Precision medicine for lung cancer expands to less common therapeutic targets
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New treatments for emerging targets have expanded the armamentarium in lung cancer, according to a speaker at Chemotherapy Foundation Symposium.
“Therapies for less common targets can be highly effective,” Gregory J. Riely, MD, PhD, medical oncologist and vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center, said during a presentation.
Riely focused on agents that target three oncogenic drivers in non-small cell lung cancer: KRASG12C mutations, MET exon 14 alterations and HER2 mutations.
KRAS G12C mutations
Researchers long sought to develop a drug targeting KRAS mutations, which occur in about 13% of patients with NSCLC, according to Riely.
The first KRAS inhibitor to arrive in clinic, sotorasib (Lumakras, Amgen), conferred an objective response of 37.1% in a single-group phase 2 trial. This led to FDA accelerated approval of the agent for patients with KRASG12C-mutant NSCLC who received prior chemotherapy.
The randomized phase 3 CodeBreaK 200 study, which evaluated sotorasib vs. docetaxel among previously treated patients with NSCLC, showed superior PFS with sotorasib (HR = 0.66; 95% CI, 0.51-0.86) but no significant difference in the secondary endpoint of OS.
The most common grade 3 or higher adverse events associated with sotorasib include diarrhea and elevated liver enzymes, which can be managed with dose interruption or dose reduction, Riely said.
Another KRASG12C inhibitor, adagrasib (MRTX849, Mirati Therapeutics), produced a response rate of 43% in a phase 1/phase 2 study and may have activity in patients with brain metastases, he added.
“This is hopefully opening the door to multiple new agents that, hopefully, will have even better efficacy than the ones we’ve seen to date,” Riely said.
MET exon 14 alterations
About 3% to 4% of patients with NSCLC have MET exon 14 alterations, which tend to occur in those who are older, Riely said.
Two FDA-approved agents are available for these patients.
Capmatinib (Tabrecta, Novartis), a selective MET inhibitor, generated response rates of 68% in the first-line setting and a respectable 41% in the second- and third-line setting, he said. Response rates for tepotinib (Tepmetko, Merck/EMD Serono), an oral MET kinase inhibitor, ranged from 40% to 50% in one of the first trials to use liquid biopsy to identify patients with MET exon 14 alterations, he added.
HER2 activating mutations
HER2, or ERBB2, mutations occur in about 2.5% of patients with NSCLC.
Researchers evaluated the HER2-targeted antibody drug conjugate ado-trastuzumab emtansine (Kadcyla, Genentech) in a phase 2 basket trial that showed a response rate of 44% among patients with advanced HER2-mutant NSCLC. The median PFS of 5 months, however, proved disappointing, Riely said.
Fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) has demonstrated greater efficacy for these patients, with an objective response rate of 55%, median PFS of 8.2 months and median OS of 17.8 months. These data led to FDA accelerated approval of the antibody-drug conjugate in August for patients with activating HER2 mutations who received a prior systemic therapy.
“I think the question next is, can this be moved into the first line?” he said. “Ongoing trials are looking to establish that.”
References:
- Jänne PA, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2204619.
- Johnson ML, et al. Ann Oncol. 2022;doi:10.1016/j.annonc/2022.08.051.
- Li BT, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.77.9777.
- Li BT, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2112431.
- Paik PK, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2004407.
- Riely G. New therapies for emerging targets. Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
- Skoulidis F, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2103695.
- Wolf J, et al. J Clin Oncol. 2019;doi:10.1200/JCO.2019.37.15_suppl.9004.
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Riely G. New therapies for emerging targets. Presented at: 40th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 9-11, 2022.
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