1. Fuerst, Mark L.

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SAN FRANCISCO-A higher dose of the checkpoint inhibitor nivolumab every 4 weeks as second-line therapy is feasible in advanced non-small cell lung cancer (NSCLC) patients who previously had disease control with nivolumab.

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Nivolumab is approved as 240 mg every 2 weeks in the European Union and Japan and at 240 mg every 2 weeks or 480 mg every 4 weeks in the U.S. and Canada for second-line treatment of advanced NSCLC.


"Pharmacokinetic modeling in various tumors predicts that exposure, efficacy, and safety can be maintained with less frequent dosing every 4 weeks, which may provide a more convenient therapeutic option," said lead author Edward B. Garon, MD, Associate Professor of Medicine at UCLA. More extended dosing would allow patients to resume more normal work schedules and travel on longer trips, he noted.


At the 2019 ASCO-Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium, Garon presented an interim analysis of efficacy and safety from CheckMate 384, an international, open-label, randomized phase IIIb/IV trial evaluating less frequent nivolumab dosing-480 mg every 4 weeks versus 240 mg every 2 weeks-in 329 patients with advanced NSCLC and prior nivolumab therapy every 2 weeks.


The patients had previously treated histologically confirmed stage IIIB/IV or recurrent NSCLC. They had relatively good performance status (ECOG 0-2) and two consecutive assessments of complete response, partial response, or stable disease. Due to therapy landscape changes in NSCLC and difficulties in recruitment, statistical analyses were amended for a reduced sample size, which means the data he presented were descriptive rather than definitive.


The patients were stratified by tumor histology (squamous or non-squamous) and response to prior nivolumab therapy at randomization, and they were then randomized to receive nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.


The interim analysis including data on 329 of the 363 patients; the final analysis will occur after all patients have had a minimum of 12 months of follow-up. Garon reported on 6-month progression-free survival (PFS), a co-primary endpoint with 12-month PFS.


After a median follow-up of 9.5 month in the every 4-week group and 10.2 months in the every 2-week group, the 6-month PFS rates were identical (72%) and median PFS was virtually identical (12.1 months vs. 12.2 months, respectively).


The safety profiles were similar in the two groups. Any grade treatment-related adverse events were slightly lower (48%) in the every 4-week group as compared to the every 2-week group (61%). Grade 3 or 4 adverse events were 8 percent and 12 percent, respectively.


In conclusion, Garon noted: "Nivolumab 480 mg every 4 weeks showed similar efficacy and safety to 240 mg every 2 weeks in patients with disease control on nivolumab, supporting the potential use of 480 mg every 4 weeks as a more convenient dosing option for second-line NSCLC therapy."


Atezolizumab in Resectable NSCLC

In another study at ASCO-SITC, neoadjuvant atezolizumab in resectable NSCLC patients yielded an encouraging major pathological response rate.


Targeting PD-L1/PD-1 to activate anti-tumor immunity leads to an improved response and survival compared to chemotherapy in NSCLC patients. Filiz Oezkan, MD, of The Ohio State University, Arthur G. James Thoracic Cancer Center, Columbus, presented a preliminary analysis of the clinical efficacy, safety, and peripheral blood immunophenotyping from an ongoing, multicenter, atezolizumab neoadjuvant immunotherapy study in resectable NSCLC.


The patients received 2 cycles of atezolizumab 1,200 mg on days 1 and 22 before resection. Tumor biopsies and peripheral blood were obtained pre-atezolizumab and pre-surgery. The biomarker evaluable population included patients with paired peripheral blood analyzed within 72 hours by 10-color flow cytometry and major pathological response assessment, defined as 10 percent or less residual tumor.


The primary endpoint was major pathological response, and secondary endpoints were safety, major pathological response by PD-L1, overall survival, and disease-free survival. Immunophenotypic analyses were correlated with treatment, major pathological response, and PD-L1 expression.


So far, the researchers have enrolled 116 patients. Oezkan reported on 54 of 180 planned patients with follow-up through surgery. The results show that three patients achieved a partial response and 49 patients have stable disease. Two patients progressed. Of the 54 patients, 50 patients underwent the planned surgery and 47 patients had major pathological response assessment.


Four patients discontinued the study pre-operatively and three patients were unresectable. Excluding five patients with EGFR or ALK mutations, the major pathological response rate was 10 of 45 (22%) patients. Of 44 patients in which baseline PD-L1 status was evaluable, 16 patients were positive for PD-L1.


In terms of side effects, 15 patients had grade 3 or 4 adverse events (three were treatment-related), and one patient had a grade 5 adverse event (sudden death) that was unrelated to treatment.


"We observed significant increases in natural killer (NK) cells, CD8+ T cells, Th1 response-related dendritic cells (DC), and decreases in B cells after atezolizumab," said Oezkan. Non-major pathological response patients showed significant increases in late activated NK cells, monocytic myeloid cells, and Th2 and Th17 response-related DCs. PD-L1-positive patients showed significant decreases of senescent T cells and monocytic myeloid cells, as well as increases of Th1 response-related DCs.


"We analyzed 22 of 54 tumor pairs and found PD-L1-positive cells increased in most patients after atezolizumab treatment," he stated.


In conclusion, Oezkan said: "Neoadjuvant atezolizumab was well-tolerated and the major pathological response rate is encouraging. Preliminary immunophenotyping data showed significant changes in peripheral blood with immunotherapy."


Mark L. Fuerst is a contributing writer.