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AACR 2018: PD-1 drugs in lung cancer: Early, earlier, earliest

By Brian Orelli, Staff Writer

CHICAGO – PD-1 drugs in lung cancer took over the second day of the American Association for Cancer Research Annual Meeting 2018 with a trio of presentations of clinical trials in patients with non-small-cell lung cancer (NSCLC), which were all concurrently published in The New England Journal of Medicine.

Merck & Co. Inc., of Kenilworth, N.J., presented data from the 616-patient phase III Keynote 189 trial testing Keytruda (pembrolizumab) plus pemetrexed and a platinum-based chemotherapy in first-line nonsquamous NSCLC.

Patients who received pemetrexed and a platinum-based chemotherapy alone lived for a median of 11.3 months. The median overall survival (OS) was not reached in patients who were also treated with Keytruda; the last six months of the 21-month Kaplan-Meier curve shows OS flatlining north of 60 percent survival, but researchers were still able to derive a hazard ratio of 0.49 in favor of Keytruda.

The OS data are especially impressive given that 50 percent of patients in the placebo arm crossed over, suggesting that early treatment is more effective.

Expression of PD-L1 didn’t seem to have an effect on whether Keytruda improved overall survival. Patients with a PD-L1 tumor proportion score (TPS) of less than 1 percent had a hazard ratio of 0.59, compared to 0.55 for patients with TPS from 1 percent to 49 percent and 0.42 for patients with TPS of 50 percent or more.

Leena Gandhi, director of thoracic medical oncology at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, hypothesized that the chemotherapy could be inducing an immune response. “I think there’s more work that needs to be done about the specifics of what’s really happening,” she explained at a press conference before the presentation.

Keytruda also produced a higher objective response (ORR) rate of 47.6 percent compared to 18.9 percent for placebo. The median progression-free survival (PFS) was also higher at 8.8 months for patients taking Keytruda, compared to 4.9 months for the control arm, producing a hazard ratio of 0.52.

Mutations = no chemo?

Following up on Checkmate 568, which showed an increase in objective response rate in patients with higher tumor mutational burden (TMB) that plateaued at 10 or more mutations/Mb, New York-based Bristol-Myers Squibb Co. added a co-primary endpoint to the phase III Checkmate 227 trial, testing Opdivo (nivolumab) plus Yervoy (ipilimumab) compared to standard-of-care chemotherapy in 299 patients with advanced NSCLC with high tumor mutational burden in the first-line setting.

About 44 percent of NSCLC patients have high TMB. While TMB testing isn’t widely performed, Matthew Hellmann, a medical oncologist at the Memorial Sloan Kettering Cancer Center Hospital, said it isn’t a wholly new concept. “TMB is like a readout of data that we’re already getting routinely” by sequencing other genes to determine the mutation status of tumors and pick the appropriate drug, he explained. “I think it’s important to think of TMB as another reason to do routine next-generation sequencing.”

The nivolumab-ipilimumab combo improved PFS, producing a median PFS of 7.2 months, compared to 5.4 months in patients treated with chemotherapy. The data look even more impressive as the trial continued, with 43 percent of patients with the combination therapy having PFS at one year, compared to just 13 percent of those on chemotherapy, resulting in a hazard ratio of 0.58.

The response rate was also improved, with 45.3 percent of patients who received nivolumab plus ipilimumab experiencing an ORR, compared to 26.9 percent of those who received chemotherapy.

Overall survival data from the trial are still maturing.