MAIA Biotechnology ($MAIA) has attracted a lot of attention with its Phase II non-small cell lung cancer (NSCLC) program, THIO-101.
THIO is a modified nucleotide that preferentially integrates into telomeric DNA causing damage that leads to further DNA damage response and immunogenic response. THIO is a targeted therapy that aims to restore sensitivity to immune checkpoint inhibitors (ICIs) in ICI-refractory or resistant patients. As such, it targets one of the largest patient populations in oncology, and one of extremely high unmet need, across numerous indications. MAIA is partnered with Regeneron, whose Libtayo (cemiplimab) is the ICI of choice for the NSCLC trial.
Overall survival (OS) data from the THIO-101 trial were presented at ESMO 2024 (abstract #8601) [1]. There, patients who received THIO as 2L treatment (n=45, mixed dose cohort) had an mOS of 10.5 months, and a progression-free survival (PFS) of 4.5 months. In the 3L (n=20, mixed dose cohort), the mPFS was 2.5 months and the mOS 5.8 months. Since this is a mixed-dose cohort, the 180mg dose selected for the registrational cohort will likely yield better efficacy. At the same time, experience shows that going from a small trial to a larger trial, efficacy outcomes become worse. Despite being a DNA analog, THIO appears fairly well tolerated and the safety profile of the combination was pretty impressive. In the 180mg cohort, the Grade ≥3 treatment-emergent adverse events (TEAEs) were all laboratory findings: ALT elevation (9.8%), AST elevation (4.9%), blood alkaline phosphatase elevation (2.4%), and gamma-glutamyltransferase elevation (2.4%).
Since this is a single-arm trial, we have to compare THIO + Libtayo’s efficacy to historical cohorts, despite such comparisons being inappropriate. The standard of care for NSCLC patients without driver mutations after progressing on ICIs is docetaxel + Eli Lilly’s Cyramza (ramucirumab). In the REVEL Phase III study [2] the objective response rate (ORR) for the combination was 23% vs 14% for docetaxel only. The mPFS was 4.5 months vs 3 months (HR: 0.76) and the mOS 10.5 months vs 9.1 months (HR: 0.86). The study only enrolled 2L patients and comparing the OS to THIO + Libtayo, it seems unlikely that THIO + Libtatyo can become a superior option, more likely there would be non-inferiority. Single-agent docetaxel is also a very popular option outside the US. While the 2L docetaxel data were previously described in the REVEL study, it is interesting to examine its efficacy in the 3L. While I am not aware of any high-quality data specifically for docetaxel in the 3L, a retrospective analysis of 173 patients treated with various chemotherapy regimens in the 3L revealed an mOS of 5.8 months [3]. This is strikingly similar to the latest results reported in THIO-101.
MAIA claims that the ORR in 3L patients treated with 180mg is 38%, which is true, however it’s true only for 8 patients total. Given that for 45 patients in the 2L, the ORR is only 9%, the high ORR in the 3L is most likely a statistical fluke. However, MAIA should not be focusing on ORR given that there is OS available. Docetaxel also has a very low ORR and yet the only regimen that has managed to best it in the 2L+ was its combination with Cyramza. Famously, even Amgen’s Lumakras (sotorasib) which was approved with a high ORR of 36%, failed to show a meaningful improvement in OS over docetaxel in the CodeBreaK 200 trial, and its sNDA was subsequently rejected by the FDA [4].
In the latest management presentation from September 2024 [5], MAIA claims that an FDA filing and accelerated approval could happen in 2026. Ultimately, discussions with the FDA will determine the registrational path for THIO. The FDA has allowed accelerated approval in this setting without a controlled trial, as was the case for Lumakras with the CodeBreaK 100 trial [6]. However, Lumakras is a biomarker-driven therapy, and such approvals are given more easily. I anticipate that the FDA would allow accelerated approval for THIO in the 3L only, after patients have exhausted the docetaxel + Cyramza option. Therefore with the current data, I believe that THIO + Libtayo could have a place in the treatment of NSCLC patients, but that place is in the 3L and not in the 2L+. Post-ICI treatment NSCLC is a notoriously difficult space to penetrate, and the current data suggest that THIO + Libtayo would not beat docetaxel in the 3L or docetaxel + Cyramza in the 2L in a head-to-head trial, at best it can show non-inferiority which however would not justify the high anticipated treatment cost.
By Sakis Paliouras, PhD
References
[1] MAIA THIO-101 ASCO 2024 Poster
[3] Retrospective Analysis of Chemotherapy Regimens
[4] FDA Issues Complete Response Letter to Sotorasib
