Neoadjuvant combination immunotherapy ‘promising’ for early-stage NSCLC
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Neoadjuvant combination immunotherapy improved outcomes for patients with operable non-small cell lung cancer, according to results of the randomized phase 2 NEOSTAR trial.
The combination of ipilimumab (Yervoy, Bristol Myers Squibb) and nivolumab (Opdivo, Bristol Myers Squibb) induced a higher rate of major pathologic response compared with historical controls of neoadjuvant chemotherapy and nivolumab monotherapy, results showed. It also enhanced immunologic memory and tumor immune infiltrates.
“Combining ipilimumab [with] nivolumab produced twice as many major pathologic responses in resected patients compared with nivolumab alone,” researcher Tina Cascone, MD, PhD, assistant professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, told Healio. “The dual therapy also resulted in a greater number of complete pathologic responses.
“[Although] these comparisons are exploratory and the results need validation in larger cohorts, when you put these findings in context with earlier studies of neoadjuvant doublet chemotherapy that have produced a rate of major pathologic responses of approximately 19% and a median pathologic complete response rate of approximately 4%, it is quite remarkable that a chemotherapy-sparing regimen produces pathologic tumor responses more frequently,” Cascone added. “Given the promising results seen with combined chemoimmunotherapy in this setting, our findings set the stage for evaluating neoadjuvant dual immune checkpoint blockade plus chemotherapy in our patients with resectable NSCLC.”
More than half of patients with localized NSCLC treated with surgery alone subsequently relapse. The addition of chemotherapy confers a modest OS benefit but is associated with toxicity.
The combination of the anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibody nivolumab has shown encouraging clinical activity for patients with metastatic NSCLC, inducing durable responses and exhibiting a tolerable safety profile. However, the regimen’s efficacy for patients with operable NSCLC had not been determined.
“First-line combination immunotherapy ... resulted in longer overall survival compared with chemotherapy [for] patients with advanced NSCLC,” Cascone said. “We also know that anti-PD-1 and anti-CTLA-4 therapies augment antitumor immunity through distinct nonredundant cellular mechanisms, so we sought to test this regimen in patients with operable, early-stage NSCLC, where patients have the greatest opportunity for a cure.”
Cascone and colleagues conducted the NEOSTAR trial to evaluate neoadjuvant nivolumab alone or in combination with ipilimumab for 44 patients (median age, 66 years; 64% men; 84% white) with operable NSCLC. Major pathologic response — defined as 10% or less viable tumor at surgery — served as the primary endpoint.
In the ipilimumab-nivolumab group, eight (38%) of 21 patients achieved major pathologic response, surpassing the prespecified primary endpoint threshold. Five (22%) of 23 patients who received nivolumab alone achieved major pathologic response.
Thirty-seven patients underwent surgery on trial. In this subgroup, researchers reported major pathologic response rates of 50% (8 of 16) in the ipilimumab-nivolumab group and 24% (5 of 21) in the nivolumab monotherapy group.
The ipilimumab-nivolumab combination also appeared associated with a higher rate of pathologic complete response (38% vs. 10%), less viable tumor (median, 9% vs. 50%), and greater frequencies of effector, tissue-resident memory and effector memory T cells.
Greater relative abundance of gut Ruminococcus spp. and Akkermansia appeared associated with major pathologic response to the ipilimumab-nivolumab regimen.
“We were enthusiastic about the results from the combination arm,” Cascone told Healio. “[Although] these results have to be validated in larger cohorts, the ability of the combination treatment to enhance immunologic memory in this setting is particularly encouraging given the tendency of early-stage NSCLCs to recur after surgical resection.
“We were also excited to see that the relative abundance of some bacteria in stool samples of patients treated with immunotherapies was associated with major pathologic response, suggesting that the gut microbiome may impact response to these therapies in the neoadjuvant setting,” Cascone added. “Of course, further studies are needed to validate these findings, and to understand the functional role of these bacteria in tumor responses.”
The researchers are evaluating neoadjuvant dual immune checkpoint inhibitors in combination with chemotherapy for patients with operable NSCLC, as results of prior studies show this approach may provide even greater clinical benefit for those with resectable disease, Cascone said.
“To see the recent progress with immunotherapy in improving outcomes for patients with both early-stage and metastatic NSCLC is incredibly exciting,” Cascone said. “However, there are still a number of patients with lung cancer whose tumors are refractory to immune checkpoint inhibitors for reasons that we don’t completely understand. So, clearly there is still much work to do.
“The identification of biomarkers that can help us to select those patients most likely to benefit from immune-based therapies would be a major step forward,” Cascone added. “I would also like to acknowledge all of my colleagues who contributed to this work, as this was truly a collaborative effort.”
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