Discussion
NSCLC, PD, toxicity
DISEASE, SOLID TUMORS, NSCLC
In this phase I clinical trial, we found that OMO-1 had an acceptable long-term safety profile at 250 mg BID. PD analysis of a paired biopsy of a patient with METex14 mutated NSCLC showed near-complete inhibition of phosphorylated MET. Moreover, we observed modest clinical efficacy of OMO-1 in patients with METex14 mutated NSCLC. The development of more highly selective MET inhibitors is crucial for optimal treatment of MET exon 14 skipping mutation-positive NSCLC patients.In the dose-escalation cohorts, OMO-1 was tolerated in the majority of the patients on the lower dose-levels (100, 200, and 250 mg BID). As discussed in the dose-escalation results section, 400 mg BID and 350 mg BID were deemed not suitable for long-term dosing. The safety profile of OMO-1 is mostly comparable to other MET TKIs, but more patients on OMO-1 had to discontinue treatment due to toxicity than with capmatinib and tepotinib (also in the lower dose cohorts).As theorized, the mean plasma tryptophan level increased 8 h after OMO-1 administration and the mean kynurenin/tryptophan ratio decreased. This supports the hypothesis that OMO-1 inhibits the active secretion of tryptophan through OCT-2. In some patients, tryptophan levels decreased which could be due to low drug exposure, but we could not confirm this. As tryptophan is an amino acid present in most protein-based foods, food intake could be a confounding factor. Validation of these results in a larger cohort with dietary monitoring would be needed to confirm this hypothesis.Following the dose-escalation part, the efficacy of OMO-1 was investigated in selected expansion cohorts; METex14 mutated NSCLC, other MET amplified, or MET mutated solid tumors (basket cohort). In METex14 mutated NSCLC, OMO-1 showed modest efficacy as almost all patients had stable disease as best response and no partial response (RECIST v.1.1) was recorded. One of the reasons for this low response rate could be the prior therapy status of the patients. Most patients had received prior anti-cancer therapy, which could have induced molecular heterogeneity and instability leading to accelerated development of resistance mechanisms. This negative effect of prior therapy has also been seen in trials with other MET TKIs.The combination of OMO-1 and an EGFR TKI in EGFR mutated and MET-amplified NSCLC (Module 2) was investigated after the dose-escalation part in Module 1. As the trial was closed prematurely due to a strategic decision (including lack of funding), only one patient was included in this combination cohort in Module 2. After failure on an EGFR TKI, OMO-1 was able to bypass the resistance to the EGFR TKI, resulting in a partial response with a treatment benefit of more than 5 months, which is comparable to similar trials.In conclusion, OMO-1 is safe and well tolerated to administer at doses up to 250 mg BID and shows preliminary clinical efficacy in pre-selected patients with METex14 mutated NSCLC.