally monitored at all centers. Results and limitations From August 9, 2011, to January 17, 2013, 75 patients were enrolled in the study. Patients with baseline CECs above the median showed a significantly longer progression-free survival than those with low CECs (22.2 mo vs 12.2 mo) with a hazard ratio of 2.5 (95% confidence interval: 1.2–5.3, p =0.016). There was no difference between CEC levels at baseline and at tumor progression (medians of 50 CECs/4ml and 52 CECs/4ml, respectively). Conclusions Under antiangiogenic treatment, the detection of higher CEC levels is associated with clinical benefit in terms of progression-free survival in ccRCC. Patient summary Antiangiogenics are the cornerstone of treatment in kidney cancer. Since they target endothelial rather than tumor cells, we studied the correlation between levels of circulating endothelial cells in peripheral blood and long-term benefit in patients on antiangiogenic therapy. Higher levels were associated with long-term benefit, suggesting that this determination could help to separate best responders from those who could require a more intensive approach.

Background: The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. Methods: Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. Results: Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). Conclusions: Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction., This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer. The authors gratefully say thanks to Ma Luz Samaniego for his help with the statistical analyses.

Introduction The analysis of predictive factors of response may aid in predicting which patients with advanced renal cell carcinoma (RCC) would be good candidates for systemic treatments. Materials and methods The expression of several biomarkers was retrospectively analyzed using immunohistochemistry (IHC), as well as 2 analytical variables in 135 patients with advanced RCC treated with cytokines (CK) and/or new targeted drugs (NTD). Results 67 patients were treated solely with NTD and 68 with CK (23 also received NTD). Univariate analysis: HIF1α did not correlate significantly with response to these drugs. Overexpression of CAIX was associated with more responses (%) to NTD (64.7 vs. 21.1; p = 0.004) and CK (22.6 vs. 0; p = 0.038). PTEN demonstrated predictive value of response to sunitinib (70.8 vs. 34.1; p = 0.005). p21 was associated with a lower response to sunitinib (35.9 vs. 65.4; p = 0.025). Thrombocytosis was not significantly associated with response to NTD, although it was with CK (0 vs. 20; p = 0.017). Neutrophilia correlated with a lower response to NTD (29.6 vs. 57.5; p = 0.045), although not with CK. Multivariate analysis: Overexpression of CAIX was an independent predictor of significantly higher response to NTD and CK; OR = 8.773 (p

Erlotinib, docetaxel, and pemetrexed are approved for the second-line treatment of non-small-cell lung cancer (NSCLC), but no head-to-head data from large clinical trials are available. We undertook the Tarceva In Treatment of Advanced NSCLC (TITAN) study to assess the efficacy and tolerability of second-line erlotinib versus chemotherapy in patients with refractory NSCLC.TITAN was an international, randomised multicentre, open-label, phase 3 study that was done at 77 sites in 24 countries. Chemotherapy-naive patients with locally advanced, recurrent, or metastatic NSCLC received up to four cycles of first-line platinum doublet chemotherapy, after which patients with disease progression during or immediately after chemotherapy were offered enrolment into TITAN. Enrolled patients were randomly assigned (1:1) by a minimisation method to ensure balanced stratification, to receive erlotinib 150 mg/day or chemotherapy (standard docetaxel or pemetrexed regimens, at the treating investigators' discretion), until unacceptable toxicity, disease progression, or death. Patients were stratified by disease stage, Eastern Cooperative Oncology Group performance status, smoking history, and region of residence. The primary endpoint was overall survival in the intention-to-treat population. TITAN was halted prematurely because of slow recruitment. This study is registered with ClinicalTrials.gov, number NCT00556322.Between April 10, 2006, and Feb 24, 2010, 2590 chemotherapy-naive patients were treated with first-line platinum doublet chemotherapy, of whom 424 had disease progression and were enrolled into TITAN. 203 patients were randomly assigned to receive erlotinib and 221 were assigned to receive chemotherapy. Median follow-up was 27·9 months (IQR 11·0-36·0) in the erlotinib group and 24·8 months (12·1-41·6) in the chemotherapy group. Median overall survival was 5·3 months (95% CI 4·0-6·0) with erlotinib and 5·5 months (4·4-7·1) with chemotherapy (hazard ratio [HR] 0·96, 95% CI 0·78-1·19; log-rank p=0·73). The adverse-event profile of each group was in line with previous studies. Rash (98/196 [50%] in the erlotinib group vs 10/213 [5%] in the chemotherapy group for all grades; nine [5%] vs none for grade 3 or 4) and diarrhoea (36 [18%] vs four [2%] for all grades; five [3%] vs none for grade 3 or 4) were the most common treatment-related adverse events with erlotinib, whereas alopecia (none vs 23 [11%] for all grades; none vs one [1%] for grade 3/4) was the most common treatment-related adverse event with chemotherapy.No significant differences in efficacy were noted between patients treated with erlotinib and those treated with docetaxel or pemetrexed. Since the toxicity profiles of erlotinib and chemotherapy differ, second-line treatment decisions should take into account patient preference and specific toxicity risk profiles.F Hoffmann-La Roche.

The availability of agents targeting the vascular endothelial growth factor or mammalian target of rapamycin [mTOR] pathways has provided new treatment options for patients with metastatic renal cell carcinoma (RCC). Based on the results of pivotal randomized clinical trials, specific recommendations have been established for management of these patients in first- and second-line settings. However, certain subgroups of patients may be excluded or under-represented in clinical trials, including patients with poor performance status, brain metastases, and cardiac or renal comorbidities, elderly patients, and those with non-clear cell histology. For these subpopulations, management recommendations have emerged from expanded access programs (EAPs), small phase II studies, retrospective analysis of clinical data, and expert opinion. This paper describes recommendations from an expert panel for the treatment of metastatic RCC in these subpopulations. The efficacy of targeted agents appears to be inferior in these patient subgroups relative to the general RCC population. Tyrosine kinase inhibitors (TKIs) and mTOR inhibitors can be administered safely to elderly patients and those with poor performance status, although dose and schedule modifications are often needed, and close monitoring and management of adverse events is essential. In addition to local surgical treatment and radiotherapy for brain metastases, systemic treatment with a TKI should be offered as part of multidisciplinary care. While there are currently no data from randomized trials, sunitinib has the greatest body of evidence, and it should be considered the first choice in patients with a good prognosis. Patients with an acute cardiac event within the previous 6 months, New York Heart Association grade III heart failure, or uncontrolled high blood pressure should not be treated with TKIs. In patients with mild or moderate renal failure, there are no contraindications to TKI treatment. TKIs can be administered to patients undergoing dialysis, but other, less nephrotoxic agents and other alternatives should always be considered. In managing RCC among patients with non-clear cell histology, sunitinib seems to be more effective than everolimus for the papillary subtype, but there are no clear data to guide treatment for other subtypes. In conclusion, individualized treatment approaches are needed to manage RCC in subpopulations that are underrepresented in registration clinical trials.

IntroductionPegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies.MethodsThe starting dose of gemcitabine was 1500 mg/m2, 10 mg/m2per minute, every 2 weeks (±250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m2every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied.ResultsThirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m2on day 1 and PLD 35 mg/m2on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m2on day 1 and PLD 35 mg/m2on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival.ConclusionThe recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m2on day 1, and gemcitabine, 1000 mg/m2on days 1 and 15 delivered at an FDRI of 10 mg/m2per minute in 28-day cycles.