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.
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).
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
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
32.5 months; HR, 0.61 95% CI, 0.37 to 0.99) and ITT (not reached
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.
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.
Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation–positive advanced non–small cell lung cancer (NSCLC); however, patients eventually progress. ...Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation–positive NSCLC.
Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation–positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017.
Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response.
These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.
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.
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).
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.
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.
Because of promising efficacy signals in single-arm studies, a placebo-controlled, double-blind, randomized phase II trial was designed to assess the efficacy and safety of adding bevacizumab to ...first-line standard chemotherapy for treatment of extensive-stage small-cell lung cancer (SCLC).
Patients with SCLC were randomly assigned to receive bevacizumab or placebo, with cisplatin or carboplatin plus etoposide, for four cycles followed by single-agent bevacizumab or placebo until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).
Fifty-two patients were randomly assigned to the bevacizumab group and 50 to the placebo group; 69% versus 66%, respectively, completed four cycles of therapy. Median PFS was higher in the bevacizumab group (5.5 months) than in the placebo group (4.4 months; hazard ratio HR, 0.53; 95% CI, 0.32 to 0.86). Median overall survival (OS) was similar for both groups (9.4 v 10.9 months for bevacizumab and placebo groups, respectively), with an HR of 1.16 (95% CI, 0.66 to 2.04). Overall response rates were 58% (95% CI, 43% to 71%) for the bevacizumab group and 48% (95% CI, 34% to 62%) for the placebo group. Median duration of response was 4.7 months for the bevacizumab group and 3.2 months for the placebo group. In the bevacizumab and placebo groups, 75% versus 60% of patients, respectively, experienced one or more grade 3 or higher adverse events. No new or unexpected safety signals for bevacizumab were observed.
The addition of bevacizumab to cisplatin or carboplatin plus etoposide for treatment of extensive-stage SCLC improved PFS, with an acceptable toxicity profile. However, no improvement in OS was observed.
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.
Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non-small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum ...clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression.
The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m(2)) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m(2) on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL).
Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups.
We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.
Assess safety and efficacy of nivolumab plus
-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial.
Fifty ...chemotherapy-naive patients received
-paclitaxel 125 mg/m
plus gemcitabine 1,000 mg/m
(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
.
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.
The safety profile of nivolumab plus
-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.
PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with ...advanced nonsquamous non–small-cell lung cancer (NSCLC).
Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m2, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m2, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed.
Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7–1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms.
Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.
Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in ...this multicenter phase II trial.
Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib.
One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib.
Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.
•We examined real-world testing for actionable biomarkers associated with targeted therapies.•Study patients were identified from a large network of community-based oncology practices.•Rate of ...testing prior to first-line treatment increased from 2016 to 2018 for all biomarkers.•The proportion of biomarker test results available before first-line treatment also increased from 2016 to 2018.•A significant proportion of biomarker test results were available only after initiation of first or later lines of treatment.•Results indicated that improvements are needed in the biomarker testing process.
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.
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).
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.
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.
Timely testing for actionable biomarkers for patients with advanced or metastatic non–small cell lung cancer can ensure that they receive the appropriate treatment at the right time, but the real-world rate of testing has varied. This study assessed molecular testing patterns in a large network of US community-based oncology practices. Although testing rates increased over time and testing turnaround times decreased, results of testing were not available for a considerable number of patients before initiation of first-line treatment.
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