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Background: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first‐line platinum‐based therapy. Here, we present results from RESILIENT part 1. Methods: This open‐label, single‐arm, safety run‐in evaluation with dose‐exploration and dose‐expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Results: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose‐limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2. Of these 25 patients (median age [range], 59.0 [48.0‐73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment‐related treatment‐emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment‐related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40‐65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45‐4.24) months and 8.08 (5.16‐9.82) months, respectively. Conclusion: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. Lay Summary: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum‐based therapy.Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes.The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum‐based therapy.No new safety concerns were reported.The most common moderate‐to‐severe side effects were diarrhea (20% of patients) and neutropenia (16%).Tumors responded to treatment in 44% of patients.Average survival was 8.08 months, and time to disease progression was 3.98 months.Liposomal irinotecan trials are ongoing. The phase 1/2 RESILIENT part 1 trial identified no new safety signals with liposomal irinotecan in adult patients with small cell lung cancer whose disease had progressed despite treatment with platinum‐based therapy. The response of tumors to treatment was promising (observed in 44% of patients) and is under further investigation in RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan. [ABSTRACT FROM AUTHOR]

• Trial enrollment was not stratified for variables related to mandatory prior CRT. • Clinical outcomes were assessed in subgroups defined by CRT-related variables. • As in the ITT population, PFS, OS and TTDM favored durvalumab use in all subgroups. • Durvalumab had a manageable safety profile irrespective of CRT-related variables. • Imbalances in baseline factors and subgroup sizes prevent robust conclusions. The PACIFIC trial demonstrated that durvalumab significantly improved progression-free and overall survival (PFS/OS), versus placebo, in patients with Stage III NSCLC and stable or responding disease following concurrent, platinum-based chemoradiotherapy (CRT). A range of CT and RT regimens were permitted, and used, in the trial. We report post-hoc, exploratory analyses of clinical outcomes from PACIFIC according to CRT-related variables. Patients were randomized 2:1 (1–42 days post-CRT) to up to 12 months durvalumab (10 mg/kg intravenously every 2 weeks) or placebo. Efficacy and safety were analyzed in patient subgroups defined by the following baseline variables: platinum-based CT (cisplatin/carboplatin); vinorelbine, etoposide, or taxane-based CT (all yes/no); total RT dose (<60 Gy/60–66 Gy/>66 Gy); time from last RT dose to randomization (<14 days/≥14 days); and use of pre-CRT induction CT (yes/no). Treatment effects for time-to-event endpoints were estimated by hazard ratios (HRs) from unstratified Cox-proportional-hazards models. Overall, 713 patients were randomized, of whom 709 received treatment in either the durvalumab (n/N = 473/476) or placebo arms (n/N = 236/237). Durvalumab improved PFS, versus placebo, across all subgroups (median follow up, 14.5 months; HR range, 0.34–0.63). Durvalumab improved OS across most subgroups (median follow up, 25.2 months; HR range, 0.35–0.86); however, the 95 % confidence interval (CI) of the estimated treatment effect crossed one for the subgroups of patients who received induction CT (HR, 0.78 [95 % CI, 0.51–1.20]); carboplatin (0.86 [0.60–1.23]); vinorelbine (0.79 [0.49–1.27]); and taxane-based CT (0.73 [0.51–1.04]); and patients who were randomized ≥14 days post-RT (0.81 [0.62–1.06]). Safety was broadly similar across the CRT subgroups. Durvalumab prolonged PFS and OS irrespective of treatment variables related to prior CRT to which patients with Stage III NSCLC had previously stabilized or responded. Limited patient numbers and imbalances in baseline factors in each subgroup preclude robust conclusions. [ABSTRACT FROM AUTHOR]

Background: This study compared the efficacy and safety of treatment with erlotinib plus pazopanib versus erlotinib plus placebo in patients with previously treated advanced non-small cell lung cancer (NSCLC).Methods: Patients with progressive-stage IV NSCLC after either 1 or 2 previous chemotherapy regimens were randomized to receive erlotinib (150 mg by mouth daily) with either pazopanib (600 mg by mouth daily) or placebo. During treatment, patients were evaluated every 8 weeks until disease progression or unacceptable toxicity. After a study amendment, pretreatment serum specimens for the VeriStrat assay were collected. The predictive value of the VeriStrat score (good vs poor) for progression-free survival (PFS) and overall survival (OS) was assessed in the overall population and in each treatment group.Results: One hundred ninety-two eligible patients were randomized between February 2010 and February 2011. PFS was prolonged with erlotinib plus pazopanib versus erlotinib plus placebo (median, 2.6 vs 1.8 months; hazard ratio, 0.58; P = .001). There was no difference in the OS of the 2 groups. A good VeriStrat score predicted longer PFS and OS in the entire group and predicted longer PFS in the subgroup receiving erlotinib plus pazopanib. The addition of pazopanib increased toxicity, and this was consistent with the known toxicity profile.Conclusions: The addition of pazopanib to erlotinib in an unselected group of patients with previously treated NSCLC improved PFS and increased treatment-related toxicity, but it had no influence on OS. The efficacy of both regimens was modest. Patients receiving erlotinib plus pazopanib had longer PFS if they had a good VeriStrat score versus a poor one. Cancer 2018;124:2355-64. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The best treatment for patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status is not well defined. In this phase 2 trial, patients were randomized to receive treatment with either single-agent pemetrexed or 1 of 2 combination regimens.Methods: Patients with newly diagnosed, histologically confirmed nonsquamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 were stratified by age and serum albumin level and were randomized (1:1:1) to 1 of 3 regimens: pemetrexed (arm 1), pemetrexed and bevacizumab (arm 2), or pemetrexed, carboplatin, and bevacizumab (arm 3). The response to treatment was assessed every 2 cycles; responding and stable patients continued treatment until progression or unacceptable toxicity.Results: One hundred seventy-two patients were randomized, 162 patients began the study treatment, and 146 patients completed 2 cycles and were evaluated for their response. The median progression-free survival (PFS) was 2.8 months in arm 1, 4.0 months in arm 2, and 4.8 months in arm 3. The overall response rates were 15% in arm 1, 31% in arm 2, and 44% in arm 3. The overall survival was similar in the 3 treatment arms. All 3 regimens were relatively well tolerated. Patients receiving bevacizumab had an increased incidence of hypertension, proteinuria, and bleeding episodes, but most events were mild or moderate.Conclusions: All 3 regimens were feasible for patients with advanced NSCLC and an ECOG performance status of 2. The addition of bevacizumab to pemetrexed increased the overall response rate. The efficacy of pemetrexed/carboplatin/bevacizumab (median PFS, 4.8 months) approached the prespecified study PFS goal of 5 months. Larger studies will be necessary to define the role of bevacizumab in addition to standard pemetrexed and carboplatin in this population. Cancer 2018;124:1982-91. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the efficacy of erlotinib, continued after tumor progression, plus sorafenib versus sorafenib alone in patients with refractory metastatic non-small cell lung cancer (NSCLC) who previously benefitted from single-agent erlotinib. Patients and Methods Patients with progressive refractory NSCLC who had previously benefitted from erlotinib (objective response or stable disease >8 weeks) were randomized to receive treatment with either erlotinib and sorafenib (400 mg orally twice daily) or sorafenib alone. Patients were evaluated for response every 8 weeks, and continued treatment until disease progression or intolerable toxicity. Results Fifty-three patients were randomized (erlotinib/sorafenib, 25; sorafenib, 28) and 52 patients received study treatment. Patients in both groups received a median of 8 weeks of treatment. The median PFS was 3.1 months for erlotinib/sorafenib versus 1.7 months for sorafenib alone; response rates were 8% and 4%, respectively. Both regimens were tolerable, but toxicity was more frequent with erlotinib/sorafenib. Conclusions These results do not suggest any benefit in continuing erlotinib after tumor progression in patients with refractory metastatic NSCLC. Both regimens tested had limited efficacy, consistent with results from other studies. ClinicalTrials.gov ID:NCT00609804 [ABSTRACT FROM AUTHOR]

Background: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC.Methods: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m2 IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity.Results: 29 of 66 patients (44%) had objective responses. The median TTP was 6 months; median overall survival (OS) was 17 months. Panitumumab increased treatment-related toxicity, notably skin rash.Conclusions: The addition of panitumumab increased toxicity, and had no discernible impact on efficacy. [ABSTRACT FROM AUTHOR]

Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small- cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance. [ABSTRACT FROM AUTHOR]

BACKGROUND Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in non-small cell lung cancer (NSCLC). Ramucirumab is a human immunoglobulin G1 monoclonal antibody that inhibits VEGF receptor 2. This phase 2 study investigated ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in advanced/metastatic NSCLC. METHODS Eligible stage IV nonsquamous NSCLC patients with no prior chemotherapy for metastatic disease were randomized 1:1 to pemetrexed and carboplatin (or cisplatin) or ramucirumab (10 mg/kg) plus pemetrexed and carboplatin (or cisplatin) once every 3 weeks. Treatment was given for 4 to 6 cycles, and this was followed by a maintenance phase with pemetrexed or ramucirumab and pemetrexed. The primary endpoint was progression-free survival (PFS) with a sample size of sufficient power to detect an increase from 7 to 10.4 months. RESULTS From October 2010 to October 2011, 140 patients were randomized (pemetrexed-platinum arm, 71; ramucirumab-pemetrexed-platinum arm, 69), and most baseline characteristics were similar for the 2 treatment arms. The median PFS was 5.6 months for the pemetrexed-platinum arm and 7.2 months for the ramucirumab-pemetrexed-platinum arm (hazard ratio, 0.75; P = .132). The objective response rates were 38.0% and 49.3% for the pemetrexed-platinum and ramucirumab-pemetrexed-platinum arms, respectively ( P = .180). The disease control rate was 70.4% for the pemetrexed-platinum arm and 85.5% for the ramucirumab-pemetrexed-platinum arm ( P = .032). The grade 3 or higher adverse events occurring in 10% or more of patients were thrombocytopenia, neutropenia, fatigue, anemia, nausea, back pain, and hypertension. CONCLUSIONS The primary endpoint of significant prolongation of PFS was not met; however, ramucirumab showed evidence of clinical activity in combination with pemetrexed and platinum in nonsquamous NSCLC patients. The addition of ramucirumab to pemetrexed and platinum did not result in new or unexpected safety findings. Cancer 2015;121:883-892. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Background: Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC. Method: Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0–1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles. Results: Eighty-two patients (median age, 63years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5months (A) and 15.7months (B), median progression free survivals were A-5.3months (95% CI 2.8–8.6) and B-6.7months (95% CI 5.1–8.4), with median overall survivals of 9.3months (95% CI 6.4–16.6) 13.2months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology. Conclusions: Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B. [Copyright &y& Elsevier]

Abstract: Background: Inhibition of angiogenesis may be effective in the treatment of small-cell lung cancer (SCLC). Sunitinib, an oral agent that inhibits the VEGF signaling pathway, may delay progression in sequence with chemotherapy. This phase II trial was designed to evaluate the role of sunitinib monotherapy following 6 cycles of irinotecan and carboplatin in patients with newly diagnosed extensive-stage (ES) SCLC. Method: Patients aged ≥18years with previously untreated ES-SCLC were eligible. Additional criteria included: ECOG PS 0–1, no active brain metastases, and adequate organ function. Patients received 28-day cycles of irinotecan (60mg/m2, days 1, 8, 15) and carboplatin (AUC=4, day 1), and were assessed for response every 8weeks. After 6 cycles of chemotherapy, patients with stable disease or responding disease proceeded to sunitinib monotherapy (25mg orally daily) until disease progression or unacceptable toxicity. The primary endpoint was 1-year overall survival (OS). Results: Between 2/09 and 10/09, 34 patients (median age 65years [range, 41–80]) were enrolled. 53% of patients were male, 47% had ECOG PS 0.21 patients (62%) completed 6 cycles of chemotherapy, and 17 (50%) initiated sunitinib monotherapy (median duration: 9weeks; range, 2–28+weeks). After a median follow-up of 50weeks (range: 37–68weeks), 22 (62%) of the patients remain alive. The objective response rate with chemotherapy was 59%, and an additional 20% had stable disease. 1-year OS was 54% and median time to progression was 7.6months. Grade 3/4 toxicity was rare during sunitinib monotherapy. Conclusions: This phase II trial provides support for further study of sunitinib maintenance therapy following platinum-doublet chemotherapy in patients with ES-SCLC. The 1year OS of 54% is encouraging, and a randomized trial would be appropriate to assess sunitinib''s impact following chemotherapy. [Copyright &y& Elsevier]

The role of tyrosine kinase inhibitors (TKIs) in the treatment of advanced malignancies is well established. Imatinib and vatalanib are oral TKIs with different mechanisms of action. This trial sought to establish the safety, tolerability, and maximum tolerated dose (MTD) of the two agents in combination. Secondary objectives included determination of potential pharmacologic interactions among vatalanib and imatinib and observation of antitumor activity. Patients with biopsy-proven advanced refractory solid tumors were enrolled in this single-center dose-escalation trial. Patients initially received imatinib and vatalanib once daily following a 14-day run-in period of daily oral vatalanib only, and were observed for a full 28-day treatment cycle prior to dose escalation. An amendment divided the vatalanib dose into two daily doses and gradually escalated the dose over a 2--3 week period. Patients continued combination therapy until disease progression or intolerable toxicity. Forty-five patients were enrolled between September 2004 and November 2007. As of September 2009, a total of 247 cycles of treatment had been administered (range: 1 --44++, median == 2). The MTD was determined to be vatalanib 1250 mg daily and imatinib 400 mg daily. Thirty-five patients (78%%) were evaluable for response; 2 patients achieved PR, while 14 patients had SD (10 had stable disease ≥≥6 cycles). The combination of vatalanib and imatinib was well tolerated. Twice-daily vatalanib dosing improved tolerability and ease of full-dose administration. These results suggest that vatalanib-containing combinations may be active and tolerable, warranting further study. [ABSTRACT FROM AUTHOR]

The article presents the study on the use of capecitabine and oxaliplatin in treating patients with refractory and recurrent carcinoma of unknown primary site (CUP). It states that CUP patients who undergo at least one preceded chemotherapy session were given capecitabine and oxaliplatin with treatment cycles every 21 days. The results show that out of the 48 patients, nine had objective responses to treatment and that capecitabine and oxaliplatin combination is tolerable for CUP patients.

The article focuses on the study which evaluates the efficacy and toxicity of bortezomib taken weekly to treat patients with recurrent multiple myeloma. It states that a schedule of weekly bortezomib is effective in patients with previously treated myeloma. The study shows that the weekly treatment is a reasonable alternative for patients that have difficulties in receiving twice-weekly treatment.

The article focuses on the study which examines the efficacy and safety of erlotinib monotherapy in patients with advanced nonsmall cell lung cancer (NSCLC). One objective of the study is to characterize the overall response rate (ORR) and overall survival (OS) associated with erlotinib therapy. According to the findings, there are no safety signals noted, and the observed ORR and survival data are uniform with the results from the pivotal trial.

The article compares the efficacy of weekly docetaxel with the combination of docetaxel and gemcitabine in elderly or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC) based on a randomized clinical trial in the U.S. The study involved 350 patients who were randomized and 345 of them received treatment. It found that treatment with docetaxel/gemcitabine produced a modest improvement but had no impact on survival when compared with single-agent weekly docetaxel.

Context A family history of certain cancers is associated with an increased risk of developing cancer. Both cancer screening and genetic services referral decisions are often based on self-reported pedigree information. Objective To determine the accuracy of self-reported family cancer history information. Data Sources English-language articles were retrieved by searching MEDLINE (1966-June 2004) using Medical Subject Headings family, genetic predisposition to disease, medical history taking, neoplasm, and reproducibility of results. Additional articles were identified through bibliography searches. Study Selection Original studies in which investigators validated self-reported family history by reviewing the identified relatives' medical records, death certificate, or cancer registry information were included, as well as studies that evaluated breast, colon, ovarian, endometrial, and prostate cancers. Data Extraction Two of the 3 investigators independently reviewed and abstracted data for estimating the likelihood ratios (LRs) of self-reported family cancer history information. Only data from studies that evaluated both positive and negative family cancer histories were included within the analyses. A total of 14 studies met the search criteria and were included in the review. Data Synthesis For patients without a personal history of cancer, the positive and negative LRs of a family history of the following cancers in a first-degree relative were 23.0 (95% confidence interval [CI], 6.4-81.0) and 0.25 (95% CI, 0.10-0.63) for colon cancer; 8.9 (95% CI, 5.4-15.0) and 0.20 (95% CI, 0.08-0.49) for breast cancer; 14.0 (95% CI, 2.2-83.4) and 0.68 (95% CI, 0.31-1.52) for endometrial cancer; 34.0 (95% CI, 5.7-202.0) and 0.51 (95% CI, 0.13-2.10) for ovarian cancer; and 12.3 (95% CI, 6.5-24.0) and 0.32 (95% CI, 0.18-0.55) for prostate cancer, respectively. Positive predictive values tended to be better in articles concerning first-degree relatives compared with second-deg... [ABSTRACT FROM AUTHOR]

Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumour activity as monotherapy and in combination with cabozantinib in patients with previously treated advanced kidney cancer. The phase 2 LITESPARK-003 study was designed to determine the antitumour activity and safety of belzutifan in combination with cabozantinib in patients with advanced clear-cell renal cell carcinoma that was previously untreated (cohort 1) or previously treated with immunotherapy (cohort 2). Here, we report results from cohort 1 of this clinical trial. LITESPARK-003 is an open-label, single-arm, phase 2 study at ten hospitals and cancer centres in the USA. In cohort 1, eligible patients were at least 18 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had received no previous systemic therapy for locally advanced or metastatic renal cell carcinoma. Patients received belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until unacceptable adverse events, disease progression, or patient withdrawal. The primary endpoint was investigator-assessed confirmed objective response according to Response Evaluation Criteria in Solid Tumors version 1.1. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT03634540 , and is ongoing. Between Sept 27, 2018, and Jan 10, 2023, we screened 138 patients for eligibility, and 50 (36%) were enrolled and assigned to cohort 1. The median age was 64 years (IQR 57–72). 40 (80%) of 50 patients were male and ten (20%) were female. 48 (96%) patients were White, one (2%) patient was Black or African American, and one (2%) was of a race in the other category. As of the data cutoff (May 15, 2023), median follow-up was 24·3 months (IQR 13·9–32·0). 35 (70%, 95% CI 55–82) of 50 patients had a confirmed objective response, including four (8%) who had a complete response and 31 (62%) who had a partial response. The most frequent grade 3–4 treatment-related adverse events were hypertension (six [12%] patients), anaemia (five [10%] patients), and fatigue (four [8%] patients). Seven (14%) of 50 patients had serious treatment-related adverse events. No treatment-related deaths occurred. Belzutifan plus cabozantinib has promising antitumour activity in treatment-naive patients with advanced clear-cell renal cell carcinoma and further investigation of an HIF-2α inhibitor in combination with a multitargeted tyrosine kinase inhibitor as a treatment option in this population is warranted. Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and the National Cancer Institute. [ABSTRACT FROM AUTHOR]

PURPOSE: Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression–based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS , IDH1/2 , BRCA1/2 , and BRAF , in patients with CUP in the MOSAIC database to highlight potential treatment options. METHODS: MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS , IDH1/2 , BRCA1/2 , and BRAF. RESULTS: CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS , IDH1/2 , BRCA , and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)–approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients. CONCLUSION: This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials. [ABSTRACT FROM AUTHOR]

Presents an analysis of predictors of drug discontinuation success in a study which reported survival data for 20 panic disorder patients. Reduction in the fear of anxiety symptoms as the best predictors of patients' ability to achieve and maintain drug abstinence; Discussion of the implications of the findings for pharmacotherapy of panic disorder.

PURPOSE: Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression–based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS , IDH1/2 , BRCA1/2 , and BRAF , in patients with CUP in the MOSAIC database to highlight potential treatment options. METHODS: MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS , IDH1/2 , BRCA1/2 , and BRAF. RESULTS: CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS , IDH1/2 , BRCA , and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)–approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients. CONCLUSION: This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials. Enabling Precision Site-Specific Therapies in CUP Patients with CancerTYPE ID [ABSTRACT FROM AUTHOR]

Background: Inhibition of the adenosine 2A receptor (A2AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the A2AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer. Methods: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab). Primary endpoints were objective response rate per RECIST v1.1 and prostate-specific antigen (PSA) response rate. Secondary endpoints included radiological progression-free survival (rPFS), overall survival, safety, and pharmacokinetics. Results: Fifty-nine patients were treated (Module 1, n = 29; Module 2, n = 30). Median number of prior therapies was 4. One confirmed complete response by RECIST (Module 1) and 2 confirmed PSA responses (1 per module) were observed. The most frequent adverse events (AEs) possibly related to AZD4635 were nausea (37.9%), fatigue (20.7%), and decreased appetite (17.2%) in Module 1; nausea (50%), fatigue (30%), and vomiting (23.3%) in Module 2. No dose-limiting toxicities or treatment-related serious AEs were observed. In Module 1, AZD4635 geometric mean trough concentration was 124.9 ng/mL (geometric CV% 69.84; n = 22); exposures were similar in Module 2. In Modules 1 and 2, median (95% CI) rPFS was 2.3 (1.6 –3.8) and 1.5 (1.3– 4.0) months, respectively. Median PFS was 1.7 versus 2.3 months for patients with high versus low blood-based adenosine signature. Conclusion: In this heavily pretreated population, AZD4635 with durvalumab or oleclumab demonstrated minimal antitumor activity with a manageable safety profile. Clinical Trial.gov identifier: NCT04089553. [ABSTRACT FROM AUTHOR]

The HER2 growth-factor receptor plays an integral role in cellular proliferation and differentiation. HER2 gene-amplification leads to overexpression of this receptor in 20-25% of breast cancers. HER2 overexpression is associated with an aggressive phenotype of breast cancer and an adverse prognosis. In women with advanced breast cancer that overexpresses HER2, trastuzumab is an effective and safe therapy, either as a single agent or in combination with chemotherapy. In a phase III trial with 469 women with metastatic HER2-overexpressing breast cancer, the combination of first-line chemotherapy and trastuzumab led to greater objective response rates, median time to progression, duration of response, and overall survival than chemotherapy alone. In this issue of "The Lancet," Elda Tagliabue and colleagues present intriguing data that suggest a role for trastuzumab, and perhaps other innovative-targeted therapies, in the perioperative setting. These investigators set out to study the impact of surgery on the proliferation of remnant breast cancer cells, in particular those cells that overexpress HER2. Recently, Burstein et al 13 reported a pilot study in which trastuzumab and paclitaxel were administered to 40 women with stage II and III HER2-positive breast cancer. Preoperative studies with trastuzumab and newer targeted agents that inhibit other members of the epidermal-growth-factor receptor family are important to improve understanding of tumour biology and how therapies--medical and surgical--affect long-term outcomes.

Background: Antibodies targeting the immune checkpoint molecules PD-1 or PD-L1 have demonstrated clinical efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). In this trial we investigated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with NSCLC who had already received platinum-based therapy.Methods: JAVELIN Lung 200 was a multicentre, open-label, randomised, phase 3 trial at 173 hospitals and cancer treatment centres in 31 countries. Eligible patients were aged 18 years or older and had stage IIIB or IV or recurrent NSCLC and disease progression after treatment with a platinum-containing doublet, an Eastern Cooperative Oncology Group performance status score of 0 or 1, an estimated life expectancy of more than 12 weeks, and adequate haematological, renal, and hepatic function. Participants were randomly assigned (1:1), via an interactive voice-response system with a stratified permuted block method with variable block length, to receive either avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m2 every 3 weeks. Randomisation was stratified by PD-L1 expression (≥1% vs <1% of tumour cells), which was measured with the 73-10 assay, and histology (squamous vs non-squamous). The primary endpoint was overall survival, analysed when roughly 337 events (deaths) had occurred in the PD-L1-positive population. Efficacy was analysed in all PD-L1-positive patients (ie, PD-L1 expression in ≥1% of tumour cells) randomly assigned to study treatment (the primary analysis population) and then in all randomly assigned patients through a hierarchical testing procedure. Safety was analysed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02395172. Enrolment is complete, but the trial is ongoing.Findings: Between March 24, 2015, and Jan 23, 2017, 792 patients were enrolled and randomly assigned to receive avelumab (n=396) or docetaxel (n=396). 264 participants in the avelumab group and 265 in the docetaxel group had PD-L1-positive tumours. In patients with PD-L1-positive tumours, median overall survival did not differ significantly between the avelumab and docetaxel groups (11·4 months [95% CI 9·4-13·9] vs 10·3 months [8·5-13·0]; hazard ratio 0·90 [96% CI 0·72-1·12]; one-sided p=0·16). Treatment-related adverse events occurred in 251 (64%) of 393 avelumab-treated patients and 313 (86%) of 365 docetaxel-treated patients, including grade 3-5 events in 39 (10%) and 180 (49%) patients, respectively. The most common grade 3-5 treatment-related adverse events were infusion-related reaction (six patients [2%]) and increased lipase (four [1%]) in the avelumab group and neutropenia (51 [14%]), febrile neutropenia (37 [10%]), and decreased neutrophil counts (36 [10%]) in the docetaxel group. Serious treatment-related adverse events occurred in 34 (9%) patients in the avelumab group and 75 (21%) in the docetaxel group. Treatment-related deaths occurred in four (1%) participants in the avelumab group, two due to interstitial lung disease, one due to acute kidney injury, and one due to a combination of autoimmune myocarditis, acute cardiac failure, and respiratory failure. Treatment-related deaths occurred in 14 (4%) patients in the docetaxel group, three due to pneumonia, and one each due to febrile neutropenia, septic shock, febrile neutropenia with septic shock, acute respiratory failure, cardiovascular insufficiency, renal impairment, leucopenia with mucosal inflammation and pyrexia, infection, neutropenic infection, dehydration, and unknown causes.Interpretation: Compared with docetaxel, avelumab did not improve overall survival in patients with platinum-treated PD-L1-positive NSCLC, but had a favourable safety profile.Funding: Merck and Pfizer. [ABSTRACT FROM AUTHOR]

Background: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC).Methods: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing.Findings: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression.Interpretation: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting.Funding: Merck KGaA and Pfizer. [ABSTRACT FROM AUTHOR]

Background: The National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1-3 positive nodes. This study evaluated the use of Ki-67 testing and treatment patterns in patients with HR+, human epidermal growth factor receptor 2-negative early breast cancer.Methods: This was an observational retrospective cohort study of patients with electronic medical records from January 2010 to August 2018 treated for HR+, HER2- early breast cancer at Sarah Cannon sites in the United States (US). Overall, 567 patients were randomly selected after using the eligibility criteria: female or male ≥18 years, without distant metastases, and with available physician and pathology reports. Multivariable logistic regression was used to investigate factors predicting Ki-67 testing and test results. Descriptive analyses were applied to treatment patterns.Results: Multivariable logistic regression analyses found no clinical or pathological factors that predicted whether Ki-67 testing had been ordered by physicians. Of all tested patients (N = 130), having Grade-2 tumors (OR, 7.95 [95% CI: 2.05, 30.9]; p = 0.0027) or Grade-3 tumors (OR, 95.3 [95% CI, 11.9, 760.7]; p < 0.001) at initial diagnosis was a predictor of high Ki-67 expression (≥20%). Ki-67 expression was tested in 23.6% (61/258) of patients with 1-3 positive nodes; 54.1% of them (33/61) had high Ki-67 expression (≥20%). While having a higher grade tumor predicted high Ki-67 (≥20%), 28.6% of patients with Grade-1 tumors also had high Ki-67 expression. Neo-adjuvant therapy was received by 16.0% of patients (91/567), most of whom (66/91; 72.5%) received CT alone. Adjuvant therapy, either endocrine and/or chemotherapy, was received by 92.6% (525/567) of patients and by 67.0% (61/91) of those who received neo-adjuvant therapy. Most (428/525, 81.5%) received ET in the adjuvant treatment setting.Conclusions: High grade tumors predicted high Ki-67 (≥20%) expression, but Ki-67 testing was not widely used in these US patients. Most HR+, HER2- early breast cancers were treated with adjuvant ET, with or without CT. [ABSTRACT FROM AUTHOR]

Purpose: Definition of the lineage of poorly differentiated neoplasms (PDNs) presenting as cancer of unknown primary site (CUP) is important since many of these tumors are treatment-sensitive. Gene expression profiling and a molecular cancer classifier assay (MCCA) may provide a new method of diagnosis when standard pathologic evaluation and immunohistochemical (IHC) staining is unsuccessful. Patients and Methods: Thirty of 751 CUP patients (4 %) seen from 2000-2012 had PDNs without a definitive lineage diagnosed by histology or IHC (median 18 stains, range 9-46). Biopsies from these 30 patients had MCCA (92-gene reverse transcriptase-polymerase chain reaction mRNA) performed. Additional IHC, gene sequencing, fluorescent in situ hybridization for specific genetic alterations, and repeat biopsies were performed to support MCCA diagnoses, and clinical features correlated. Seven patients had MCCA performed initially and received site-specific therapy. Results: Lineage diagnoses were made by MCCA in 25 of 30 (83 %) patients, including ten carcinomas (three germ cell, two neuroendocrine, five others), eight sarcomas [three peritoneal mesotheliomas, one primitive neuroectodermal tumor (PNET), four others], five melanomas, and two lymphomas. Additional IHC and genetic testing [BRAF, i(12)p] supported the MCCA diagnoses in 11 of 16 tumors. All seven patients (two germ cell, two neuroendocrine, two mesothelioma, one lymphoma) responded to site-specific therapy based on the MCCA diagnosis, and remain alive (five progression-free) from 25+ to 72+ months. Conclusion: The MCCA provided a specific lineage diagnosis and tissue of origin in most patients with PDNs unclassifiable by standard pathologic evaluation. Earlier use of MCCA will expedite diagnosis and direct appropriate first-line therapy, which is potentially curative for several of these tumor types. [ABSTRACT FROM AUTHOR]

Background Molecular tumor profiling (MTP) is a potentially powerful diagnostic tool for identifying the tissue of origin in patients with cancer of unknown primary (CUP). However, validation of the accuracy and clinical value of MTP has been difficult because the anatomic primary site in most patients is never identified. Methods From March 2008 through January 2010, clinicopathologic data from 171 CUP patients who had MTP (CancerTYPE ID; bioTheranostics, Inc, San Diego, CA) performed on archived material were evaluated. The accuracy of MTP diagnoses was evaluated by comparison with 1) latent primary tumor sites found months/years later; 2) initial single diagnoses by immunohistochemistry (IHC); and 3) additional directed IHC and/or clinicopathologic findings evaluated after MTP diagnoses. Results A single MTP diagnosis was made in 144 of 149 patients with adequate tumor specimens. Eighteen of 24 patients with latent primaries discovered months to years later had correct diagnoses by MTP (75%), and these diagnoses compared favorably with IHC. Single IHC diagnoses matched MTP diagnoses in 40 of 52 patients (77%). IHC predictions of 2 or more possible primaries compared poorly with MTP diagnoses. However, additional targeted IHC and clinical/histologic evaluation supported the MTP diagnosis in 26 of 35 patients (74%). Clinical features were usually consistent with MTP diagnoses (70%). Conclusions The diagnostic accuracy of this MTP assay was supported by a high level of agreement with identified latent primaries (75%), single IHC diagnoses (77%), and additional directed IHC and/or clinical/histologic findings (74%) prompted by the MTP diagnoses. MTP complements standard pathologic evaluation in determining the tissue of origin in patients with CUP, particularly when IHC is inconclusive. [ABSTRACT FROM PUBLISHER]

Romidepsin is a potent histone deacetylase inhibitor; preclinical studies showed potential synergy with the nucleoside analog gemcitabine. This phase 1 trial was conducted to determine the maximum tolerated dose for two schedules of romidepsin plus gemcitabine in patients with advanced solid tumors in which gemcitabine had previously demonstrated clinical activity. The recommended phase 2 dose was 12 mg/m2 romidepsin plus 800 mg/m2 gemcitabine on days 1 and 15 every 28 days. Results suggest additive hematologic toxicities of romidepsin plus gemcitabine, but the level of antitumor activity observed warrants more formal trials of this combination to further assess safety and efficacy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the activity of panobinostat in refractory renal carcinoma. Patients and Methods: Patients with advanced clear cell renal carcinoma who had received previous therapy with at least one angiogenesis inhibitor and one mTOR inhibitor were treated with panobinostat 45 mg orally twice a week, and were reevaluated after 8 weeks. Results: Twenty patients were treated with no objective responses. All patients progressed or stopped treatment prior to the 16-week reevaluation. Panobinostat was generally well-tolerated. Conclusion: Panobinostat had no activity in this group of patients with refractory renal carcinoma. Further development of panobinostat in renal carcinoma is not recommended. [ABSTRACT FROM AUTHOR]

The article details a study which examined the activity and tolerability of combined bevacizumab and everolimus in patients with metastatic melanoma. The study included patients with metastatic melanoma who received up to two previous chemotherapy or immunotherapy, who were given bevacizumab and everolimus. Study authors concluded that combined bevacizumab and everolimus has moderate activity and was well tolerated in patients with metastatic melanoma.

The article analyzes the effectiveness and toxicity of the combination of fludarabine and rituximab, followed by a monoclonal antibody called alemtuzumab, as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Four courses of fludarabine and rituximab were administered to patients. Study populations were required to give written informed consent before participating in a nonrandomized phase 2 trial. Characteristics of patients who entered the trial are cited.

Background : Taxanes and anthracyclines are the two most active classes of cytotoxic agents in the treatment of patients with metastatic breast cancer. Epirubicin, a doxorubicin analog, has shown modest toxicity advantages when compared to the parent compound. In this Phase II trial, we evaluated the activity and toxicity of a docetaxel/epirubicin combination. Methods : Thirty patients with previously untreated metastatic breast cancer were treated with docetaxel 60 mg/m 2 one-hour IV infusion and epirubicin 90 mg/m 2 IV bolus; both drugs were repeated at 21-day intervals. Patients were evaluated for response after 2 courses of treatment; responding and stable patients continued treatment for a total of 6 courses. Results : Fifteen patients (50 percent) had objective response to treatment; an additional 20 percent of patients had stable disease of more then 6 months duration. The median and 2-year progression-free survivals were 12 months and 34 percent, respectively. Median and 2-year overall survivals were 18 months and 42 percent, respectively. Myelosuppression was the most common Grade 3/4 toxicity, and 2 patients in this trial (6 percent) had treatment-related mortality associated with severe sepsis. Conclusion: The results of this Phase II trial confirm previous observations regarding the efficacy and toxicity profile of the docetaxel/epirubicin combination. This combination has activity similar to other taxane/anthracycline combinations used in the first-line treatment of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: The National Comprehensive Cancer Network recommends that patients with hormone receptor-positive early breast cancer be considered for adjuvant endocrine therapy (ET) after primary treatment like surgical excision. Adjuvant chemotherapy (CT) use primarily depends on risk of recurrence. Biomarkers such as Ki-67 potentially have most value in patients with intermediate risk factors, such as involvement of 1–3 positive nodes. This study evaluated the use of Ki-67 testing and treatment patterns in patients with HR+, human epidermal growth factor receptor 2-negative early breast cancer. Methods: This was an observational retrospective cohort study of patients with electronic medical records from January 2010 to August 2018 treated for HR+, HER2− early breast cancer at Sarah Cannon sites in the United States (US). Overall, 567 patients were randomly selected after using the eligibility criteria: female or male ≥18 years, without distant metastases, and with available physician and pathology reports. Multivariable logistic regression was used to investigate factors predicting Ki-67 testing and test results. Descriptive analyses were applied to treatment patterns. Results: Multivariable logistic regression analyses found no clinical or pathological factors that predicted whether Ki-67 testing had been ordered by physicians. Of all tested patients (N = 130), having Grade-2 tumors (OR, 7.95 [95% CI: 2.05, 30.9]; p = 0.0027) or Grade-3 tumors (OR, 95.3 [95% CI, 11.9, 760.7]; p < 0.001) at initial diagnosis was a predictor of high Ki-67 expression (≥20%). Ki-67 expression was tested in 23.6% (61/258) of patients with 1–3 positive nodes; 54.1% of them (33/61) had high Ki-67 expression (≥20%). While having a higher grade tumor predicted high Ki-67 (≥20%), 28.6% of patients with Grade-1 tumors also had high Ki-67 expression. Neo-adjuvant therapy was received by 16.0% of patients (91/567), most of whom (66/91; 72.5%) received CT alone. Adjuvant therapy, either endocrine and/or chemotherapy, was received by 92.6% (525/567) of patients and by 67.0% (61/91) of those who received neo-adjuvant therapy. Most (428/525, 81.5%) received ET in the adjuvant treatment setting. Conclusions: High grade tumors predicted high Ki-67 (≥20%) expression, but Ki-67 testing was not widely used in these US patients. Most HR+, HER2− early breast cancers were treated with adjuvant ET, with or without CT. [ABSTRACT FROM AUTHOR]

Background: Poly(ADP‐ribose) polymerase (PARP) inhibitors may synergize with programmed cell death receptor‐1 (PD‐1) inhibitors to enhance adaptive and innate antitumor immune responses. In the phase 2 JASPER study (NCT04475939), the PARP inhibitor niraparib was evaluated in combination with the PD‐1 inhibitor pembrolizumab in patients with metastatic and/or locally advanced non–small cell lung cancer (NSCLC). Methods: Patients whose tumors had programmed cell death ligand 1 (PD‐L1) tumor proportion scores (TPS) ≥50% (cohort 1) or 1%‐49% (cohort 2) received first‐line niraparib (200 mg once daily) plus pembrolizumab (200 mg every 3 weeks). The primary end point was investigator‐assessed objective response rate (ORR). Secondary end points included duration of response (DoR), progression‐free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Results: Thirty‐eight patients were enrolled in cohorts 1 and 2. In cohort 1, ORR (95% confidence interval [CI]) was 56.3% (9 of 16 patients; 29.9%‐80.2%); 2 of 16 patients had complete responses and 7 of 16 had partial responses (PRs). In cohort 2, ORR was 20.0% (5.7%‐43.7%) with 4 of 20 PRs. In cohorts 1 and 2, the median DoR was 19.7 months (95% CI, 4.2 months to not estimable [NE]) and 9.4 months (95% CI, 4.2 months to NE), the median PFS was 8.4 months (95% CI, 3.9‐22.1 months) and 4.2 months (95% CI, 2.0‐6.2 months), and the median OS was NE (95% CI, 6.0 months to NE) and 7.7 months (95% CI, 4.0‐12.5 months), respectively. Grade ≥3 treatment‐emergent adverse events occurred in 88.2% and 85.7% of patients in cohorts 1 and 2, respectively. Safety was consistent with known profiles of single‐agent niraparib and pembrolizumab. Conclusions: Niraparib plus pembrolizumab showed clinical activity in patients with advanced and/or metastatic NSCLC. Lay Summary: The JASPER clinical trial studied a new combination treatment for advanced or metastatic non–small cell lung cancer (NSCLC).Pembrolizumab, a drug approved for NSCLC, was given with niraparib.Previous research showed that these 2 drugs together might work better than either drug alone.This study found that more than half of patients with high levels of a tumor marker responded to the combination, and one‐fifth of patients with lower levels of the marker responded.The types of side effects from the combination were similar to side effects from both drugs alone.These results support more research on this combination. The poly(ADP‐ribose) polymerase inhibitor niraparib, in combination with the programmed cell death receptor 1 inhibitor pembrolizumab, shows clinical activity and a manageable safety profile in patients with advanced or metastatic non–small cell lung cancer (NSCLC) in the phase 2 JASPER study. These results warrant further evaluation of this novel combination in NSCLC. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "A phase II trial of erlotinib and bevacizumab for patients with metastatic melanoma," that was published in a previous issue of the journal is presented.

PURPOSE: Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type–specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs. MATERIALS AND METHODS: A retrospective analysis of 26,004 patient records with NGS data available was conducted. Time to treatment failure and overall survival analyses were performed. Hazard ratios and associated statistics were computed in the R programming language. The study was considered exempt from internal review board review and data were considered nonhuman subjects. RESULTS: Response to CPIs varied between tumor types with melanoma and lung cancer performing relatively better on CPIs than other tumor types. Within tumor types, response to CPIs was stratified by mutations in specific genes. Tumor-agnostic markers including high tumor mutation burden and microsatellite instability-high were also associated with longer time to treatment failure on CPIs. Importantly, within the high tumor mutation burden and microsatellite instability-high groups, mutations in individual genes correlate with response to CPIs. CONCLUSION: The results from commercial NGS panels may be used to stratify patients for response to CPIs. In tumors where CPIs show relatively low efficacy, there may be distinct patient populations—based on gene mutation status—that are predicted to have better response to CPIs. Likewise, there may be distinct patient populations who do relatively worse on CPIs within tumor types known to respond well to CPIs. Different molecular biomarkers are associated with immune checkpoint inhibitor response across tumor types. [ABSTRACT FROM AUTHOR]

Background: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway.Methods: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing.Findings: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths.Interpretation: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population.Funding: F Hoffmann-La Roche-Genentech. [ABSTRACT FROM AUTHOR]

• Anti-CTLA-4 antibody quavonlimab + pembrolizumab was assessed in extensive-stage SCLC. • Encouraging antitumor activity was observed in patients with extensive-stage SCLC. • The combination was tolerable with manageable toxicities. This first-in-human phase I study (NCT03179436) investigated anti–cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti–programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non–small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy. Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumors v1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints. Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7–33) among all patients, 7% (<1–34) for PD-L1–positive tumors (n = 14), and 19% (5–42) for PD-L1–negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%. Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1–positive and PD-L1–negative tumors. The combination was tolerable with manageable toxicities. [ABSTRACT FROM AUTHOR]

PURPOSE: Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS: We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS: The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor–positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION: Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone. Real-world NGS data from >2,000 breast cancer patients reveals distinct gene amplification and mutation patterns [ABSTRACT FROM AUTHOR]

PURPOSE: Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type–specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs. MATERIALS AND METHODS: A retrospective analysis of 26,004 patient records with NGS data available was conducted. Time to treatment failure and overall survival analyses were performed. Hazard ratios and associated statistics were computed in the R programming language. The study was considered exempt from internal review board review and data were considered nonhuman subjects. RESULTS: Response to CPIs varied between tumor types with melanoma and lung cancer performing relatively better on CPIs than other tumor types. Within tumor types, response to CPIs was stratified by mutations in specific genes. Tumor-agnostic markers including high tumor mutation burden and microsatellite instability-high were also associated with longer time to treatment failure on CPIs. Importantly, within the high tumor mutation burden and microsatellite instability-high groups, mutations in individual genes correlate with response to CPIs. CONCLUSION: The results from commercial NGS panels may be used to stratify patients for response to CPIs. In tumors where CPIs show relatively low efficacy, there may be distinct patient populations—based on gene mutation status—that are predicted to have better response to CPIs. Likewise, there may be distinct patient populations who do relatively worse on CPIs within tumor types known to respond well to CPIs. Different molecular biomarkers are associated with immune checkpoint inhibitor response across tumor types. [ABSTRACT FROM AUTHOR]

PURPOSE: Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS: We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS: The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor–positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION: Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone. Real-world NGS data from >2,000 breast cancer patients reveals distinct gene amplification and mutation patterns [ABSTRACT FROM AUTHOR]

• In the JAVELIN Lung 200 phase 3 trial, avelumab did not improve OS vs docetaxel. • In avelumab vs docetaxel arms, 4% vs 26 % received a subsequent immune checkpoint inhibitor (ICI). • Post hoc analysis suggested that OS was affected by subsequent ICI use • Some subgroups showed trends for higher subsequent ICI use. The JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS. Patients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (≥1% of tumor cells) and full analysis set (PD-L1+ or PD-L1−). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics. In the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9–20.4) and 5.7 months (range, 0.1–24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62−1.04] vs 0.86 [95 % CI, 0.68−1.09], respectively). In the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172. [ABSTRACT FROM AUTHOR]

• KRAS mutant non-small cell lung cancer (NSCLC) is a major unmet clinical need. • RHOA-focal adhesion kinase (FAK) pathway is a signaling axis for KRAS mutant NSCLC. • KRAS mutant NSCLC models with TP53 or CDKN2A alterations respond to FAK inhibition. • Defactinib (VS-6063) is a selective oral inhibitor of FAK. • Defactinib had modest effects in KRAS mutant NSCLC, independent of TP53 or CDKN2A. KRAS mutations, which occur in approximately 25% of lung adenocarcinoma cases, represent a major unmet clinical need in thoracic oncology. Preclinical studies have demonstrated that KRAS mutant NSCLC cell lines and xenografts with additional alterations in either TP53 or CDKN2A (INK4A/ARF) loci are sensitive to focal adhesion kinase (FAK) inhibition. Defactinib (VS-6063) is a selective oral inhibitor of FAK. Patients with previously treated advanced KRAS mutant NSCLC were prospectively assigned to one of four molecularly defined cohorts based on the presence or absence of TP53 or CDKN2A alterations and received treatment with defactinib 400 mg orally BID until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 12 weeks. Fifty-five patients were enrolled. Mean age was 62 years; 51% were female. The median number of prior lines of therapy was 4 (range 1–8). Fifteen (28%) patients met the 12-week PFS endpoint, with one patient achieving a partial response. Median PFS was 45 days. Clinical efficacy did not correlate with TP53 or CDKN2A status. The most common adverse events were fatigue, gastrointestinal, and increased bilirubin, and were generally grade 1 or 2 in severity. In heavily pretreated patients with KRAS mutant NSCLC, defactinib monotherapy demonstrated modest clinical activity. Efficacy was not associated with TP53 and CDKN2A status. Defactinib was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer.Methods: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141.Findings: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths.Interpretation: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer.Funding: F Hoffmann-La Roche/Genentech. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with nonsmall cell lung cancer (NSCLC) most likely to respond to singleagent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PDL1 expression on IC was more prevalent and likely reflected IFN- γ-induced adaptive regulation accompanied by increased tumorinfiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PDL1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22%ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response. [ABSTRACT FROM AUTHOR]

Abstract Background Nivolumab, a programmed death-1 inhibitor, prolonged overall survival and had a favourable safety profile versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the phase III CheckMate 057 trial. Aim To evaluate health-related quality of life (HRQoL) using patient-reported outcomes. Methods Disease-related symptoms and general health status were assessed using two validated patient-reported instruments, the Lung Cancer Symptom Scale (LCSS) and the European Quality of Life Five Dimensions (EQ-5D), respectively. The proportion of patients with disease-related symptom improvement at 12 weeks on the LCSS average symptom burden index (ASBI) was a secondary end-point. LCSS 3-item global index (3-IGI), EQ-5D utility index and EQ-5D visual analogue scale (VAS) scores were also determined. Mixed-effects model repeated measures (MMRM) and time to first deterioration analyses assessed longitudinal changes. Results Mean baseline LCSS ASBI scores were similar in both arms. By week 12, rates of disease-related improvement (95% confidence interval) were similar between nivolumab (17.8% [13.6–22.7]) and docetaxel (19.7% [15.2–24.7]); however, numerical differences in LCSS ASBI mean change from baseline favoured nivolumab. Subsequently, LCSS ASBI scores improved with nivolumab and worsened with docetaxel, with statistically significant between-arm differences at weeks 12, 24, 30 and 42. HRQoL improvements with nivolumab versus docetaxel were also supported by the LCSS 3-IGI, EQ-5D VAS and MMRM analysis. Time to first HRQoL deterioration was longer with nivolumab than with docetaxel. Conclusion Nivolumab improved disease-related symptoms and overall health status versus docetaxel for second-line treatment of advanced non-squamous NSCLC. Clinical trial registration NCT01673867. Highlights • Nivolumab provided improvements in health-related quality of life in CheckMate 057. • Docetaxel was associated with stable or worsening of quality of life. • Disease-related deterioration was delayed with nivolumab versus docetaxel. [ABSTRACT FROM AUTHOR]

Introduction Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study. Methods Patients with NSCLC received atezolizumab 1–20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. Results Eighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%–72%), 33% (20%–48%), 29% (18%–41%) and 11% (1%–35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%–33%). Median duration of response was 16.4 months (range, 7.2–53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%–73%), 37% (26%–47%) and 28% (18%–38%), respectively. Conclusions Single-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. ClinicalTrials.gov identifier NCT01375842 . [ABSTRACT FROM AUTHOR]