Tepotinib Plus Gefitinib Shows Improved PFS Compared With Chemotherapy in EGFR, MET+ NSCLC in INSIGHT Study

Yi-Long Wu, MDS

Yi-Long Wu, MD

Tepotinib combined with gefitinib (Iressa) showed durable antitumor activity in patients withEGFR-mutant non-small cell lung cancer (NSCLC) who were MET IHC3+ or hadMETamplification, according to the 18-month follow-up results of the phase II INSIGHT study.

In this study, the primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. The data presented at the 2019 World Conference on Lung Cancer show that the overall population of patients who received tepotinib plus gefitinib had a median PFS of 4.9 months compared with 4.4 months for chemotherapy.

Among patients with MET IHC3+ specifically, the median PFS was 8.3 months versus 4.4 months for chemotherapy. Finally, patients withMETamplification had the longest median PFS at 21.2 months compared with 4.2 months with chemotherapy.

Investigators also found that one of the secondary endpoints, ORR, was superior with tepotinib plus gefitinib versus chemotherapy. In the overall population, the ORR was 45.2% with the combination versus 33.3% for chemotherapy. The MET IHC3+ patients had an ORR of 68.4% compared with 33.3% with chemotherapy. Patients withMETamplification showed an ORR of 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy.

The data also showed that patients who received tepotinib plus gefitinib had better OS rates in all arms compared with chemotherapy. The highest median OS with the combination was seen in patients withMETamplification (37.3 vs 13.1 months).

For the final secondary endpoint, safety, the median range of treatment duration was 21.4 months for patients who received tepotinib plus gefitinib and 18 months for those who received chemotherapy. There was a total of 4 patients who discontinued treatment due to adverse events (AEs), and 6 patients whose dosage was reduced due to AEs. No patients in either group died as a result of AEs.

Based on the results, the investigators concluded that the combination of tepotinib and gefitinib improved PFS and OS more than chemotherapy, with a hazard ratio for PFS of 0.13 (90% CI, 0.04-0.43) and a hazard ratio for OS of 0.09 (90% CI, 0.01-0.54). There was also a higher ORR with tepotinib plus gefitinib than with chemotherapy.

The phase II INSIGHT study is currently ongoing with 70 participants, 3 of whom are reported to still be receiving treatment with tepotinib and gefitinib ≥27 months.

In an interview withTargeted Oncology, Yi-Long Wu, MD, tenured professor, Guangdong Lung Cancer Institute, and chair of the Chinese Thoracic Oncology Group, Guangdong General Hospital discusses the results of the INSIGHT study and other agents and combinations for the treatment of patients withEGFR-mutant NSCLC.

TARGETED ONCOLOGY:How common is bothEGFRmutation andMETdysregulation in a patient with NSCLC? Is MET dysregulation in anEGFR-mutant patient only a result of acquired resistance to an EGFR inhibitor?

Wu: The EGFR pathway is very important in the East-Asian population. In Eastern Asia, about 40% of the patients with NSCLC areEGFRmutant. With treatment from an EGFR inhibitor, patients have a good response rate, and now the OS is almost 24 to 36 months. Yet most patients develop a resistance to an EGFR inhibitor. Among them, about 24% of patients develop aMETamplification. I think this resistance mechanism is very important.

TARGETED ONCOLOGY:What responses do patients withMETalterations have to tepotinib? Why is it being considered in combination with gefitinib?

Wu: Because of resistance to EGFR tyrosine kinase inhibitors (TKIs), we wanted to see if there is activity with this combination inEGFR-mutant NSCLC and in the MET pathway. Based on this, we have developed the combination with EGFR TKIs plus MET inhibitors.

In this study, when a developed resistance, we would continue using the gefitinib—this is the EGFR TKI in the first line. Then we added in the tepotinib to further treat the patient, or chemotherapy. Now, we have a very good result. We followed the patients for almost 18 months and now, at this meeting, we are proud to release the long-term results of the follow-up of 18 months.

TARGETED ONCOLOGY:What were the results of this study and what are next steps with this research?

Wu: We are reporting the results for theMEToverexpression, especially for those with MET IHC3. It was a good result. The PFS and OS were longer, especially the OS, which was almost 34.7 months in patients withMETIHC3 overexpression andMETamplification population. But, for the chemotherapy arm there’s only 17.9 months. This means that tepotinib plus the gefitinib improved the response rate, PFS, and OS.

I think this may be an indication that in the near future, this combination will become the standard treatment for EGFR TKI resistance in patients withcMETamplification.

TARGETED ONCOLOGY: What other combinations do you believe could be beneficial for treatment of patients withEGFR-mutated,MET-positive NSCLC?

Wu: Because cMET is an important pathway, if we are done with the first generation, the second generation will be better, [like with EGFR TKIs, where the third-generation osimertinib (Tagrisso) is also very important in terms of the resistance mutations]. This is important to theMETamplification mechanism of resistance.

We have developed another clinical trial with osimertinib, a third-generation TKI, plus a cMET inhibitor to overcome the osimertinib resistance. I think this is also interesting and important.

TARGETED ONCOLOGY: What real-world data has been seen with tepotinib treatment for patients with uncommonEGFRmutations?

Wu: Tepotinib is a cMET inhibitor. There are 2 forms ofMETdysregulation; one form is the exon 14 skipping mutation. And tepotinib also works well on uncommonEGFRmutations. Recently, the data reported show a very good response rate and PFS. The response rate in these patients is over 60% and PFS is longer than with other agents. I think that in the near future, tepotinib will be the best tool for uncommonEGFRmutations andMEToverexpression/amplification.

TARGETED ONCOLOGY: What final responses were seen in the study of frontline afatinib (Gilotrif) inEGFR-mutant NSCLC?

Wu: For afatinib, the second-generation EGFR TKI, in the front line we have 2 clinical trials, one is the LUX-Lung 3 and the other is the LUX-Lung 6. In terms of frontline treatment, the clinical trial results show that afatinib is superior to chemotherapy. The afatinib response rate was more than 75% and the PFS was 10 to 11 months.

Also, the overall survival for the exon 19 patients was better than with chemotherapy. I think that afatinib has good results in the frontline treatment setting for patients withEGFR-mutant NSCLC.

Editor’s note: This transcript was edited for clarity.

Reference:

Wu YL, Cheng Y, Zhou J, et al. Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with EGFR-Mutant NSCLC and MET Dysregulation: 18 Month Follow-Up. Presented in: Proceedings of the 2019 World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract 1783.