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Oncología de precisión; Datos clinicogenómicos Oncologia de precisió; Dades clinicogenòmiques Precision oncology; Clinicogenomic data Precision oncology, where patients are given therapies based on their genomic profile and disease trajectory, is rapidly evolving to become a pivotal part of cancer management, supported by regulatory approvals of biomarker-matched targeted therapies and cancer immunotherapies. However, next-generation sequencing (NGS)–based technologies have revealed an increasing number of molecular-based cancer subtypes with rare patient populations, leading to difficulties in executing/recruiting for traditional clinical trials. Therefore, approval of novel therapeutics based on traditional interventional studies may be difficult and time consuming, with delayed access to innovative therapies. Real-world data (RWD) that describe the patient journey in routine clinical practice can help elucidate the clinical utility of NGS-based genomic profiling, multidisciplinary case discussions, and targeted therapies. We describe key learnings from the setup of WAYFIND-R (NCT04529122), a first-of-its-kind global cancer registry collecting RWD from patients with solid tumors who have undergone NGS-based genomic profiling. The meaning of ‘generalizability’ and ‘high quality’ for RWD across different geographic areas was revisited, together with patient recruitment processes, and data sharing and privacy. Inspired by these learnings, WAYFIND-R’s design will help physicians discuss patient treatment plans with their colleagues, improve understanding of the impact of treatment decisions/cancer care processes on patient outcomes, and provide a platform to support the design and conduct of further clinical/epidemiologic research. WAYFIND-R demonstrates user-friendly, electronic case report forms, standardized collection of molecular tumor board-based decisions, and a dashboard providing investigators with access to local cohort-level data and the ability to interact with colleagues or search the entire registry to find rare populations. Overall, WAYFIND-R will inform on best practice for NGS-based treatment decisions by clinicians, foster global collaborations between cancer centers and enable robust conclusions regarding outcome data to be drawn, improve understanding of disparities in patients’ access to advanced diagnostics and therapies, and ultimately drive advances in precision oncology.

Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non–small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaïve patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.

4057 Background: DESTINY-Gastric01 (NCT03329690) is a randomized, phase 2 study evaluating trastuzumab deruxtecan (T-DXd) in patients with HER2-positive advanced gastric cancer who progressed after ≥2 regimens. T-DXd significantly improved objective response rate (51% vs. 14%; P < 0.001) and overall survival (median OS; 12.5 vs. 8.4 months; P = 0.01) relative to chemotherapy (irinotecan or paclitaxel), leading to regulatory approval in USA and Japan. This post hoc analysis evaluated the overall effect of treatment differences on the quality of survival after discounting for time spent with toxicities or disease progression by comparing the Q-TWiST for patients who received T-DXd versus those who received chemotherapy. Methods: Patients were randomized 2:1 to receive T-DXd or chemotherapy. For each treatment arm, OS, truncated at 10.1 months (the median OS for the entire analysis population, following Q-TWiST convention), was partitioned into three health states: time with grade ≥3 toxicities before disease progression (TOX), time before disease progression without symptoms of disease progression or toxicity (TWiST), and time following disease progression prior to death or censoring (PROG). Mean duration in each state was weighted by a utility score, determined first in a threshold analysis, using a range of hypothetical utility values to generate quality-adjusted states, and then based on observed EQ-5D-5L scores, for that state; the sum of the utility-weighted durations yielded the Q-TWiST value for the time until the end of 10.1 months’ follow-up. In both threshold and observed utility analyses, 95% confidence intervals (CIs) and two-sided P values were calculated using the bootstrap method. Results: Relative to patients receiving chemotherapy (n = 62), patients receiving T-DXd (n = 125) had significantly longer unweighted durations of TOX (3.0 vs. 1.6 months; P < 0.01) and TWiST (3.1 vs. 2.1 months; P < 0.05) and a shorter unweighted duration of PROG (2.4 vs. 3.7 months; P < 0.01). Using a matrix of 25 hypothetical utility-weight combinations, with a TWiST utility of 1 and TOX and PROG utilities ranging from 0 to 1, Q-TWiST differences between treatment arms ranged from −0.5 to 2.3 months, favoring T-DXd in 22 combinations, of which 15 were statistically significant. Using observed EQ-5D-5L utility values, Q-TWiST was 0.9 months (95% CI, 0.2-1.5) longer for T-DXd than for chemotherapy (6.6 vs. 5.7 months), significantly favoring T-DXd ( P < 0.05). Conclusions: Over a 10-month follow-up period, treatment with T-DXd was associated with a statistically significant gain in quality-adjusted OS versus chemotherapy among previously treated patients with gastric cancer. An analysis using observed EQ-5D-5L utility scores found a statistically significant advantage in Q-TWiST for T-DXd. Clinical trial information: NCT03329690.

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.

2590 Background: CD4 T helper cells are key orchestrators of immunity in states of persistent antigen exposure. In chronic viral infection, loss of immune control is associated with CD4 differentiation skewing (CD4ds) resulting from decline of early progenitors and gain in abundance of exhausted and terminally differentiated subsets. Here, we set out to identify whether a similar process occurs within the tumour microenvironment, contributing to immune dysfunction. Methods: Multiregional samples of tumour and non-tumour lung tissue from patients with untreated, surgically resected non-small cell lung cancer (NSCLC) within the first 100 recruited to the prospective lung TRACERx study were analysed by high dimensional flow cytometry of tumour infiltrating lymphocytes (TILs) and paired bulk tumour exome and RNA sequencing. We additionally reanalysed publically available single T cell and bulk tumour RNA sequencing from patients with NSCLC. Results: Unsupervised clustering and dimension reduction revealed a heterogenous landscape of CD4 TILs, with evidence of CD4ds in association with tumour mutational burden. Loss of PD1-CCR7+ T central memory enriched early differentiated cells was accompanied by gain in abundance of PD1+ populations with exhausted (CD57-ICOShiCTLA4hi) and terminally differentiated effector (CD57+Eomes+) phenotypes. Further characterisation of these populations by single cell RNA sequencing revealed differential expression of key genes involved in transcriptional regulation, co-inhibition and co-stimulatory pathways. A validated gene signature of CD4ds was associated with worse outcomes in TRACERx and TCGA cohorts. Conclusions: Our findings reveal remodelling of the CD4 differentiation landscape in association with tumour genomic characteristics, underscoring how mutational burden in the context of chronic stimulation may lead to loss of immune fitness and elucidating key regulatory pathways in potentially clinically relevant CD4 subsets.

Purpose Inhibiting angiogenesis is one of the most promising avenues for new therapies for ovarian cancer. We investigated the efficacy and safety of a novel agent, BIBF 1120, a triple angiokinase inhibitor, after chemotherapy for relapsed disease. Patients and Methods We conducted a randomized, double-blind, controlled phase II trial in 83 patients who had just completed chemotherapy for relapsed ovarian cancer, with evidence of response, but at high risk of further early recurrence. The patients were randomly assigned to receive maintenance therapy using BIBF 1120 250 mg or placebo, twice per day, continuously for 36 weeks. End points were progression-free survival (PFS), toxicity, and overall survival. Results Thirty-six–week PFS rates were 16.3% and 5.0% in the BIBF 1120 and placebo groups, respectively (hazard ratio, 0.65; 95% CI, 0.42 to 1.02; P = .06). Four patients continued on BIBF 1120, including two patients for another year or more. The proportion of patients with any grade 3 or 4 adverse events was similar between the groups (34.9% for BIBF 1120 v 27.5% for placebo; P = .49; mostly grade 3). However, more patients on BIBF 1120 experienced diarrhea, nausea, or vomiting (mainly grade 1 or 2 and no grade 4). There was a higher rate of grade 3 or 4 hepatotoxicity in patients on BIBF 1120 (51.2%) compared with patients on placebo (7.5%; P < .001), but this was rarely of clinical significance, and patients continued with the trial treatment. A single-level dose reduction to 150 mg was made in 15 patients, all on active drug. Conclusion BIBF 1120 is well tolerated and associated with a potential improvement in PFS. The observed treatment effect is sufficient to justify further study within a large phase III trial.

Purpose The Cancer Research UK “Over 50s” trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years. Patients and Methods Between 1987 and 1997, 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010). Results There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant. Conclusion Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.

TPS5615Background: The benefit of lymphadenectomy on survival in stage 1 endometrial cancer remains uncertain. STATEC is a surgical trial designed to evaluate the use of nodal status after lymph no...

5551Background: ROC patients (pts), heavily pretreated with IV chemotherapy (CT) are a heterogenous group, median OS 3-9 mo. Oral MCy is well tolerated, avoids IV CT and has been shown to have clin...

Purpose To replicate an earlier National Cancer Institute of Canada (NCIC) trial that examined the effect on survival of the timing of thoracic radiotherapy (TRT) in patients with limited disease small-cell lung cancer (SCLC). Patients and Methods Patients received three cycles of cyclophosphamide, doxorubicin, and vincristine alternating with three cycles of etoposide and cisplatin. Three hundred twenty five chemotherapy- and radiotherapy-naïve patients were randomly assigned to either early TRT administered concurrently in the second cycle or late TRT administered concurrently with the sixth cycle; the dose was 40 Gy in 15 fractions over 3 weeks. Results TRT was received by 92% and 82% of patients in the early and late arms, respectively (P = .01). Sixty-nine percent of patients in the early arm received all six courses of chemotherapy compared with 80% in the late arm (P = .003). There was no evidence of a survival difference; median overall survival time was 13.7 and 15.1 months in the early and late arms, respectively (P = .23). In a meta-analysis of all eight trials that compared early and late TRT, there were three in which the proportion of patients who completed their planned chemotherapy was similar between the TRT arms (hazard ratio [HR] = 0.73; 95% CI, 0.62 to 0.86) and five in which proportionally fewer patients in the early TRT arm completed their chemotherapy (HR = 1.06; 95% CI, 0.97 to 1.17). Conclusion This study failed to show a survival advantage for early TRT with chemotherapy in limited-stage SCLC, unlike the NCIC trial. However, the results of a meta-analysis suggest that it is essential to ensure that the delivery of chemotherapy is optimal when administered with early TRT.

TPS9099 Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study of patients with radically resected primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through genetic analysis of multi-region and longitudinal tumour sampling. DARWIN II is an investigator initiated study for patients who are enrolled within the TRACERx trial, or who have multi-region sequencing of their primary disease, but subsequently relapse with metastatic disease. This study will examine the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy. Methods: This multicentre non-randomised phase II molecularly stratified umbrella study will examine how clonal dominance and ITH influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between ITH and cfDNA/CTCs will also be explored in DARWIN II. The study arms: Arm 1: Patients either -1) without an actionable mutation and PDL1 positive or 2) without an actionable mutation and PDL1 negative following first line cytotoxic chemotherapy - Atezolizumab. Arm 2: BRAFV600 - Vemurafenib. Arm 3: ALK/RET gene rearrangement - Alectinib. Arm 4: Her2 Amplification - Trastuzumab Emtansine. Primary Outcome Measures: Progression free survival (PFS), defined as the period between the date of registration to the date of subsequent progression or death will be assessed according to: Neo-antigen burden, mutational burden, ITH as assessed using an ITH ratio index and genomic instability as assessed using a weighted genome instability index (wGII). Trial Sponsor: University College London. Clinical trial information: NCT02314481.

TPS5604Background: Ovarian cancer is the second most common gynaecological malignancy in the Western world. The majority of patients present in an advanced stage and the survival rates are still po...

5528 Background: Advanced mEOC responds poorly to standard therapy. It comprises < 8% pts in ovarian cancer trials, so it is difficult to examine treatment effects in this subgroup. We conducted th...

e21500 Background: A marginal interaction between gender and type of alkylating agent (cyclophosphamide or ifosfamide) on event-free survival was observed in the randomized controlled trial (RCT) E...

7507 Background: Argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM) cells are sensitive to arginine deprivation. We examined the efficacy and safety of the arginin...

e17551 Background: COMPARZ and PISCES were randomized, phase 3 trials of PAZ vs SUN in patients with mRCC who had not received prior systemic therapy. COMPARZ demonstrated non-inferiority of PAZ vs...

4581 Background: In a phase 3, randomized, open-label trial (NCT00720941), PAZ demonstrated non-inferiority for progression-free survival vs SUN in mRCC patients with no prior therapy (NEJM 2013; 3...

e17646 Background: Clinical trialsshow efficacy and safety for PAZO and SUNIfor aRCC but few studies have examined real world treatment patterns. This study compares persistence and adherence among...

346 Background: Pazopanib and sunitinib are targeted therapies associated with particular treatment-related side effects that may affect patients’ QoL. COMPARZ was a randomized, open-label, parallel group, phase III study of pazopanib vs. sunitinib in 1,110 subjects with advanced RCC who had not received prior systemic therapy. The study demonstrated pazopanib is non-inferior to sunitinib with respect to progression-free survival. The study also confirmed the differentiated safety profiles of the two drugs. Methods: QoL endpoints were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), the Functional Assessment of Cancer Therapy-Kidney Symptom Index-19 (FKSI-19), the Cancer Therapy Satisfaction Questionnaire (CTSQ), and a Supplementary Quality of Life Questionnaire (SQLQ). Research to validate the SQLQ is currently ongoing. Each instrument was administered at baseline (except CTSQ) and then day 28 of every cycle. Changes in mean scores over time were analyzed and compared using a repeated measures analysis of covariance. Comparisons were pre-specified at the first 6 months of treatment as this time was expected to be a key interval during which tolerability issues may have occurred. Results: During the first 6 months, treatment differences in change from baseline for 11 of the 14 QoL domains studied were statistically significant (p < 0.05), all of which favored pazopanib. Further analysis up to 12 months of treatment, showed the treatment differences observed for fatigue scores increased over time with pazopanib improving and sunitinib remaining relatively flat. The difference in limitations due to foot soreness between the two treatments also progressively increased with time over 12 months favoring pazopanib. Conclusions: In this study, better patient-reported QoL scores for pazopanib indicate subjects experienced less worsening of fatigue, as well as mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, while on pazopanib compared with sunitinib. The differences observed are likely to be clinically meaningful. The FACIT-F and SQLQ results are also highly consistent with the previously-reported PISCES study.

5501 Background: BIBF 1120 is a new targeted therapeutic agent for maintenance therapy in OC. It is a unique triple angiokinase inhibitor, targeting 3 receptor classes involved in the formation of blood vessels (VEGFR, PDGFR, and FGFR). Methods: Continuous BIBF 1120 (250 mg, oral, twice daily) for up to 9 months (mo) was compared with placebo in a novel application of a randomized double-blind trial in pts who responded to their last (at least second line) chemotherapy. The primary endpoint, progression-free survival at 36 weeks, was confirmed by CT assessment, performed at 12-week intervals. Results: 84 pts were randomized (44 BIBF 1120; 40 placebo), mean age 60y (range 27–76). All had responded according to GCIG criteria. Treatment-free interval before prior chemotherapy was [Table: see text]

5586 Background: Chemoradiation (CRT) is the standard of care for locally advanced cervical cancer but survival is poor among women with large tumours, advanced stage, or positive nodes. Neoadjuvant chemotherapy (NACT) prior to CRT to down-stage tumours and lengthen the exposure to systemic treatment is designed to improve outcome. Methods: Patients (pts) with locally advanced cervical cancer received dose-dense carboplatin (AUC2) and paclitaxel (80 mg/m2) weekly, for 6 cycles, followed by CRT (external and brachytherapy) in week 7 with weekly cisplatin (40 mg/m2). The primary end-point was complete and partial response rate (RR) 12 weeks post CRT. Secondary objectives were RR for NACT at 6 weeks, toxicity and survival. The target RRs were 50% and 85% for NACT and post CRT (12-weeks) respectively. Results: Baseline characteristics were: median age at diagnosis 43 yrs (23–71); 74% squamous-, 20% adeno- and 6% adenosquamous carcinomas; FIGO stage IB2 (11%), II (50%), III (33%), IV (6%). The trial closed in Oct 08 with 46 pts. Of the first 36 pts enrolled 9 failed to complete protocol therapy (7 did not complete 6 NACT cycles, 2 did not complete the pre-specified minimum of 4 cycles of concomitant cisplatin). Using data currently available, the RR associated with NACT is 72% (95% CI 53–86%), and 81% at 12 weeks (95% CI 63–92%). Nonhaematological grade 3/4 toxicity was rare ( [Table: see text]

8045 Background: We hypothesised that the oral anti-angiogenic agent thalidomide might be an effective treatment for lung cancer when combined with chemotherapy and as maintenance treatment. Method...