New Targeted Therapies Show Promise for METex14-Altered NSCLC

Karen L. Reckamp, MD

Two highly selective MET inhibitors, tepotinib and capmatinib (INC280), showed promising clinical activity in the first- and second-line treatment of patients with MET exon 14 (METex14)-altered advanced non—small cell lung cancer (NSCLC), according to presentations at the 2019 ASCO Annual Meeting.^1,2

In the phase II GEOMETRY study,¹ capmatinib showed an objective response rate (ORR) by independent review (IR) of 67.9% (95% CI, 47.6%-84.1%) in treatment-naive patients with METex14-altered NSCLC. Additionally, in the phase II VISION study,² the ORR by IR with tepotinib was 58.8% in untreated patients with NSCLC and an METex14 alteration determined by liquid biopsy.

“These are small cohorts of patients; the numbers of frontline patients are relatively small. When trying to parse down some of these data, we do see that response rates are high and are promising,” said ASCO invited discussant Karen L. Reckamp, MD, from City of Hope Comprehensive Cancer Center. “We did see in the second-line setting that responses drop off, which might be due to age and comorbidities. But the numbers are small in the first-line setting. Overall, we need more data.”

MET exon 14 skipping mutations have been identified in approximately 3% to 4% of NSCLC cases and are associated with a poor response to currently available therapies. Prior studies exploring MET inhibition have primarily examined multikinase inhibitors, such as crizotinib and cabozantinib. Both capmatinib and tepotinib, however, are more selective for MET, with IC50 measures of 0.6 nM and 3.0 nM, respectively, as compared with 7.8 nM and 22.5 nM, respectively, for cabozantinib and crizotinib.

Capmatinib in GEOMETRY

The GEOMETRY trial is examining capmatinib across several cohorts, with cohort 4 and 5b selected for presentation at ASCO. Cohort 4 contained pretreated patients with METex14 alterations in the second- or third-line setting (n = 69) while cohort 5b included treatment-naive patients (n = 28). The median age across both cohorts was 71 years, and approximately three-fourths had an ECOG status of 1. In cohort 4, 15.9% of patients had brain metastases compared with 10.7% in cohort 5b. The most common prior therapy used was platinum-based chemotherapy (88.4%).

In pretreated patients, the ORR by IR was 40.6% (95% CI, 28.9%-53.1%). The disease control rate (DCR; ORR plus stable disease) was 78.3% (95% CI, 66.7%-87.3%). In the frontline setting, the ORR by IR was 67.9% (95% CI, 47.6%-84.1%) and the DCR was 96.4% (95% CI, 81.7%-99.9%). “Deep responses were observed in a majority of patients across both cohorts,” lead investigator Juergen Wolf, MD, from the Center for Integrated Oncology, University Hospital Cologne, said during a presentation of the findings at ASCO.

The median duration of response (DOR) by IR was 9.72 months in pretreated patients and 11.14 months in those receiving capmatinib in the frontline setting. The median progression-free survival was 5.42 months in the pretreated group and 9.69 months for those treated in the frontline setting.

“Capmatinib is a potent and selective MET Inhibitor that represents a new potential treatment option in this rare but challenging patient population of advanced NSCLC harboring METexl4 mutations,” Wolf said. “Capmatinib has demonstrated clinically meaningful efficacy in advanced NSCLC patients harboring METex14 mutations, and also demonstrated efficacy in patients with brain metastases.”

Approximately half of the patients with brain metastases at baseline experienced an intracranial response with capmatinib (7 of 13; 54%). Of these patients, 4 had a complete resolution of brain lesions (31%). The intracranial DCR was 92.3% (12 of 13).

“Deep responses and duration of response were observed independently of type of MET mutation leading to METex14 or co-occurrence of MET amplification,” said Wolf. “There was high concordance between next generation sequencing [NGS] and RT-PCR in detection of METex14 in tumor tissue.”

Safety was assessed across all cohorts examined in the study, which each included patients with MET dysregulated NSCLC (N = 334). Grade 3 treatment-related adverse events (AEs) occurred in 31.1% of patients and a grade 4 event was seen in 4.5% of patients. Peripheral edema was the most common grade 3/4 event (7.5%) followed by fatigue (3.0%). The most common treatment-related AE of any grade was peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%).

Tepotinib in VISION

The VISION study consisted of 2 cohorts: cohort A enrolled patients with METex14 skipping mutations and cohort B included those with MET amplification. In both groups, tepotinib was administered at 500 mg once daily in a 21-day cycle. In cohort A, 87 patients were enrolled and treated, with METex14 determined using liquid (n = 57) and tumor biopsy (n = 58).

The median age of patients was 74 years, and the most common ECOG status was 1 (74.7%). Brain metastases were present in 9.2% of patients. Overall, 33 patients were treatment-naive, and 54 were treated in the second-line or beyond.

Across all lines of treatment, the ORR by IR in liquid biopsy-identified METex14-positive tumors was 50%. The median DOR was 12.4 months and the DCR was 66.7%. For those identified by tissue biopsy, the ORR was 45.1% and the median DOR was 15.7 months with a DCR of 72.5%.

By line of therapy, the ORR by IR was 58.8% in the first-line and 53.3% in the second-line in the liquid biopsy-identified patients. In the second-line and beyond, the ORR by IR was 45.2%. For those with tissue biopsy assessed tumors, the ORR by IR was 44.4% and 50%, in the first- and second-line, respectively. In the second-line or greater, the ORR by IR was 45.5%.

“Tepotinib has shown durable clinical activity in patients with NSCLC harboring METex14 mutations, detected by liquid biopsy or tissue biopsy,” said lead investigator Paul K. Paik, MD, from the Memorial Sloan Kettering Cancer Center. “Promising and consistent activity was observed across treatment lines, and patients with brain metastases at baseline benefitted equally from treatment.”

Across all treatment lines, median PFS was 9.5 months by IR in liquid biopsy assessed tumors and was 10.8 months in tumor biopsy-identified tumors. The median duration of response across arms was 14.3 months.

There were no grade 4 or 5 treatment-related AEs with 500 mg tepotinib. The most common treatment-related AEs were peripheral edema (48.3%), nausea (23.0%), diarrhea (20.7%), and blood creatinine increase (12.6%), although there were no signs of kidney impairment, Paik noted. The only commonly occurring grade 3 treatment-related AE was peripheral edema, which occurred in 8% of patients.

Future Developments

The FDA has granted designations to help speed up the development of both agents, based on the early promise. Capmatinib has received an orphan drug designation and a breakthrough therapy designation for METex14 skipping mutation positive metastatic NSCLC following platinum-based chemotherapy. Tepotinib holds a fast track designation for advanced METex14-mutated NSCLC.

As these therapies move toward the clinic, it emphasizes the need to make NGS a standard of care for patients with NSCLC, Reckamp noted. “If patients aren't being tested for these alterations, then they aren't being treated,” she said. “We're at the frontier of liquid biopsies. They're here, and they're here to stay. Upfront NGS testing is actually more cost effective than sequential testing, exclusionary testing, and hot spot panel testing.”

References

1. Wolf J, Setons T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019;37 (suppl; abstr 9004).
2. Pain PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol. 2019;37 (suppl; abstr 9005).

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