Neoadjuvant Chemo–ICI Boosts NSCLC Survival

New findings from two Spanish trials show that patients with operable non–small cell lung cancer (NSCLC) continue to benefit from neoadjuvant immune checkpoint inhibition (ICI) combined with chemotherapy. Besides increasing pathologic complete response (pCR) rates, this strategy may also boost progression-free survival (PFS) and overall survival (OS). Researchers have also uncovered biomarkers that could better pinpoint the subset of patients who, despite treatment, are at high risk of disease progression.

Buoyed by results from the single-arm, phase II NADIM I study—adding neoadjuvant nivolumab (Opdivo; Bristol Myers Squibb) to chemotherapy nearly tripled OS at 3 years, compared with historical chemotherapy-only rates (J Clin Oncol 2022;40:2924–33)—the investigators launched NADIM II. In this phase II trial, 86 patients were randomly assigned 2:1 to receive either neoadjuvant nivolumab plus chemotherapy or chemotherapy alone, followed by surgery. Combination chemo–immunotherapy significantly increased pCR rates: 36.2% versus 6.8%, respectively (J Clin Oncol 40:16s, 2022 [suppl; abstr 8501]). These data were consistent with that of CheckMate 816, a phase III trial also pitting neoadjuvant ICI plus chemotherapy against chemotherapy alone; its pCR rates were 24% versus 2.2%, respectively (N Engl J Med 2022;386:1973–85).

Updated data from NADIM II were presented at the International Association for the Study of Lung Cancer's 2022 World Conference on Lung Cancer (WCLC) in Vienna, Austria, August 6–9. Lead investigator Mariano Provencio, MD, PhD, of Hospital Universitario Puerta de Hierro Majadahonda in Madrid, reported that at 24 months, the respective PFS and OS rates were 66.6% and 84.7% compared with 42.3% and 63.4% in the control arm. “We've confirmed the superiority of neoadjuvant chemo–immunotherapy,” Provencio said, “and this is the first [such] trial to show OS improvement.”

Discussant Masahiro Tsuboi, MD, of National Cancer Center Hospital East in Chiba, Japan, reminded attendees that stage IIIA/B NSCLC is a heterogeneous, complex disease to manage. Surgery alone cures roughly 20% of patients, but whether the primary tumor is “resectable or not is always a matter of debate in clinical practice—it has to do with the surgeon's experience and skill” as much as anything else, he said. Neoadjuvant regimens, while promising, aren't entirely toxicity-free, he added. The best treatment strategy then—if there is one—remains unclear and will likely be “highly individualized.”

“My key message is that any patients being considered for induction chemo–immunotherapy should be deemed operable up front by a multidisciplinary team, and [team] discussions are essential,” Tsuboi said.

Another discussant, Corinne Faivre-Finn, MD, PhD, of The Christie Hospital in Manchester, UK, agreed, adding that the likelihood of achieving a complete resection—no tumor cells seen microscopically at the primary site—should be taken into account. Otherwise, with incomplete resections (the rates were 7.5% and 35% in NADIM II's combination and control arms), postoperative radiotherapy (PORT) might come into play, potentially increasing the risk of cardiopulmonary toxicity (Lancet Oncol 2022;23:104–14).

“We need to move away from this concept that ‘PORT will mop it up’ in cases of residual disease,” Faivre-Finn remarked. As well, to her, “the time is ripe” for a trial comparing NADIM I/II and CheckMate 816's approach with “a nonsurgical strategy—for instance, concurrent chemoradiotherapy and ICI” in stage III NSCLC.Unearthing Potential Resistance Markers

Meanwhile, a group of researchers at Provencio's institute took a retrospective look at NADIM I's data, using a 395-gene RNA sequencing panel to examine surgical tissue samples from 36 patients. Their aim was to identify potential biomarkers of progression risk in those who did not achieve pCRs with neoadjuvant nivolumab plus chemotherapy.

At the WCLC, doctoral candidate Marta Casarrubios reported that non-pCR samples had upregulated expression of proliferation and tumor marker genes, including CDK1 and TWIST1, and “seem to have a higher proportion of T follicular helper cells.” High AKT1 expression, dendritic cell activation, and neutrophil infiltration were also associated with an increased risk of disease progression.

Analyzing pretreatment samples from NADIM I too, “interestingly, we found an established [IFNγ] signature in patients who went on to achieve pCRs,” Casarrubios added. “It may be significant; perhaps their tumor microenvironment is already stimulated and better poised to respond to treatment.”

Discussant Linda Martin, MD, of the University of Virginia in Charlottesville, wondered whether mutations in STK11 and IDO1—both linked with ICI resistance—might also influence progression risk. “Another question is how quickly this information can be obtained. Ideally, you'd use it in real time to inform adjuvant therapy,” she said.

Overall, the researchers could have “just celebrated their [pCR] wins with NADIM,” Martin observed. “I applaud them for choosing instead to see where there could be room for improvement, learning more about what drives resistance to neoadjuvant chemo–immunotherapy.” –Alissa Poh

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