Combination Immune Checkpoint Blockade Promising in Operable NSCLC

The addition of ipilimumab (anti-CTLA4) to nivolumab (anti–PD-1) has been shown to improve outcomes in some patients with metastatic non–small cell lung cancer (NSCLC), but the efficacy of this combination in resectable NSCLC—in which the rate of recurrence after surgery with curative intent is more than 50%—is not known. To test this, Cascone and colleagues initiated a randomized, phase II clinical trial of neoadjuvant nivolumab or nivolumab plus ipilimumab in 44 patients with resectable NSCLC, with 23 patients being randomized to receive nivolumab alone and 21 patients being randomized to receive the combination treatment followed by surgery, and using major pathologic response (MPR) as primary endpoint, defined as having ≤ 10% of tumor cells from resected tumors being viable as determined histopathologically. (Due to its previously reported positive association with survival outcomes, MPR is being investigated as a surrogate endpoint in operable NSCLC.). Thirty-seven patients (21 in the monotherapy group and 16 in the combination therapy group) ultimately received on-trial surgery (two additional patients underwent surgery off trial after other therapies); the seven patients who did not undergo surgery on trial were considered to have no MPR in the intention-to-treat (ITT) analysis. Patients could also receive additional treatments postoperatively: Of those who underwent surgery on trial, postoperative chemotherapy or radiotherapy was given to 17 patients (46%) or 4 patients (11%), respectively. Among the 44 patients included in the ITT analysis, 22% (5/23 patients) of those who received nivolumab alone and 38% (8/21 patients) of those who received the combination treatment had an MPR. Additionally, an analysis of only the 37 patients whose tumors were resected on trial showed that the MPR rate was 24% (5/21 patients) in the nivolumab arm and 50% (8/16 patients) in the nivolumab plus ipilimumab arm. Interestingly, an exploratory investigation of possible interactions between gut microbiota and response revealed that response to the combination treatment was associated with higher levels of gut Ruminococcus and Akkermansia species. The investigators also found higher levels of immune cell infiltration in tumors treated with combination therapy. In summary, these results suggest that the combination of nivolumab plus ipilimumab may be promising in the neoadjuvant setting in NSCLC.

Cascone T, William Jr WN, Weissferdt A, Leung CH, Lin HY, Pataer A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Med 2021;27:504–14.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.