Gillianne G.Y. Lai, MBBS, of the National Cancer Centre, Singapore, discussed the presentations on novel agents for exon 20 insertion mutations in non–small cell lung cancer (NSCLC), which account for about one-third of tyrosine kinase resistance mutations. Although tyrosine kinase mutations are commonly referred to as “rare,” she said, they actually constitute 10% of all EGFR mutations—a frequency similar to that of other oncogenic drivers for which clinicians routinely test. “Hence,” she said, “exon 20 insertions represent an important unmet need.”
Mutant-specific effects of rare EGFR mutations impede their clinical responsiveness to currently available EGFR tyrosine kinase inhibitors. Of the first-, second-, and third-generation EGFR tyrosine kinase inhibitors currently approved, Dr. Lai commented: “Existing evidence suggests that their activity in patients with rare EGFR alterations is modest at best. The question is how we can improve on the treatment of this subset.”
Gillianne G.Y. Lai, MBBS
Novel Agents Under Study in Postplatinum Setting
Two candidates in the postplatinum setting are mobocertinib, a selective EGFR and HER2 inhibitor, and amivantamab, a fully human anti–EGFR-MET–bispecific antibody that blocks these downstream signaling pathways.
In the study presented by Caicun Zhou, MD, mobocertinib led to an overall response rate of 26%, with 82% of patients demonstrating some tumor shrinkage. This activity was, however, offset to some degree by toxicity, she said. “EGFR wild-type–driven toxicity is still a significant issue, with more than 20% of the postplatinum cohort experiencing grade 3 or 4 diarrhea. This is due to the lack of selectivity of mobocertinib upon exon 20 insertions, as compared with EGFR wild-type and other kinases, thus limiting its clinical utility,” she commented.
In the CHRYSALIS study, presented by Joshua K. Sabari, MD, amivantamab led to responses in 40% of patients in the postplatinum setting and a median duration of response of 11.1 months. EGFR exon 20 insertions are “heterogeneous,” with 25 distinct variants; of note, insertions located near exon 19 were associated with better responses in the study, “suggesting the relative distance to exon 19 potentially had a bearing on the depth of response,” Dr. Lai said.
“Although chemotherapy is still regarded as the most suitable front-line strategy for exon 20 insertion mutations, there is growing interest in new targeted agents. Mobocertinib and amivantamab join the list of viable candidates (such as poziotinib and CLN-081) in this evolving space,” she added.
On the Horizon
Dr. Lai said she looks forward to data in the treatment-naive setting and with combination regimens, which may come from several ongoing randomized phase III trials. For instance, EXCLAIM 2 is comparing mobocertinib as a first-line treatment with a platinum-based doublet. The phase III PAPILLON trial is comparing amivantamab with or without pemetrexed/carboplatin chemotherapy.
DISCLOSURE: Dr. Lai disclosed relationships with Amgen, AstraZeneca, BMS, Pfizer, Merck, and Roche. For full disclosures of both Dr. Sabari and Dr. Zhou, see page 26.
