NEW YORK – Janssen Pharmaceutical said on Monday its investigational new drug amivantamab demonstrated activity and was well-tolerated in non-small cell lung cancer patients with EGFR exon 20 insertions in a Phase I trial.
CHRYSALIS is a Phase I, open-label trial evaluating the safety, pharmacokinetics, and efficacy of amivantamab as a monotherapy and in combination with lazertinib, a third-generation EGFR tyrosine kinase inhibitor Janssen is developing with Korean pharmaceutical company Yuhan.Â
Cohort D in the CHRYSALIS study evaluated NSCLC patients diagnosed with an EGFR exon 20 insertion, who have progressed on or after standard of care treatment and who have not been previously treated with a drug directly targeting EGFR exon 20 insertions. Out of the 50 NSCLC patients with EGFR exon 20 insertions who received the recommended Phase II dose of amivantamab, 39 were evaluable for response. The overall response rate was 36 percent in all patients, and 41 percent in the 29 patients who received platinum-based chemotherapy previously.
Among the 14 responders, the median duration of response was 10 months for all response-evaluable patients and 7 months for patients who received chemotherapy before. Nine patients reported ongoing responses at the time of data cutoff in October 2019. Median progression-free survival was 8.3 months for all response-evaluable patients and 8.6 months for chemotherapy-treated patients.
In total, 67 percent of all patients reported a clinical benefit on the drug, characterized as a partial response or better, or stable disease for at least 12 weeks. (Partial response is defined in the trial as at least a 30 percent decrease in the sum diameters of target lesions.) In patients treated with chemotherapy, the clinical benefit rate was 72 percent.
Amivantamab is an EGFR-MET bispecific antibody which targets and inhibits activating and resistance-driving mutations in the EGFR and cMET signaling pathways.
"Exon 20 insertion mutations affect the [receptor] binding of the traditional tyrosine kinase inhibitors, including the most recent one, osimertinib. Those drugs can't get in [to cancer cells] and can't block the signaling pathway," said Craig Tendler, VP of oncology clinical development and global medical affairs at Janssen. "When you look at the prognosis of these patients, it's much worse compared to [patients with] the more traditional EGFR exon 19 deletions or L858 resistance mutations that are typically targeted by the frontline EGFR targeted agents."
NSCLC patients with exon 20 insertions have an estimated median overall survival of about 16 months, and there is currently no FDA approved targeted therapy for this patient population. The standard of care is conventional chemotherapy.
Takeda and Spectrum Pharmaceuticals are also developing EGFR exon 20 insertion-targeted drugs. At the American Association for Cancer Research's Virtual Annual Meeting in April, Takeda reported that mobocertinib had a 43 percent response rate in 28 NSCLC patients harboring EGFR exon 20 insertions, with a median progression-free survival of 7.3 months.
During the same meeting, Spectrum reported that poziotinib had a 14.8 percent response rate and a duration of response of 7.4 months in 115 previously treated NSCLC patients with EGFR exon 20 insertions.
According to Janssen, now also vying for a spot in this market, the emerging data are promising for its product. Tendler noted that the early data with amivantamab shows a very favorable safety profile, with mostly grade one or two adverse events reported during the trial and an adverse event-related discontinuation rate of 6 percent.
"Even though the drug is targeting a mutant EGFR receptor, we're not seeing the usual very high incidence and severity of rash and diarrhea that are seen with some of the other EGFR targeted agents. We saw no grade 3 or higher rash events with amivantamab in this cohort and only one grade 3 diarrhea was reported," said Tendler. "At this stage of development, that's very encouraging and suggests that this might be a very differentiated type of treatment to manage this difficult-to-treat patient population with the exon 20 insertion mutation."
The US Food and Drug Administration in March granted amivantamab breakthrough therapy designation for patients with metastatic NSCLC with EGFR exon 20 insertions whose disease has already progressed on platinum-based chemotherapy. "That's the indication we're pursuing with this cohort of patients," said Tendler.
The manageable safety profile could be attributed to the fact that an antibody works differently in this setting versus a small molecule inhibitor, Tendler suggested. Â
"Perhaps we're able to get better specific targeting of these particular resistance mutations. And maybe, it also has to do with the dosing required to shut down signaling from these resistance mutations," Tendler posited. "But this is just a preliminary report on 50 patients … we'll have to see if this [safety] profile is maintained as we treat a larger number of patients."
Janssen is currently enrolling patients in the second part of the dose expansion phase in CHRYSALIS. The trial is also exploring amivantamab's activity in other cohorts, which include NSCLC patients with other types of resistance mutations, like cMET amplifications and MET exon 14 skipping mutations.
The study is also investigating the combination of lazertinib with amivantamab across different NSCLC cohorts.
"Hopefully, we can achieve the best profiles of both drugs in a synergistic combination so they improve outcomes [as a] frontline treatment for patients with EGFR-mutated non-small cell lung cancer," said Tendler. Janssen anticipates filing a new drug application for amivantamab with the FDA in the second half of 2020.