Sequist Sheds Light on Osimertinib/Savolitinib Combo in MET-Amplified NSCLC

Lecia V. Sequist, MD

The combination of osimertinib (Tagrisso) and savolitinib led to early responses with no significant toxicities in patients with EGFR-positive non—small cell lung cancer (NSCLC) who developed MET-driven resistance, demonstrating that the regimen is efficacious in a biomarker-driven population, said Lecia V. Sequist, MD.

Interim findings from 2 expansion cohorts of the phase Ib TATTON study were presented at the 2019 AACR Annual Meeting. The 2 cohorts consisted of patients with EGFR-mutant NSCLC with acquired MET amplification following first- or second-generation EGFR inhibition, and heavily pretreated patients with EGFR-mutant disease with acquired MET amplification following osimertinib or an investigational third-generation EGFR TKI.

The first cohort was comprised of 46 patients who were given osimertinib at 80 mg once daily and daily savolitinib at 600 mg. Results showed an overall response rate (ORR) of 52%—all of which were partial responses.¹ Furthermore, the median duration of response was 7.1 months with the combination of the third-generation EGFR TKI and MET inhibitor.

The second cohort, comprised of 48 patients who progressed on osimertinib or a third-generation EGFR TKI, were given the same regimen. Treatment with the combination resulted in an ORR of 25% with 12 patients achieving a partial response.² The median duration of response was 9.7 months.

In patients with oncogene-driven NSCLC, the importance of performing repeat biopsies is especially important, said Sequist, a thoracic medical oncologist and director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center, especially if resistance to targeted therapies is acquired.

“When a patient responds to targeted therapy but then begins to progress through it, this is the perfect time for another biopsy,” she said. “This is one of the things that could be tested for small cell lung cancer transformation. There will be more targets to come.”

OncLive: How would you define the history of EGFR-targeted therapy in EGFR-positive NSCLC?

Could you expand on the role of MET amplification in resistance to EGFR therapy?

What was the rationale for this particular combination in the TATTON trial?

In an interview with OncLive, Sequist highlighted the expansion cohort data from the TATTON study and explained how these findings could impact the treatment landscape of EGFR-mutant NSCLC.Sequist: EGFR mutations were discovered about 15 years ago; this was the first example that we had in NSCLC of testing a patient, finding a mutation, and treating them with a corresponding targeted therapy. Over the past 15 years, we acquired 5 FDA-approved EGFR TKIs. There have been many clinical trials looking to refine which ones we use and the specific indications. The current standard of care is to receive osimertinib, a third-generation EGFR TKI, as first-line treatment.Along with the development of EGFR inhibitors, we have also expanded our understanding of what drives resistance to these drugs. Thanks to previous studies and many biopsies of patients, we have a better picture of what causes resistance. The main player—especially with the newer-generation EGFR TKIs—is MET amplification. We know that MET amplification can come up as a bypass pathway and cause resistance to EGFR inhibitors. From preclinical models, we know the best way to target this resistance may be to combine an EGFR inhibitor and a MET inhibitor. It looks like either drug alone would not be sufficient, but when you have a combination, you can attack this resistance pathway.The TATTON clinical trial looks at patients with EGFR-mutant NSCLC who have MET as an acquired resistance mechanism. In this trial, investigators treated these patients with osimertinib and the MET inhibitor savolitinib. The preclinical work that looked at MET as a resistance pathway suggested that both of those components together would be necessary in order for the treatment to be effective.

What was the goal and design of the TATTON trial?

What were the key takeaways from the expansion cohorts?

Could you expand on the toxicity observed with this combination?

What are the clinical implications of these early data?

There have been prior trials looking at this type of combination, but, unfortunately, those trials were not done in a biomarker-selected patient population. This is the first clinical trial using these two drugs in a patient group with that biomarker signature. It's exciting to see this concept work when you apply this approach to selected patients.TATTON was a phase I study and there were many different components to it—looking at different combinations of drugs. The part that I presented was of osimertinib and savolitinib. This combination was first tested in a first-in-human way. What we presented at this meeting were data from some of the expansion cohorts. Once the dose was established, the baseline safety was established, and a larger population of patients were tested in these expansion arms. One arm was comprised of EGFR-mutant patients who had developed MET-driven resistance with a first- or second-generation TKI. The second group was a more heavily pretreated population who developed resistance on third-generation TKIs.Osimertinib plus savolitinib had activity in both of these cohorts. In the cohort where the patients who had received only a first- or second-generation TKI, we saw response rates of about 52%, with a median duration of response of about 7 months. In the other cohort, we saw response rates of about 25%, with another quite long duration of response of 9.7 months. Therefore, in both cohorts we see that the treatment designed around these biomarker signatures is generating some nice responses, with only a little bit of added toxicity to what we usually see with osimertinib alone.The toxicity of two drugs together is usually more than what you'd expect with one drug by itself; that's what we saw in TATTON. Osimertinib is fairly familiar to many oncologists; it's been FDA approved for a few years now. When we added savolitinib, we certainly added more toxicity but not to an unmanageable level. It tended to be an addition of mild gastrointestinal toxicities.There are several clinical implications of this research. One is this proof-of-principle that the combination works in this biomarker-driven population. This needs to be confirmed in larger phase II trials, and these have been planned: one is called SAVANNAH and the other is called ORCHARD.

Importantly, another take-home point for clinicians is that we still need to think about doing repeat biopsies. We have been trying to emphasize that repeat biopsies can indicate additional modalities needed for treatment.

References

1. Yu H, Ahn M-J, Kim S-W, et al. TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT032.
2. Sequist LV, Lee JS, Jan, J-Y, et al. TATTON phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT033.