Discussant of the exploratory analysis of the POSEIDON trial, Chia Puey Ling, MBBS, MMed, MRCP, FRACP, PhD, a medical oncologist at Tan Tock Seng Hospital, Singapore, noted that although 30% of the mutation-evaluable population had KRAS mutations, only a small percentage of patients had co-mutated tumors of STK11 and KEAP1, and only 1% of patients had triple co-mutated tumors, which is the highest risk group. Dr. Ling also highlighted the poor overall survival for the KRAS-mutated population in comparison to the KRAS wild-type population who were randomly assigned to chemotherapy alone (10.4 months vs 14.4 months).

“Combination therapy with tremelimumab, durvalumab, and chemotherapy appears to result in a survival difference compared with chemotherapy alone in the KRAS wild-type population, which may imply that a more intensified treatment upfront for this group of patients be considered,” said Dr. Ling. 

“It would be very interesting in the trials to come to determine the optimal sequencing of therapy for the KRAS-mutated population,” Dr. Ling continued. “Would it be best to use KRAS inhibitors, for example, in patients with G12C mutations or a combination of chemotherapy with dual immunotherapies, such as the approach taken in the POSEIDON studies?”

Chia Puey Ling, MBBS, MMed, MRCP, FRACP, PhD

With respect to patients with STK11 and KEAP1 mutation status, Dr. Ling noted the lack of benefit for those randomly assigned to durvalumab plus chemotherapy vs chemotherapy alone. According to Dr. Ling, previous studies have shown that lung cancer harboring STK11 mutations is associated with reduced PD-L1 expression and diminished response to immune checkpoint inhibitors.

“This exploratory analysis shows, however, that overall survival is significantly improved with the addition of tremelimumab to durvalumab and chemotherapy, suggesting this combination should be studied and may potentially be a first-line treatment option for the harder-to-treat populations,” Dr. Ling said. “However, these numbers are still very, very small, so we must await larger data sets to draw better conclusions.” 

DISCLOSURE: Dr. Ling reported financial relationships with Amgen, AstraZeneca, Bayer, Merck, Pfizer, and Roche.