Patients with relapsed small-cell lung cancer (SCLC) have few treatment options and dismal survival. Phase I/II data show activity of nivolumab in previously treated SCLC.
CheckMate 331 is a ...randomized, open-label, phase III trial of nivolumab versus standard chemotherapy in relapsed SCLC. Patients with relapse after first-line, platinum-based chemotherapy were randomized 1 : 1 to nivolumab 240 mg every 2 weeks or chemotherapy (topotecan or amrubicin) until progression or unacceptable toxicity. Primary endpoint was overall survival (OS).
Overall, 284 patients were randomized to nivolumab and 285 to chemotherapy. Minimum follow-up was 15.8 months. No significant improvement in OS was seen with nivolumab versus chemotherapy median OS, 7.5 versus 8.4 months; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.72-1.04; P = 0.11. A survival benefit with nivolumab was suggested in patients with baseline lactate dehydrogenase ≤ upper limit of normal and in those without baseline liver metastases. OS (nivolumab versus chemotherapy) was similar in patients with programmed death-ligand 1 combined positive score ≥1% versus <1%. Median progression-free survival was 1.4 versus 3.8 months (HR, 1.41; 95% CI, 1.18-1.69). Objective response rate was 13.7% versus 16.5% (odds ratio, 0.80; 95% CI, 0.50-1.27); median duration of response was 8.3 versus 4.5 months. Rates of grade 3 or 4 treatment-related adverse events were 13.8% versus 73.2%.
Nivolumab did not improve survival versus chemotherapy in relapsed SCLC. No new safety signals were seen. In exploratory analyses, select baseline characteristics were associated with improved OS for nivolumab.
•The primary endpoint of OS with nivolumab versus chemotherapy as second-line treatment of SCLC was not met.•Crossing of the survival curves indicates higher long-term survival with nivolumab in a subset of patients.•Post hoc analyses suggest patients with baseline LDH ≤ ULN and those without liver metastases may benefit from nivolumab.•The safety profile of nivolumab was consistent with prior studies and more favorable than that of chemotherapy.
Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. ...Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics.
MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab high tumor mutational burden (TMB). The primary endpoint is the objective response rate (ORR).
As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease >4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred.
Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination.
•Pertuzumab + trastuzumab produced a response in 60% (9/15) of patients with HER2-amplified/overexpressing salivary cancer.•Stable disease was observed in a patient with HER2-mutated salivary cancer treated with pertuzumab + trastuzumab.•Vismodegib, vemurafenib, and atezolizumab produced responses in salivary tumors with matched genomic alterations.•Safety for each treatment was consistent with previously reported safety profiles.•Results support use of molecular profiling to identify effective chemotherapy-free targeted treatments for salivary cancers.
In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer ...(NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression.
Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan–Meier-estimated medians).
In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%–24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups HR, 95% confidence interval (CI); medians: TC ≥25% (0.41, 0.26–0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43–0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33–0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48–1.11; 10.7 versus 5.6 months), 1%–24% 0.49, 0.30–0.80; not reached (NR) versus 9.0 months, and unknown (0.59, 0.42–0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30–0.83; NR versus 21.1 months), <25% (0.89, 0.63–1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41–0.83; NR versus 29.6 months), 1%–24% (0.67, 0.41–1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43–0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71–1.84; 33.1 versus 45.6 months). Safety was similar across subgroups.
PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.
•Tumour tissue acquisition (pre-chemoradiotherapy) and tumour cell (TC) PD-L1 expression testing were not mandated.•However, outcomes were assessed based on PD-L1 expression in subgroups defined by pre-specified and post hoc TC cut-offs.•Treatment benefit with durvalumab, versus placebo, was observed irrespective of PD-L1 expression in terms of PFS.•OS improvement was demonstrated overall and across all subgroups, apart from the post hoc TC <1% subgroup.•Limitations (few events and baseline imbalances) and a wide CI for OS HR (includes 1) prevent robust conclusions for TC <1%.
Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile ...with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC.
Patients were randomized 1 : 1 to nivolumab (3mg/kg every 2weeks) or docetaxel (75mg/m2 every 3weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses.
After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% 95% confidence interval (CI), 14% to 21% versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%).
After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated.
CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.
Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.
Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors ...received an initial flat dose of quavonlimab as monotherapy 25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3) followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab 25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E) plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.
Thirty-nine patients were enrolled in DE n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3) and 134 in DC n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E). Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% 95% confidence interval (CI), 24.9-56.7; arm A, 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.
Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
•Quavonlimab, a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a first-in-human study.•The combination therapy was safe and tolerable and showed antitumor activity in patients with advanced NSCLC.•Data from this study led to a recommended phase II dose of 25 mg Q6W for quavonlimab when used with pembrolizumab.
Imetelstat, a novel telomerase inhibitor, failed to improve significantly median PFS and OS as maintenance therapy (±bevacizumab) in advanced NSCLC. Telomere length (TL) biomarker results were ...consistent with the hypothesis that telomerase inhibition is of greater benefit to patients with tumors possessing shorter telomeres; the patients with shorter TL had a trend toward longer median PFS and OS.
Continuation or ‘switch’ maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC.
The primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0–1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization.
Of 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control hazard ratio (HR) = 0.844; 95% CI 0.54–1.31; P = 0.446. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14–1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11–1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39–1.88; and HR = 0.51; 95% CI 0.2–1.28; P = 0.145).
Maintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.
Bevacizumab is a monoclonal antibody against vascular endothelial growth factor. Severe pulmonary haemorrhage (PH) is a rare but serious potential adverse event associated with bevacizumab therapy ...for advanced non-squamous non-small-cell lung cancer (NSCLC).
A panel of expert oncologists, pulmonologists and radiologists reviewed the available data to identify predictive factors for PH in order to help guide physicians using bevacizumab in patients with NSCLC.
Patients with NSCLC are at an increased risk of PH owing to the underlying disease process. Patients with squamous histology and/or a history of grade ≥2 haemoptysis (≥2.5 ml per event) should not receive bevacizumab. No clinical or radiological features (including cavitation and central tumour location) reliably predict severe PH in bevacizumab-treated patients. Major blood vessel infiltration and bronchial vessel infiltration, encasement and abutting may predict PH; however, standardised radiological criteria for defining infiltration have not been established. Eligibility for bevacizumab is not affected by patient age, performance status or anticoagulation or antiplatelet therapy.
An individualised risk–benefit assessment should be undertaken in all patients with NSCLC in whom bevacizumab is being considered. Further research is required to elucidate the mechanisms underlying PH and the clinical risk factors.
First-line nivolumab plus ipilimumab prolongs survival versus chemotherapy in advanced non-small-cell lung cancer (NSCLC). We further characterized clinical benefit with this regimen in a large ...pooled patient population and assessed the effect of response on survival.
Data were pooled from four studies of first-line nivolumab plus ipilimumab in advanced NSCLC (CheckMate 227 Part 1, 817 cohort A, 568 Part 1, and 012). Overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety were assessed. Landmark analyses of OS by response status at 6 months and by tumor burden reduction in responders to nivolumab plus ipilimumab were also assessed.
In the pooled population (N = 1332) with a minimum follow-up of 29.1-58.9 months, median OS was 18.6 months, with a 3-year OS rate of 35%; median PFS was 5.4 months (3-year PFS rate, 17%). Objective response rate was 36%; median duration of response was 23.7 months, with 38% of responders having an ongoing response at 3 years. In patients with tumor programmed death-ligand 1 (PD-L1) <1%, ≥1%, 1%-49%, or ≥50%, 3-year OS rates were 30%, 38%, 30%, and 48%. Three-year OS rates were 30% and 38% in patients with squamous or non-squamous histology. Efficacy outcomes in patients aged ≥75 years were similar to the overall pooled population (median OS, 20.1 months; 3-year OS rate, 34%). In the pooled population, responders to nivolumab plus ipilimumab at 6 months had longer post-landmark OS than those with stable or progressive disease; 3-year OS rates were 66%, 22%, and 14%, respectively. Greater depth of response was associated with prolonged survival; in patients with tumor burden reduction ≥80%, 50% to <80%, or 30% to <50%, 3-year OS rates were 85%, 72%, and 44%, respectively. No new safety signals were identified in the pooled population.
Long-term survival benefit and durable response with nivolumab plus ipilimumab in this large patient population further support this first-line treatment option for advanced NSCLC.
•Pooled analyses from four 1L NIVO + IPI studies support the durable efficacy of this regimen for advanced NSCLC treatment.•Durable responses and long-term survival benefit with NIVO + IPI were observed across histologies/PD-L1 expression levels.•Patients who had a response at 6 months with 1L NIVO + IPI had improved post-landmark survival benefit.•Responders with higher tumor burden reduction from baseline derived long-term OS benefit.
Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β2 glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy ...of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC).
Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS).
A total of 597 patients were enrolled. Median OS was 10.5months in the docetaxel+bavituximab arm and was 10.9months in the docetaxel+placebo arm (HR 1.06; 95% CI 0.88–1.29; P=0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82–1.22; P=0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels≥200µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63–1.06; P=0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26–0.81; P=0.006).
The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation.
NCT01999673.
Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment ...with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs.
Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized.
Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents.
Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.
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