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Neoadjuvant nivolumab feasible, safe in early-stage resectable NSCLC
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COPENHAGEN, Denmark — Neoadjuvant treatment with the PD-1 inhibitor nivolumab demonstrated activity in patients with early-stage resectable non–small cell lung cancer, according to study results presented at the European Society for Medical Oncology Congress.
“[Treatment] did not delay or interfere with surgical resection, and there were no safety signals,” Patrick Forde, MD, assistant professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, said during a presentation.
Nivolumab (Opdivo, Bristol-Myers Squibb) has induced durable responses and extended survival among patients with previously treated metastatic or advanced NSCLC. However, neoadjuvant PD-1 blockade had not been investigated in patients with early-stage disease.
Forde and colleagues assessed the feasibility and safety of nivolumab administration to patients with early-stage NSCLC prior to resection. Researchers defined feasibility as not delaying surgery.
The analysis included 18 patients (median age, 68; range, 55-84) with treatment-naive, resectable stage I to stage IIIA NSCLC. Nine patients (50%) were men, and 12 (67%) had nonsquamaous histology. Three patients had stage IA or IB disease, seven had stage IIA disease, two had stage IIB disease and six had stage IIIA disease. All patients had ECOG performance status of 0 (n = 11; 61%) or 1 (n = 7; 39%).
All but one patient were current or former smokers.
All patients underwent tumor biopsy and then received two 3-mg/kg doses of nivolumab — one at 4 weeks prior to surgical resection and the other 2 weeks prior to resection. Patients underwent standard adjuvant chemotherapy at investigator discretion.
Exploratory endpoints included degree of pathologic regression, as well as molecular and immunophenotypic changes in tumor and peripheral blood.
Six patients (32%) experienced treatment-related adverse events. One patient experienced a grade 3 or grade 4 adverse event, leading to treatment discontinuation.
Exploratory analysis of treatment response showed four patients (22%) achieved partial response, 13 (72%) achieved stable disease and one (6%) experienced progressive disease.
Seven patients (39%) achieved pathologic downstaging from their pretreatment clinical stage.
Seven patients (39%; 95% CI, 20-61) of per-protocol patients achieved major pathologic responses, defined as resected specimens with less than 10% of residual viable tumor cells remaining at resection. One patient achieved pathologic complete response.
“Comprehensive genomic, immunohistochemical, T-cell receptor clonality and tumor-infiltrating lymphocytes functionality studies are ongoing,” Forde said.
Forde and colleagues expanded the study based on these results. One cohort will receive a third neoadjuvant dose of nivolumab, and another cohort will receive neoadjuvant treatment with nivolumab plus the anti–CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb).
Pieter Postmus, MD, PhD, chair of thoracic oncology at University of Liverpool in the United Kingdom, cautioned that potential for bias exists when comparing a small biopsy with a resected tumor. He also emphasized that “this is not a validated way to measure response” to treatment, and although it describes a biological effect, the effect on survival remains unproven.
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumor cells in tumor biopsies taken before and 4 to 8 weeks after immunotherapy,” Postmus said in a press release. “If in this way regression — as defined in the preoperative study — correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies.” – by Mark Leiser
For more information: Forde PM, et al. Abstract LBA41_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Stand Up to Cancer, American Association for Cancer Research and LUNGevity provided funding for this study. Bristol-Myers Squibb supplied nivolumab and funding for PD-L1 testing. Forde reports research grants to his institution for research outside this work from AstraZeneca, Bristol-Myers Squibb, Kyowa and Novartis, as well as uncompensated consultant or advisory board roles with AstraZeneca and Celgene. Please see the abstract for a list of all other researchers’ relevant financial disclosures.