Tepotinib/Osimertinib Combo Induces ORR Benefit in EGFR-mutated NSCLC

Tepotinib (Tepmetko) plus osimertinib (Tagrisso) is a promising combination in patients with osimertinib-pretreated, EGFR-mutated, MET amplified non­–small cell lung cancer (NSCLC), according to Julien Maziéres, MD, PhD. He emphasized that further research with MET amplification should be conducted to determine whether this biomarker is predictive of clinical benefit in certain subsets of patients.

The phase 2 INSIGHT 2 trial (NCT03940703), which evaluated tepotinib plus osimertinib in this population, revealed that the combination elicited an overall response rate (ORR) of 45.8% (95% CI, 31.4%-60.8%) in patients with MET amplification detected through fluorescence in situ hybridization (FISH) who had at least 3 months of follow-up (n = 48) and an ORR of 54.5% (95% CI, 32.2%-75.6%) in those who had at least 9 months of follow-up (n = 22). The ORR was 8.3% (95% CI, 0.2%-38.5%) in patients with MET amplification detected through FISH who received tepotinib alone and had at least 6 months of follow-up (n = 12).

Investigators also observed favorable responses with the combination in patients with MET amplification detected through next-generation sequencing, with ORRs of 56.5% (95% CI, 34.5%-76.8%) at 3 or more months of follow-up (n = 23) and 50.0% (95% CI, 24.7%-75.3%) at 9 or more months of follow-up (n = 16). Maziéres presented findings from this study at the 2022 ESMO Congress.¹

“It’s important to monitor the mechanism of resistance through either a tissue biopsy, which is a standard of care, or liquid biopsy to identify MET amplification and to propose to the patient new combinations of targeted drugs,” Maziéres said in an interview with OncLive^®.

He explained the importance of defining a second-line standard of care in the EGFR-mutated NSCLC population, highlighted the long-term benefits seen with tepotinib plus osimertinib, and previewed the next steps that should be taken toward more individualized patient care. Maziéres is a professor of medicine at University Hospital and a researcher at the Claudius Regaud Institute in Toulouse, France.

OncLive^®: What was the rationale for the INSIGHT 2 trial?

Maziéres: Patients with EGFR mutations will eventually display resistance, and 15% to 30% of this resistance relies on MET amplification. For those patients, we don’t have a standard of care, we don’t know if we should treat them with targeted therapy or chemotherapy.

The aim of INSIGHT 2 was to assess the combination of tepotinib, a MET inhibitor, plus osimertinib, an EGFR inhibitor, in the context of MET amplification, in patients who were treated with first line osimertinib.

What were some of the baseline characteristics of the patient population that was enrolled in the trial?

The patient population was [what one would] expect. It [consisted of] patients with EGFR mutations, with a median age of 60 years. The majority of patients were female, from Asia, and never smokers. What was also interesting in our population was that 27% of the patients enrolled presented with brain metastases at the time of enrollment.

What methods were used in this study?

This was a 2-arm, open-label study. The first arm studied tepotinib as a single agent in 12 patients. The most important arm studied a combination of tepotinib and osimertinib.

The main inclusion criteria were patients with EGFR mutations treated in the first line with osimertinib. Patients needed to be in good shape, [with an ECOG] performance status of 0 or 1. Brain metastases were allowed.

What results did you share at ESMO?

The main results of the study pertained to efficacy and safety. The primary objective of this study was ORR based on the identification of MET amplification through a tissue biopsy, using a FISH assay. [In total,] 48 patients had a follow-up of 3 months or more, and 22 patients had a follow-up of 9 months [or more].

In the population of patients with the longer follow-up, the response rate was 54.5%. These results are quite good. Looking at the other cohort, patients with a shorter follow-up, [the response rate was similar]. In patients in whom the diagnosis was performed through liquid biopsy and not through tissue biopsy, the response rates were almost the same [as those in patients who underwent tissue biopsy], ranging from 50% to 56.5%.

In the tepotinib monotherapy arm, 12 patients were enrolled, with only 1 response reported. There was an 8.3% response rate, which is really low. This highlights the need for these patients to [receive] a combination and not a MET inhibitor alone.

What next steps are you hoping to take with this combination?

These are preliminary results. We need longer follow-up to confirm these promising results regarding both efficacy and safety, as the safety of this combination was quite good, similar to what we observed with either drug alone.

Other clinical trials are ongoing with other MET inhibitors. We need to compare the results to determine the best combination.

Another important perspective is to identify the patients who will benefit most from [tepotinib plus osimertinib]. Using the biomarker, if we look at the level of MET amplification in our study, we do not see any [corresponding] effect on patient response. That means patients benefit from the [combination] regardless of their level of MET amplification. This benefit was the same regardless of the type of diagnosis, either liquid biopsy or tissue biopsy. We need to go into more details with the biomarker to see if we can identify some subgroup of patients [who will benefit more from the combination].

Additionally, we observed good responses in patients with brain metastases. We should specifically study this population to see if there is any intracranial activity to confirm that the drug [has systemic and intracranial activity].

What key takeaway from your presentation would you like to impart to colleagues?

It’s important to screen patients and to monitor the molecular biology of patients with EGFR mutations, because at the time of recurrence, in patients treated with osimertinib, we can identify some mechanism of resistance that can lead to other targeted therapy. That means we can spare patients chemotherapy.

What other abstracts or studies were you excited to hear come out of the ESMO Congress?

This meeting was important for lung cancer. In lung cancer, we have 2 main novelties, immunotherapy and targeted therapy. We saw many updates from clinical trials concerning the efficacy of immunotherapy in both lung cancer and mesothelioma.

However, the most important [advances] are in the field of targeted therapy, with what we reported in [EGFR mutations in INSIGHT 2], but also with other clinical trials regarding patients with EGFR mutations. The phase 3 CodeBreak 200 study [NCT04303780] confirmed that sotorasib [Lumakras], a specific KRAS G12C inhibitor, was superior to docetaxel chemotherapy in pretreated patients. That means that for 12% to 15% of our patients, we now have a new drug available.

Reference

Mazieres J, Kim TM, Lim BK, et al. Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study. Ann Oncol. 2022;33(suppl 7):S1419-S1420. doi:10.1016/j.annonc.2022.08.054