FDA Grants Fast Track Status to Bemcentinib Combo for STK11-Altered Advanced or Metastatic NSCLC

FDA

The FDA has granted a fast track designation to the selective AXL inhibitor bemcentinib (BGB324) in combination with a PD-1/PD-L1 agent in the treatment of patients with STK11-altered advanced or metastatic non–small cell lung cancer (NSCLC) without actionable mutations.¹

Evidence from both preclinical and translational research efforts have indicated that AXL inhibition could prove to be synergistic with checkpoint inhibitors, targeted therapies, and chemotherapy agents.²

Because AXL is upregulated in nonresponders to immunotherapy, there is a rationale that AXL inhibition could improve the efficacy achieved with checkpoint inhibitors. To this end, bemcentinib has been shown to increase efficacy of checkpoint blockade in preclinical models, and to reverse immunosuppression in both animal models and patient samples.

Moreover, the agent has also demonstrated promising signals of activity when combined with targeted therapies in those with EGFR-positive NSCLC. In a subset of patients who experienced disease progression on erlotinib (Tarceva), the addition of the agent served to reverse resistance. Specifically, 6 weeks following treatment with bemcentinib plus erlotinib, 3 of 9 patients who had prior resistance to EGFR-targeted therapy achieved disease stability, and 2 patients experienced sustained benefit for a prolonged period.

There is also rationale for leveraging the AXL inhibitor to improve upon the efficacy achieved with chemotherapy in patients with NSCLC, as it is known that the tumor microenvironment responds to chemotherapy by activating the AXL pathway and that AXL downregulation improves response to chemotherapy agents. In animal models of NSCLC, the addition of bemcentinib has been shown to boost response to docetaxel.

“We are very pleased to receive fast track designation from the FDA for the second time this year and look forward to continuing to explore bemcentinib’s potential as a treatment option for [patients with] NSCLC,” Martin Olin, chief executive officer of BerGenBio, stated in a press release. “It has been reported that patients harboring STK11 mutations represents up to 20% of the total NSCLC patient population, representing a large, identifiable subgroup of patients who may benefit from treatment with an AXL inhibitor such as bemcentinib.”

Data to be presented at the 2021 SITC Annual Meeting showed preclinical and clinical evidence that bemcentinib restored response to PD-1 therapies in patients with NSCLC whose tumors harbored STK11 mutations.³ Investigators evaluated sensitivity to PD-1 blockade in the absence and presence of bemcentinib in preclinical mouse models of STK11-mutated NSCLC and showed that systemic AXL inhibition with the agent led to an expansion of tumor-associated T cells and restoration of therapeutic response to PD-1 inhibition.

Bemcentinib is also under evaluation in combination with pembrolizumab (Keytruda) in the treatment of patients with previously treated, advanced adenocarcinoma of the lung, as part of an ongoing phase 2 trial (NCT03184571; BGBC008).⁴

The trial is anticipated to enroll up to 106 patients and will be comprised of 3 cohorts. Cohort A will include those who received a maximum of 1 prior line of platinum-containing chemotherapy and no previous immunotherapy. Cohort B will enroll those who received a maximum of 1 prior line of PD-1 or PD-L1 therapy as a monotherapy. Cohort C will comprise those who received a maximum of 1 prior line of therapy with a PD-1 or PD-L1 therapy plus a platinum-containing chemotherapy.

To be eligible for enrollment, patients need to be at least 18 years of age, have histopathologically or cytologically documented stage IV adenocarcinoma NSCLC, measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and acceptable organ function.

If they had disease that was eligible for local therapy administered with curative intent, received more than 1 prior line of chemotherapy for advanced or metastatic adenocarcinoma of the lung, a known additional malignancy that is progressing and requires active treatment, known active central nervous system metastases and/or carcinomatous meningitis, or a history of cardiac conditions, they were excluded.

The primary outcome measure for the trial is objective response rate, and secondary outcome measures include disease control rate, duration of response, progression-free survival, overall survival, safety, and pharmacokinetics, among others.

Early data from the trial, also to be presented during the SITC Meeting, demonstrated that 3 of 3 evaluable patients with STK11-mutated NSCLC who received the combination experienced objective clinical responses and derived clinical benefit.

“While the data are limited, they suggest a mechanism by which treatment with bemcentinib could restore sensitivity to anti–PD-1 treatment in [patients with] NSCLC harboring STK11 mutations,” Olin added in another press release.

References

1. BerGenBio receives FDA fast track designation for bemcentinib in STK11-mutated advanced/metastatic non-small cell lung cancer (NSCLC). News release. BerGenBio ASA. November 9, 2021. Accessed November 9, 2021. https://cisn.co/3klf3V3
2. Bemcentinib NSCLC. BerGenBio ASA website. Accessed November 9, 2021. https://bit.ly/3wveTze
3. BerGenBio presents pre-clinical and clinical data on bemcentinib in STK11-positive NSCLC at SITC Annual Meeting 2021. News release. BerGenBio ASA. November 9, 2021. Accessed November 9, 2021. https://bit.ly/309EG40
4. Bemcentinib (BGB324) in combination with pembrolizumab in patients with advanced NSCLC. ClinicalTrials.gov. Updated October 14, 2021. Accessed November 9, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03184571