Sapanisertib Gets FDA Fast Track Status for Pretreated NRF2-Mutated Squamous NSCLC

The FDA has granted a fast track designation to sapanisertib (CB-228) for use as a potential therapeutic option in patients with unresected or metastatic squamous non–small cell lung cancer (NSCLC) whose tumors harbor an NRF2 mutation and who have previously received platinum-based chemotherapy and immune checkpoint inhibition.¹

“While there have been significant advances in targeted treatments for lung cancer, little progress has been made specifically for patients with squamous lung cancer. In addition, we know that patients with lung cancers that harbor mutations in the NRF2/KEAP1 pathway typically have poorer outcomes than those whose tumors do not have these mutations,” Susan Molineaux, chief executive officer of Calithera Biosciences, Inc., stated in a press release. “This fast track designation allows for a variety of benefits, including the possibility of priority review of sapanisertib as we seek to provide a first-in-class treatment option that may help address the major unmet need in this patient population.”

The oral and highly selective mTORC 1/2 inhibitor was designed to suppress both mTORC1 and mTORC2.² In preclinical models, it was found that efficacy with the agent was associated with total exposure and to be independent of the dosing schedule utilized. However, the tolerability of sapanisertib was noted to differ depending on the schedule.

As such, investigators launched a first-in-human phase 1 study (NCT01058707) of the agent, in which they explored the safety and efficacy of the agent administered at several dosing schedules in patients with advanced solid tumors. Here, the maximum tolerated doses of the agent were identified as 6 mg daily, 50 mg weekly, 9 mg daily for 3 days weekly, and 7 mg daily for 5 days weekly. The most common dose-limiting toxicities reported with the agent were hyperglycemia, maculopapular rash, asthenia, and stomatitis.

For the expansion phase of the research, investigators selected 5 mg daily and 30 mg weekly as the dosing schedules to examine further. Data showed that 1 patient with renal cell carcinoma (RCC) achieved a complete response to treatment. Partial responses were observed in 7 patients with RCC, 1 patient with carcinoid tumor, and in 1 patient with endometrial cancer.

Data from an investigator-initiated phase 2 trial (NCT02417701) revealed that sapanisertib elicited an objective response rate (ORR) of 27% among 11 heavily pretreated patients with NRF2-mutated squamous NSCLC.³ In these patients, the median progression-free survival (PFS) was 8.9 months (95% CI, 7–not reached) with the agent.

Now, sapanisertib is under exploration for use as a monotherapy in patients with NRF2-mutated squamous NSCLC whose disease progressed on or following platinum-doublet chemotherapy and immune checkpoint inhibitor treatment with or without an anti–CTLA-4 agent, as part of a multicenter, open-label, phase 2 trial (NCT05275673).⁴

To be eligible for enrollment, patients are required to have stage IV squamous disease, radiographically measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and acceptable organ function.

They cannot have nonsquamous histology, nor could they have had a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with assessment of the study drug. Other exclusion criteria include having received another investigational drug within 4 weeks of their first dose of sapanisertib, chemotherapy within 3 weeks, and any radiotherapy within 2 weeks of randomization. They also could not have undergone a major surgical procedure or have received another anticancer therapy within 4 weeks.

Study participants are receiving sapanisertib at a twice-daily dose of 2 mg or a once-daily dose of 3 mg.

Investigator-assessed ORR by RECIST v1.1 criteria and safety are the primary end points of the trial. Key secondary end points include duration of response, PFS, and overall survival. The study is designed to confirm the selective activity of the agent in those with NRF2-mutated tumors vs NRF2 wild-type tumors, and to refine dosing in this biomarker-selected population.

Data from the trial are expected to be shared by the first quarter of 2023.

References

1. Calithera receives FDA fast track designation for sapanisertib for the treatment of NRF2-mutated squamous lung cancer. News release. Calithera Biosciences, Inc. October 3, 2022. Accessed October 3, 2022. https://bit.ly/3SB6RiF
2. Voss MH, Gordon MS, Mita M, et al. Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Br J Cancer. 2020;123(11):1590-1598. doi:10.1038/s41416-020-01041-x
3. Paik PK, Ahn LSH, Plodkowski AJ, et al. Phase II study of TAK228 in patients with advanced non-small cell lung cancer (NSCLC) harboring NFE212 and KEAP1 mutations. J Clin Oncol. 2020;38(suppl 15):9607. doi:10.1200/JCO.2020.38.15_suppl.9607
4. A study of sapanistertib in relapsed/refractory NFE2L2-mutated and wild-type squamous non-small cell lung cancer. ClinicalTrials.gov. Updated August 8, 2022. Accessed October 4, 2022. https://clinicaltrials.gov/ct2/show/NCT05275673