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Researchers identify mutations associated with treatment sensitivity, resistance in NSCLC
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BARCELONA — STK11 and KEAP1 mutations appeared associated with poorer outcomes among patients with metastatic non-small cell lung cancer regardless of treatment with chemotherapy or immunotherapy, according to results of an exploratory analysis of the phase 3 MYSTIC trial presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
Researchers also found that ARID1A mutations predicted OS benefit among patients who received durvalumab (Imfinzi, Medimmune/AstraZeneca) and tremelimumab (CP-675,206, AstraZeneca).
“MYSTIC was a phase 3 trial comparing durvalumab monotherapy or durvalumab-tremelimumab vs. chemotherapy, and when we analyzed a subset of patients with high tumor mutational burden, we found a significant improvement in response, PFS and OS,” Naiyer A. Rizvi, MD, Price family professor of medicine, director of thoracic oncology and co-director of cancer immunotherapy at Columbia University Irving Medical Center, as well as research director of the Price Family Comprehensive Center for Chest Care at New York-Presbyterian Hospital, said during a press conference. “As part of our exploratory analysis, we looked at specific mutations that have been implicated in sensitivity and resistance to chemotherapy, [and which have been implicated as] prognostic factors.”
These mutations included those in tumor suppressor genes STK11, KEAP1 and ARID1A, which researchers assessed in baseline plasma samples from 1,003 patients, representing 89.7% of the intention-to-treat population. Researchers used the GuardantOMNI platform (Guardant Health), comprised of a 500-gene panel, to assess circulating tumor DNA in the samples.
“STK11 and KEAP1 mutations are relatively common, the third and fourth most common mutations in lung cancer, and they do influence outcomes,” Rizvi said. “ARID1A mutations occur in about 10% of the population.”
Results showed 170 patients had mutated KEAP1, 147 had mutated STK11, and 114 had mutated ARID1A.
In an analysis that looked at all treatment arms of the trial, researchers observed shorter OS among patients with mutated KEAP1 (median OS, 7.4 months vs. 12.9 months; HR = 1.64; 95% CI, 1.37-1.97) or STK11 (median OS, 6.8 months vs. 12.6 months; HR = 1.52; 95% CI, 1.25-1.85) compared with patients with the wild-type version of these genes. Conversely, patients with mutated ARID1A had longer OS, but this did not reach statistical significance (median OS, 12.6 months vs. 11.4 months; HR = 0.94; 95% CI, 0.74-1.17).
Among all patients, researchers observed lower overall response rates among those with mutated KEAP1 (17.6% vs. 27.7%) and STK11 (16.3% vs. 27.6%) compared with patients with wild-type mutations, with a better ORR observed among those with mutated vs. wild-type ARID1A (35.1% vs. 24.6%). These trends persisted whether patients received chemotherapy or durvalumab monotherapy.
In the cohort of patients treated with durvalumab-tremelimumab, ARID1A mutations predicted for a much higher ORR, at 51.3%, compared with 19.4% among those with wild-type ARID1A.
“Intriguingly, the patients with KEAP1 and STK11 mutations also appeared to do a little bit better in terms of response rate with the combination vs. with chemotherapy, but the numbers are small,” Rizvi said.
For that treatment group, ORR was 20.6% for patients with mutated KEAP1 and 21.6% for mutated STK11.
When researchers looked at the KEAP1-mutated vs. wild-type cohorts, they did not observe significant differences in OS between patients who received durvalumab vs. chemotherapy or durvalumab-tremelimumab vs. chemotherapy.
Among STK11-mutated patients, OS appeared to benefit those who received durvalumab alone (HR = 0.64; 95% CI, 0.41-1) or with tremelimumab (HR = 0.76; 95% CI, 0.48-1.21) compared with chemotherapy.
“There was a tail on the curve, which suggests a possible effect with immunotherapy in these patients, but when one looks at the OS, they still tended to be fairly poor,” Rizvi said.
Patients with mutated ARID1A showed the most dramatic improvement with durvalumab-tremelimumab vs. chemotherapy, with a median OS of 23.2 months vs. 10.6 months (HR = 0.42; 95% CI, 0.24-0.76).
“These exploratory analyses provide insights into the potential impact of specific mutations on response to immunotherapy,” Rizvi said. – by Alexandra Todak
Reference:
Rizvi NA, et al. Abstract OA04.07. Presented at: Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Rizvi reports advisory board roles with or research funding or honoraria from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Merck, NeoGenomics, Novartis, Pfizer and Regeneron. He also reports stock ownership in ARMO, Bellicum Pharmaceuticals and Gritstone Oncology.