medwireNews: Phase 2 data point to the promising efficacy of adding ipilimumab to neoadjuvant nivolumab plus chemotherapy in people with operable non-small-cell lung cancer (NSCLC).
The researchers explain that the NEOSTAR trial previously showed the potential of neoadjuvant treatment with nivolumab or nivolumab plus ipilimumab in this setting, and subsequently it has “evolved into a platform trial of sequential, single-center, single-arm, phase 2 studies with a modular design.”
The current analysis focused on arms C and D, which comprised patients with stage IB tumors of at least 4 cm or stage IIA, IIB, or IIIA disease who received up to three cycles of nivolumab 360 mg plus chemotherapy every 3 weeks either without or with the CTLA-4 inhibitor ipilimumab given at a dose of 1 mg/kg on day 1 of the first cycle, respectively.
As reported in Nature Medicine, the primary endpoint of major pathologic response (MPR) was achieved by 50.0% of the 22 participants who received ipilimumab alongside nivolumab plus chemotherapy and 32.1% of the 22 who received just the PD-1 inhibitor and chemotherapy.
The pathologic complete response (pCR) rate was an identical 18.2% for each regimen.
Both treatment arms “met the prespecified boundary of six [major] responses to be considered efficacious,” note Tina Cascone (The University of Texas MD Anderson Cancer Center, Houston, USA) and co-investigators.
And they add that the MPR rates in both arms were significantly higher than “the historical conservative MPR rate of approximately 15% produced by neoadjuvant [chemotherapy].”
When individuals with known EGFR mutations and ALK alterations were excluded from the analysis, the MPR and pCR rates rose to 62.5% and 25.0%, respectively, with the triplet regimen and to 41.2% and 23.5% with nivolumab plus chemotherapy.
At a median follow-up of 24.0 months in the ipilimumab arm and 39.2 months in the nivolumab plus chemotherapy arm, the median event-free survival (EFS) and overall survival times were not reached with either regimen. The corresponding 12-month EFS rates were 82% and 96%, while the 24-month rates were 77% and 73%.
Cascone and colleagues highlight that the addition of ipilimumab to nivolumab plus chemotherapy “maintained an overall acceptable toxicity and allowed curative-intent surgery without adverse postoperative outcomes.”
All but two of the patients in the ipilimumab arm underwent planned surgery, with the two exceptions being a patient who died of COVID-19-related complications during the first cycle of neoadjuvant therapy and another whose surgeon decided against surgery. In the nivolumab plus chemotherapy cohort, all patients had surgery as planned. The respective R0 resection rates were 95% and 90%.
Complications within 30 days of surgery occurred in 65.0% of individuals given the triplet regimen and 31.8% of those given nivolumab–chemotherapy. The 30- and 90-day mortality rates were 0% in both arms.
Treatment-related adverse events of grade 1 or 2 occurred in 80% of participants in the ipilimumab arm and 55% of those in the nivolumab plus chemotherapy arm, while events of grade 3–4 occurred in a corresponding 20% and 45%.
The study authors also conducted single-cell sequencing and multi-platform immune profiling, which showed that “immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, […] were preferentially increased in the [ipilimumab] cohort.”
They conclude that “[a]lthough the trial was not directly designed to compare both arms, our clinical and pathological findings of potential enhanced activity of [ipilimumab, nivolumab, plus chemotherapy] are supported by our translational analyses demonstrating compositional changes consistent with marked tumor immune infiltration with an anti-tumor activity phenotype in tumors from the [ipilimumab] cohort compared with those treated with [nivolumab plus chemotherapy].
The team adds: “The addition of CTLA-4 blockade to PD-(L)1 inhibition plus [chemotherapy] deserves further investigation for patients with resectable NSCLC.”
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