Capmatinib shows efficacy in lung cancer subset, including patients with brain metastases
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The investigational MET inhibitor capmatinib appeared effective for treatment of certain patients with metastatic non-small cell lung cancer, including those with brain metastases, according to cohort analyses of the phase 2 GEOMETRY mono-1 study presented at the virtual American Association for Cancer Research Annual Meeting.
Capmatinib (INC280; Novartis, Incyte) induced deep and durable responses among patients with MET exon 14-mutated advanced NSCLC, results showed. It also had a manageable safety profile.
The multicohort, multicenter GEOMETRY mono-1 trial is investigating the efficacy and safety of capmatinib among adults in with ALK-negative and EGFR wild-type, MET exon 14-mutated or MET-amplified stage IIIB or stage IV NSCLC, including patients with neurologically stable or asymptomatic brain metastases.
“The GEOMETRY mono-1 study was designed to thoroughly evaluate the role of capmatinib in patients with abnormalities involving the MET gene,” Edward B. Garon, MD, associate professor of medicine in the division of hematology/oncology at David Geffen School of Medicine at University of California, Los Angeles, said during a presentation.
Cohort 4 of the study included patients who had two or three previous lines of therapy, whereas cohort 5b included treatment-naive patients. Patients in both cohorts received capmatinib dosed at 400 mg twice daily.
Overall response rate as determined by a blinded independent review committee using RECIST version 1.1 served as the study’s primary endpoint. Key secondary endpoints included duration of response, PFS and safety.
Ninety-seven patients, including 69 in cohort 4 (58.3% women) and 28 in cohort 5b (64.3% women), were eligible for evaluation as of April 15. Median age of patients in both cohorts was 71 years.
Patients who had no previous treatment for their disease appeared to have a greater response to capmatinib than those who had previous lines of therapy. Results showed an ORR of 40.6% (95% CI, 28.9-53.1) for cohort 4 and 67.9% (95% CI, 47.6-84.1) for cohort 5b, with median duration of response of 9.72 months (95% CI, 5.55-12.98) vs. 11.14 months (95% CI, 5.55 to not estimable).
Median PFS was 5.42 months (95% CI, 4.17-6.97) in cohort 4 and 9.69 months (95% CI, 5.52-13.86) in cohort 5b.
Thirteen patients in both cohorts had evaluable baseline brain metastases as determined by the blinded independent review committee, with a median 3.3 (range, 1-8) brain lesions per patient.
Neurological assessments based on modified RECIST version 1.1 showed seven of these patients (54%) had an intracranial response to therapy, with four showing complete response for all brain lesions. All but one patient had evidence of intracranial disease control.
The most common treatment-related adverse events across all cohorts in the GEOMETRY mono-1 trial (n = 334) included peripheral edema (41.6%), nausea (33.2%), increased blood creatinine level (19.5%) and vomiting (18.9%). About one-third of adverse events (35.6%) were grade 3 or grade 4, and 21.9% of patients required a dose adjustment due to treatment-related adverse events. No treatment-related deaths occurred.
“In the group of patients with MET exon 14 skipping mutations — a group with typically poor outcomes using standard therapies — clinically meaningful activity has been shown [with] capmatinib,” Garon said. “As might be anticipated by the agent’s potency against MET, results were rapid and deep, leading to an impressive duration of response in both treatment-naive and previously treated patients.”
Garon acknowledged the small size of the treatment-naive cohort in the trial. Nevertheless, the “particularly important results” underline the need for early molecular evaluation of tumors, he said.
Garon concluded by highlighting the significance of the results among patients with brain metastases.
“The preclinical suggestion that efficacy in the central nervous system should be seen clinically is now demonstrated among patients in the GEOMETRY mono-1 trial, and it will be exciting to see further validation of this data,” he said. – by Drew Amorosi
Reference:
Garon EB, et al. Abstract CT082. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: Garon reports financial relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Eli Lilly, EMD Serono, Genentech, Iovance, Merck, Mirati, Neon and Novartis. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Nicholas Rohs, MD
It's great to see data coming out for selective MET inhibitors for MET-altered NSCLC. These data generally ‘tick off’ the boxes of what I am looking for in modern targeted therapies: relatively high ORR with good durability, meaningful CNS penetration and good tolerability. It’s encouraging to see a high response rate in both treatment-naive and pretreated disease. Given the high rate of CNS metastasis in genetically altered NSCLC, it is also critical for us to understand how these medications affect CNS metastasis. Seeing prompt intracranial responses on the same timeline as systemic responses may allow us to spare some patients upfront brain radiation. The adverse event profile seems as expected for this class of medication. This study also highlights the need for practitioners to ensure they are doing comprehensive genetic testing at diagnosis to ensure that patients have access to these therapies. MET is becoming an even more relevant target with its high expression in previously treated EGFR-mutated lung cancers. Ideally, next steps would be to see a head-to-head trial of some of the emerging, selective MET targeted therapies with continued good translational science.
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Taofeek K. Owonikoko, MD, PhD, MSCR
Capmatinib appears to be an effective therapy against MET-driven tumors. However, there appears to be a disparity between those who have been previously treated and those who are treatment-naive.
The reasons for this difference in sensitivity are unclear, but various factors could impact these results. They include poor tolerability of the agent by heavily pretreated patients and possible acquisition of other survival signaling programs that limited the efficacy of capmatinib.
The similar duration of response between cohorts could suggest the differences in ORR may be related to the small sample size of the treatment-naive cohort, which could come down as the sample size gets larger.
Capmatinib also showed highly encouraging signals of efficacy against cranial metastases. Although we do not know the pattern of disease progression, it would be intriguing to see if capmatinib delayed the development of additional brain metastases. This is particularly relevant given the direct implication of capmatinib in the development of brain metastases in patients with lung or breast cancer.
Finally, the limited duration of response at 12 months, especially among treatment-naive patients, highlights the need to better understand the mechanisms of action for this promising agent.
Capmatinib has shown reproducible efficacy and an overall acceptable safety profile; the requirement of a specialized diagnostic platform could be a hindrance for inclusion of its treatment algorithm in the regular care of patients. Future basic and translational research will be needed to determine the mechanism of resistance and inform combinational strategies.
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