A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆.

BACKGROUND: Approved first-line treatments for patients with BRAF V600-mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). PATIENTS AND METHODS: A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. RESULTS: In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. CONCLUSION: Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

BACKGROUND: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). METHODS: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). RESULTS: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. CONCLUSIONS: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.

Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis.

BACKGROUND: Temozolomide (TMZ) is widely used for chemotherapy of metastatic melanoma. We hypothesized that epigenetic modulators will reverse chemotherapy resistance, and in this article, we report studies that sought to determine the recommended phase 2 dose (RP2D), safety, and efficacy of decitabine (DAC) combined with TMZ. PATIENTS AND METHODS: In phase I, DAC was given at two dose levels: 0.075 and 0.15 mg/kg intravenously daily × 5 days/week for 2 weeks, TMZ orally 75 mg/m(2) qd for weeks 2-5 of a 6-week cycle. The phase II portion used a two-stage Simon design with a primary end point of objective response rate (ORR). RESULTS: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m(2). The phase II portion enrolled 35 patients, 88% had M1c disease; 42% had history of brain metastases. The best responses were 2 complete response (CR), 4 partial response (PR), 14 stable disease (SD), and 13 progressive disease (PD); 18% ORR and 61% clinical benefit rate (CR + PR + SD). The median overall survival (OS) was 12.4 months; the 1-year OS rate was 56%. Grade 3/4 neutropenia was common but lasted >7 days in six patients. CONCLUSIONS: The combination of DAC and TMZ is safe, leads to 18% ORR and 12.4-month median OS, suggesting possible superiority over the historical 1-year OS rate, and warrants further evaluation in a randomized setting.

Assessing oncologic benefit in clinical trials of immunotherapy agents.

BACKGROUND: USA Food and Drug Administration approval for cancer therapy requires demonstration of patient benefit as a marker of clinical efficacy. Prolonged survival is the gold standard for demonstration of efficacy, but other end points such as antitumor response, progression-free survival, quality of life, or surrogate end points may be used. DESIGN: This study was developed based on discussion during a roundtable meeting of experts in the field of immunotherapy. RESULTS: In most clinical trials involving cytotoxic agents, response end points use RECIST based on the premise that 'effective' therapy causes tumor destruction, target lesion shrinkage, and prevention of new lesions. However, RECIST may not be appropriate in trials of immunotherapy. Like other targeted agents, immunotherapies may mediate cytostatic rather than direct cytotoxic effects, and these may be difficult to quantify with RECIST. Furthermore, significant time may elapse before clinical effects are quantifiable because of complex response pathways. Effective immunotherapy may even mediate transient lesion growth secondary to immune cell infiltration. CONCLUSIONS: RECIST may not be an optimal indicator of clinical benefit in immunotherapy trials. This article discusses alternative clinical trial designs and end points that may be more relevant for immunotherapy trials and may offer more effective prediction of survival in pivotal phase III studies.