Integration of Genetic Testing and Counseling in Patients With Breast Cancer in a Large, Multisite Community-Based Practice.

PURPOSE: Despite data-driven consensus recommendations, there remains significant nonadherence to genetic screening and testing. More than 300,000 patients are diagnosed with breast cancer annually, with one third of these estimated to be eligible for homologous recombination deficiency (HRD)/BRCA testing following National Comprehensive Cancer Network (NCCN) guidelines. Only 35% of eligible patients are referred for genetic counseling. METHODS: The goal of this project was to apply NCCN guidelines for germline genetic testing to all new patients with breast cancer within a large community oncology practice to improve HRD/BRCA testing. Plan-Do-Study-Act methodology was used, and cycles were built on a proven teaching infrastructure. In cycle 1, providers were educated and directed to use electronic health record (EHR) templates in the setting of an initial diagnosis visit and treatment planning. Discreet data fields were created in the EHR during cycle 2 to streamline and automate the process. Appropriate patients were referred to the genetics team for further evaluation, counseling, and testing. Adherence to the plan was maintained and measured using data analytic reports and chart audits. RESULTS: Of the 1,203 patients with breast cancer eligible for inclusion, 1,200 (99%) were screened according to NCCN guidelines. Of the screened patients, 631 (52.5%) met the referral/testing criteria. In total, 585 (92.7%) of the 631 were referred to a genetic specialist. Seven percent had previous referrals. A total of 449 (71%) patients were acceptable to genetics referral while 136 (21.5%) patients refused. CONCLUSION: The implemented methods of education, NCCN guidelines imbedded within provider notes, and discreet data fields in the EHR have proven to be highly effective in screening appropriate patients and ordering subsequent genetic referrals.

Sustainable Integration of US Food and Drug Administration-Approved Biosimilars: Pharmacy- Versus Physician-Driven Change.

PURPOSE: Biosimilars are clinically equivalent to branded products yet cost significantly less. Interchangeability is a US Food and Drug Administration (FDA) designation that allows generic drugs to be substituted for reference drugs at the pharmacy, without a physician's consent. Currently, no oncologic biosimilar has FDA approval for interchangeability. METHODS: Building on pharmacy auto-substitution processes with therapeutic interchange, Plan-Do-Study-Act methodology was used to automate conversions from reference biological products to Pharmacy and Therapeutics-/Physician-approved biosimilars. After establishing the baseline metrics, cycle 1 focused on full staff education (completed July 2020) with systematic pharmacy-driven biosimilar conversion initiated in September 2020 for rituximab, trastuzumab, and bevacizumab. Physician-initiated conversion of Neulasta biosimilar products was encouraged but not mandated. During cycle 2 (May 1, 2021-November 30, 2021), pharmacy-driven Neulasta biosimilar conversion was mandated. In cycle 3 (December 1, 2021-April 30, 2023), stakeholder education was reinforced and the sustainability of conversions was confirmed. RESULTS: Systematic pharmacy-driven conversion to biosimilar products improved over cycles 1 and 2 from baseline: 1.8% to 90.3% for rituximab, 9.2% to 89.7% for trastuzumab, and 20.5% to 96.1% for bevacizumab. Physician-driven biosimilar conversion for Neulasta was lower at 12.7% through April 2021. Pharmacy-driven Neulasta biosimilar conversion was initiated during cycle 2, resulting in a conversion rate of 39.7%. The conversion rates remained sustainable through April 2023. CONCLUSION: Pharmacy-driven auto-substitution of biosimilar products results in rapid and statistically significant biosimilar adoption. The pharmacy-based substitution approach was found to be far more effective than physician-driven substitution. Rapid conversion from branded products to FDA-approved biosimilar is feasible, measurable, and sustainable and can be scaled. Barriers to Neulasta conversion warrant further investigation.

Closing the Testing Gap: Standardization of Comprehensive Biomarker Testing for Metastatic Non-Small-Cell Lung Cancer in a Large Community Oncology Practice.

PURPOSE: Non-small-cell lung cancer (NSCLC), the leading cause of cancer death in the United States, accounts for 85% of all lung cancer cases. Biomarker testing is an integral part of the care of patients with NSCLC. Despite broad consensus recommendations that all patients with metastatic NSCLC (mNSCLC) undergo comprehensive biomarker testing (comprehensive genomic profiling and PD-L1), testing rates remain suboptimal. METHODS: The primary goal of this project was to apply National Comprehensive Cancer Network (NCCN) guidelines for comprehensive biomarker testing to all new patients with mNSCLC within a large community practice. Plan-Do-Study-Act methodology was used, with cycle 1 focused on provider education and the creation of a mNSCLC initial consult Note (electronic health record template/McKesson iKnowMed G2) and accompanying order set. Staging, template/order set utilization, and comprehensive biomarker testing rates were recorded while workflow processes were monitored. Cycle 2 centered on improved cancer staging, data analytic reporting, auditing, and reeducation. RESULTS: The comprehensive biomarker testing rates increased from a historic rate of 68% to 92.7% during the 1-year intervention period. The template utilization rate was 71% with complete staging (TNM stage and relevant biomarkers) documented in 40%. CONCLUSION: Implementation and standardization of comprehensive biomarker testing of patients with mNSCLC in a large multisite community-based oncology practice is feasible and results in significant improvement in comprehensive biomarker testing and reporting. Establishing reliable and measurable tracking metrics to ensure that these new processes are used and maintained can assist in scaling these processes. Efforts to scale this best practice are planned across the US Oncology Network.

MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy.

INTRODUCTION: Sitravatinib, a receptor tyrosine kinase inhibitor targeting TYRO3, AXL, MERTK receptors, and vascular epithelial growth factor receptor 2, can shift the tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with checkpoint inhibitors (CPIs) may augment antitumor activity. METHODS: The phase 2 MRTX-500 study evaluated sitravatinib (120 mg daily) with nivolumab (every 2 or 4 wk) in patients with advanced nonsquamous NSCLC who progressed on or after previous CPI (CPI-experienced) or chemotherapy (CPI-naive). CPI-experienced patients had a previous clinical benefit (PCB) (complete response, partial response, or stable disease for at least 12 weeks then disease progression) or no PCB (NPCB) from CPI. The primary end point was objective response rate (ORR); secondary objectives included safety and secondary efficacy end points. RESULTS: Overall, 124 CPI-experienced (NPCB, n = 35; PCB, n = 89) and 32 CPI-naive patients were treated. Investigator-assessed ORR was 11.4% in patients with NPCB, 16.9% with PCB, and 25.0% in CPI-naive. The median progression-free survival was 3.7, 5.6, and 7.1 months with NPCB, PCB, and CPI-naive, respectively; the median overall survival was 7.9 and 13.6 months with NPCB and PCB, respectively (not reached in CPI-naive patients; median follow-up 20.4 mo). Overall, (N = 156), any grade treatment-related adverse events (TRAEs) occurred in 93.6%; grade 3/4 in 58.3%. One grade 5 TRAE occurred in a CPI-naive patient. TRAEs led to treatment discontinuation in 14.1% and dose reduction or interruption in 42.9%. Biomarker analyses supported an immunostimulatory mechanism of action. CONCLUSIONS: Sitravatinib with nivolumab had a manageable safety profile. Although ORR was not met, this combination exhibited antitumor activity and encouraged survival in CPI-experienced patients with nonsquamous NSCLC.

Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics.

MET dysregulation promoting tumorigenesis in non-small cell lung cancer (NSCLC) is associated with worse outcomes following chemotherapy as compared to non-driver mutated NSCLC and occurs either through mutations causing MET exon 14 skipping (METex14) or gene amplification and overexpression that result in enhanced receptor signaling. Capmatinib is the first FDA-approved targeted therapy for NSCLC with METex14 skipping mutations, approved in 2020. FoundationOne® CDx, a comprehensive genomic profiling test for solid tumors, was concurrently approved as a companion diagnostic for capmatinib use. The GEOMETRY mono-1 phase II trial of capmatinib monotherapy demonstrated an overall response rate (ORR) of 68% in treatment naïve (n=28) and 41% in pre-treated (n=69) METex14 skipping advanced NSCLC; in MET amplified advanced NSCLC (gene copy number ≥ 10) ORRs of 40% in treatment naïve and 29% in pre-treated disease was seen. This review outlines the clinical data supporting capmatinib approval in the treatment of NSCLC and FoundationOne® CDx approval as a companion diagnostic. We detail the practical clinical administration of capmatinib, including dosing and toxicity management, compare capmatinib to other approved and investigational MET-targeted therapies, discuss limitations of capmatinib, and highlight ongoing trials of capmatinib in combinatorial approaches.

Understanding Contemporary Molecular Biomarker Testing Rates and Trends for Metastatic NSCLC Among Community Oncologists.

INTRODUCTION: Although guidelines recommend testing for actionable biomarkers for patients with advanced or metastatic non-small cell lung cancer (NSCLC), testing rates have varied. This study aimed to assess molecular testing patterns in a large network of US community-based oncology practices. METHODS: This retrospective observational study examined adult patients with newly diagnosed stage IV NSCLC with ≥ 2 visits in The US Oncology Network from July 1, 2016 to September 30, 2019. Testing patterns were examined using electronic health record structured fields and chart review. Structured data were analyzed for the overall study population (cohort A), and structured and unstructured data were analyzed for a select cohort of 300 patients (cohort B). RESULTS: In cohort A (n = 3337), programmed death ligand 1 (37%) was the most frequently tested biomarker documented in structured data, followed by epidermal growth factor receptor (36%), anaplastic lymphoma kinase (35%), ROS1 (20%), and BRAF (16%). According to unstructured data in cohort B (n = 300), epidermal growth factor receptor (80%) was the most frequently tested biomarker, followed by anaplastic lymphoma kinase (79%), programmed death ligand 1 (72%), ROS1 (71%), and BRAF (56%). The proportion of tests ordered prior to first-line (1L) treatment increased from 2016 to 2018 for all biomarkers, as did the proportion of test results available prior to 1L treatment. However, some of the test results became available after 1L or later lines of treatment were in progress. CONCLUSION: Our study found increased testing rates over time and decreases in testing turnaround times. However, rates of testing for all biomarkers still need to improve, as does completion of testing prior to initiation of therapy.

Treatment patterns and outcomes of patients with advanced malignant pleural mesothelioma in a community practice setting.

Aim: To assess real-world treatment patterns and outcomes among patients with advanced malignant pleural mesothelioma. Patients & methods: Retrospective database analysis. Results: In all, 469 patients received first-line systemic anticancer therapy (SACT) at community centers. Median follow-up from diagnosis was 11.6 months. Pemetrexed + platinum was the most common first-line SACT; similar proportions of patients received cisplatin or carboplatin with pemetrexed. Only a small proportion of patients received second- and third-line therapies. Median overall survival for first-line SACT was 12.0 months (95% CI: 10.7-14.2). Results were similar with pemetrexed + cisplatin and pemetrexed + carboplatin. Median overall survival with second-line SACT was 6.4 months (95% CI: 5.1-7.6). Conclusion: There is a need for more effective SACTs for advanced malignant pleural mesothelioma.

Lay abstract Real-world data on treatment patterns and outcomes among patients with advanced malignant pleural mesothelioma (MPM), largely a cancer of the lining surrounding the lungs, are limited. In this analysis based on patients treated in the USA, pemetrexed + cisplatin or pemetrexed + carboplatin was shown to be the most common treatment received by patients when first diagnosed with advanced MPM. Only a few patients received any subsequent treatments. Survival among patients receiving treatment was poor, with a median of approximately 12 months. Immunotherapy regimens are currently being investigated, with nivolumab + ipilimumab being the first immunotherapy regimen approved in October 2020 for the treatment of advanced MPM.

Recommendations to Streamline and Standardize Clinical Trial Site Feasibility Assessments: An ASCO Research Statement.

PURPOSE: Feasibility assessments (FAs) are important to establish site capabilities to conduct clinical trials and their suitability for specific trials. However, current FA methods used by biotechnology and pharmaceutical (biotech-pharma) trial sponsors and contract research organizations (CROs) are costly, inefficient, unnecessarily burdensome, and resource intensive. These methods delay trial start-up, act as a barrier to site participation, and ultimately reduce timely patient access to clinical trials and novel treatments. METHODS: An ASCO Task Force was convened to assess the specific burdens and challenges with FAs and to develop recommendations to improve their efficiencies and effectiveness. Stakeholders (including trial sites, biotech-pharma sponsors, and CROs) provided insights into challenges and offered solutions through two surveys and an in-person meeting. The Task Force used the feedback to formulate consensus recommendations to improve FAs for oncology clinical trials. RESULTS: Three key recommendations were identified for application across all biotech-pharma sponsored trials: (1) implement a streamlined and uniform FA process across trials and sponsors; (2) minimize and standardize questions; and (3) leverage technology to centralize FAs, facilitate communications, and reduce redundancies. CONCLUSION: There is an urgency to improve the current FA process, which is costly, inconsistent, inefficient, labor intensive, and of uncertain effectiveness. All stakeholders stand to benefit from implementing these recommendations, which aim to minimize burdens and ensure that more trial sites and patients have timely access to oncology clinical trials. To have meaningful impact, adoption and consistent execution of these recommendations across all trials, sponsors, CROs, and sites are essential.

Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153.

PURPOSE: Limited data exist on the optimal duration of immunotherapy, including for non-small-cell lung cancer (NSCLC). We present an exploratory analysis of CheckMate 153, a largely community-based phase IIIb/IV study, to evaluate the impact of 1-year fixed-duration versus continuous therapy on the efficacy and safety of nivolumab. METHODS: Patients with previously treated advanced NSCLC received nivolumab monotherapy (3 mg/kg every 2 weeks). Those still receiving treatment at 1 year, including patients perceived to be deriving benefit despite radiographic progression, were randomly assigned to continue nivolumab until disease progression or unacceptable toxicity or to stop nivolumab with the option of on-study retreatment after disease progression (1-year fixed duration). RESULTS: Of 1,428 patients treated, 252 were randomly assigned to continuous (n = 127) or 1-year fixed-duration (n = 125) treatment (intent-to-treat [ITT] population). Of these, 89 and 85 patients in the continuous and 1-year fixed-duration arms, respectively, had not progressed (progression-free survival [PFS] population). With minimum post-random assignment follow-up of 13.5 months, median PFS was longer with continuous versus 1-year fixed-duration treatment (PFS population: 24.7 months v 9.4 months; hazard ratio [HR], 0.56 [95% CI, 0.37 to 0.84]). Median overall survival from random assignment was longer with continuous versus 1-year fixed-duration treatment in the PFS (not reached v 32.5 months; HR, 0.61 [95% CI, 0.37 to 0.99]) and ITT (not reached v 28.8 months; HR, 0.62 [95% CI, 0.42 to 0.92]) populations. Few new-onset treatment-related adverse events occurred. No new safety signals were identified. CONCLUSION: To our knowledge, these findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy in previously treated advanced NSCLC and suggest that continuing nivolumab beyond 1 year improves outcomes.

Retrospective Observational Study of ALK-Inhibitor Therapy Sequencing and Outcomes in Patients with ALK-Positive Non-small Cell Lung Cancer.

BACKGROUND: Data are sparse concerning the sequential use of multiple anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). OBJECTIVE: This study investigated sequencing and outcomes among patients receiving multiple ALK inhibitors. PATIENTS AND METHODS: This was a retrospective observational cohort study of adult patients with ALK-positive NSCLC treated with available first- and second-generation ALK inhibitors from 1 September 2011 to 31 December 2017. Duration of therapy (DOT) and overall survival (OS) were assessed with the Kaplan-Meier method. A multivariable linear regression analysis was performed to assess if DOT with a preceding ALK inhibitor was predictive of DOT for subsequent ALK inhibitor treatments. RESULTS: A total of 410 patients were analyzed: 57% received 1 ALK inhibitor; 35%, 2 ALK inhibitors; and 8%, 3-4 ALK inhibitors. Among those receiving > 1 ALK inhibitor (n = 177), 60% received a crizotinib-led sequence and 39% an alectinib-led sequence. Nearly 60% of the overall population received chemotherapy prior to their first ALK inhibitor. Median OS for the study population was 28 months, 15 months in patients who received 1 ALK inhibitor, 42 months in patients who received 2 ALK inhibitors, and 56 months in patients who received 3-4 ALK inhibitors. Longer DOT of the first ALK inhibitor was associated with increased DOT of the second (p < 0.0001), and longer DOT of the second ALK inhibitor was associated with increased DOT of the third (p < 0.0001). CONCLUSIONS: This study provides initial information on real-world treatment patterns following the introduction of new ALK inhibitors, and supports the use of sequential ALK therapies.

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer.

PURPOSE: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. PATIENTS AND METHODS: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. RESULTS: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67+ CD8+/CD4+ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67+ CD8+ T-cell values were higher in responders than in nonresponders. CONCLUSIONS: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Early Impact of COVID-19 on the Conduct of Oncology Clinical Trials and Long-Term Opportunities for Transformation: Findings From an American Society of Clinical Oncology Survey.

The coronavirus disease 2019 (COVID-19) pandemic has disrupted all aspects of clinical care, including cancer clinical trials. In March 2020, ASCO launched a survey of clinical programs represented on its Cancer Research Committee and Research Community Forum Steering Group and taskforces to learn about the types of changes and challenges that clinical trial programs were experiencing early in the pandemic. There were 32 survey respondents; 14 represented academic programs, and 18 represented community-based programs. Respondents indicated that COVID-19 is leading programs to halt or prioritize screening and/or enrollment for certain clinical trials and cease research-only visits. Most reported conducting remote patient care where possible and remote visits and monitoring with sponsors and/or contract research organizations (CROs); respondents viewed this shift positively. Numerous challenges with conducting clinical trials were reported, including enrollment and protocol adherence difficulties with decreased patient visits, staffing constraints, and limited availability of ancillary services. Interactions with sponsors and CROs about modifying trial procedures were also challenging. The changes in clinical trial procedures identified by the survey could serve as strategies for other programs attempting to maintain their clinical trial portfolios during the COVID-19 pandemic. Additionally, many of the adaptations to trials made during the pandemic provide a long-term opportunity to improve and transform the clinical trial system. Specific improvements could be expanded use of more pragmatic or streamlined trial designs, fewer clinical trial-related patient visits, and minimized sponsor and CRO visits to trial programs.

Safety and Efficacy Results of a Phase I, Open-Label Study of Concurrent and Delayed Nivolumab in Combination With nab-Paclitaxel and Carboplatin in Advanced Non-small Cell Lung Cancer.

Introduction: Multicenter, phase I study of concurrent and delayed nivolumab plus nab-paclitaxel/carboplatin in advanced non-small cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients with advanced NSCLC (ineligible for potentially curative radiation or surgery) received nab-paclitaxel 100 mg/m2 (days 1, 8, 15) and carboplatin area under the curve 6 (day 1) intravenously every 21 days (first 4 cycles); nivolumab 5 mg/kg was administered intravenously (day 15) beginning in cycle 1 (concurrent) or cycle 3 (delayed) in separate cohorts and continued beyond the 4 chemotherapy cycles. The primary objective was to assess safety. Secondary objectives were to assess tolerability and explore antitumor activity. Results: All 32 patients received chemotherapy; 20 of 22 and 6 of 10 patients also received concurrent or delayed nivolumab, respectively. No dose-limiting toxicities were reported in the concurrent cohort; 1 dose-limiting toxicity was reported in the delayed cohort. In the concurrent cohort, 20 patients (91%) had ≥1 grade 3/4 treatment-emergent adverse event (TEAE), and 7 (32%) discontinued treatment due to TEAEs. In the delayed cohort, all patients had ≥1 grade 3/4 TEAE, and 2 (20%) discontinued due to TEAEs. The median progression-free and overall survival, respectively, were 10.5 and 29.3 months in the concurrent cohort and 4.1 and 8.2 months in the delayed cohort. Conclusions: The safety profile of the combination was consistent with that of individual agents and generally similar in the 2 cohorts. Efficacy outcomes in the concurrent cohort, but not in the delayed cohort, were encouraging and support the rationale for concurrent administration of nivolumab with nab-paclitaxel/carboplatin for the treatment of advanced NSCLC. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02309177.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Safety, Efficacy, and Patient-Reported Health-Related Quality of Life and Symptom Burden with Nivolumab in Patients with Advanced Non-Small Cell Lung Cancer, Including Patients Aged 70 Years or Older or with Poor Performance Status (CheckMate 153).

INTRODUCTION: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials. METHODS: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs). RESULTS: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved. CONCLUSIONS: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.

Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: A randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures.

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.

Amrubicin and carboplatin with pegfilgrastim in patients with extensive stage small cell lung cancer: A phase II trial of the Sarah Cannon Oncology Research Consortium.

PURPOSE: First-line treatment for patients with extensive-stage small cell lung cancer (SCLC) includes treatment with platinum-based combination chemotherapy. Amrubicin is a synthetic anthracycline with single-agent activity in relapsed/refractory SCLC. In an attempt to improve treatment efficacy, we evaluated amrubicin/carboplatin as first-line therapy for extensive-stage SCLC. PATIENTS AND METHODS: In this multicenter phase II trial, patients received amrubicin (30 mg/m2 daily on Days 1, 2, and 3) and carboplatin (AUC = 5 on Day 1); cycles were repeated every 21 days for 4 cycles. Pegfilgrastim (6 mg subcutaneously) was administered on Day 4 of all cycles. Overall survival (OS) proportion at 1 year was the primary endpoint. The target 1-year OS rate was 47%, an improvement of 35% from historical results with carboplatin/etoposide. RESULTS: Eighty patients received study treatment, and 62% completed the planned 4 courses. The overall response rate was 74% (13% complete responses). The 1-year survival rate was 38% (95% CI: 25, 50). The median survival was 10 months. Myelosuppression was severe but manageable. CONCLUSIONS: The combination of amrubicin/carboplatin was an active first-line treatment for extensive stage SCLC, but showed no indication of increased efficacy compared to standard treatments. Severe myelosuppression was common with this regimen, in spite of prophylactic pegfilgrastim. These results are consistent with those of other trials in showing no role for amrubicin in the first-line treatment of SCLC.

Phase II trial of preoperative pemetrexed plus carboplatin in patients with stage IB-III nonsquamous non-small cell lung cancer (NSCLC).

OBJECTIVES: The combination of pemetrexed and carboplatin is a standard first-line treatment for patients with advanced NSCLC. In this pilot phase II trial, we evaluated the feasibility of using pemetrexed and carboplatin as neoadjuvant therapy, prior to definitive surgical resection, for patients with localized NSCLC. PATIENTS AND METHODS: Patients with potentially resectable, previously untreated, clinical stage IB-III, nonsquamous NSCLC were eligible for this trial. All patients received 4 cycles of pemetrexed (500 mg/m2) and carboplatin (AUC 6.0) administered at 21 day intervals. Three to 6 weeks after completion of chemotherapy, definitive surgical resection was attempted. The primary endpoint of this trial was the 3-year survival rate. RESULTS: Forty-six patients began protocol treatment, and 40 completed 4 courses of pemetrexed/carboplatin. Surgical resection was performed in 27 patients (59%); all had pathologic partial responses. The estimated 3-year survival rate for the entire group was 46%. Toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin. CONCLUSIONS: Administration of 4 courses of pemetrexed/carboplatin was feasible. The efficacy was similar to neoadjuvant regimens previously investigated. A significant number of patients 19 of 46 (41%) in this trial did not have surgical resection after neoadjuvant therapy. Further investigation of the role of neoadjuvant pemetrexed/carboplatin requires a larger, randomized clinical trial.

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation. BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer. METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS). RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen. CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.