FDA Issues Complete Response Letter to Cosibelimab for Cutaneous Squamous Cell Carcinoma

FDA

The FDA has issued a complete response letter to the biologic license application (BLA) seeking the approval of cosibelimab (formerly CK-301) for use in patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not eligible for curative surgery or radiation.¹

The letter follows a multi-sponsor inspection of the pharmaceutical company’s third-party contract manufacturing organization. The regulatory agency cites the findings that arose during that inspection as “approvability issues” to address in the resubmission. No concerns regarding the clinical data package, safety, or labeling of the drug were flagged.

In March 2023, the FDA accepted the cosibelimab BLA for filing and set a decision date of January 3, 2024, under the Prescription Drug User Fee Act.² The application was supported by findings from a registration-enabling phase 1 trial (NCT03212404) in which the drug induced a confirmed objective response rate of 47.4% (95% CI, 36.0%-59.1%) by independent central review (ICR) and RECIST v1.1 criteria in the cohort of patients with metastatic CSCC (n = 78);3,4 the cORR was 54.8% (95% CI, 36.0%-72.7%) by ICR in the locally advanced CSCC cohort (n= 31).

“As the only deficiencies relate to the FDA’s inspection of our third-party contract manufacturing organization, we believe we can address the feedback in a resubmission to enable marketing approval in 2024,” James Olivero, president and chief executive officer of Checkpoint Therapeutics, stated in a press release. “We are committed to working closely with our third-party manufacturer and the FDA on our resubmission in order to make cosibelimab available to patients living with CSCC.”

Patients with histologically confirmed metastatic CSCC that was not amenable to surgery were enrolled in the phase 1 study. They were 18 years of age or older, had an ECOG performance status ranging from 0 to 1, and had a life expectancy of longer than 3 months. Patients who had prior exposure to an immune checkpoint inhibitor, who received concurrent immunosuppressive doses of corticosteroids, or who had an active, suspected, or documented history of autoimmune disease, were excluded.

They received 800 mg of intravenous cosibelimab every 2 weeks until confirmed complete response (CR), progressive disease (PD), unacceptable toxicity, or clinical deterioration. After treatment, they entered follow-up.

In addition to ORR by ICR and RECIST v1.1 criteria serving as the trial’s primary end point, secondary end points of interest included duration of response (DOR) for those who achieved a CR or partial response (PR) and treatment-emergent adverse effects (AEs). Investigators also analyzed other clinical laboratory data.

In January 2022, the trial had met its primary end point for the metastatic CSCC cohort.³ Data presented at the 2022 ASCO Annual Meeting indicated that robust and durable reductions in target lesions were achieved at the data cutoff date of November 18, 2021.⁴ At a median follow-up of 15.3 months (95% CI, 12.0-20.5), cosibelimab responders had achieved a CR (7.7%), PR (39.7%), or stable disease (15.4%); a total 26.9% of patients experienced PD. The median DOR had not yet been reached and ranged from 1.4 months to 31.8 months. The majority of patients (75.7%) were still responding to treatment at the data cutoff. Moreover, the Kaplan Meier–estimated DOR probability rate at 6 months was 88.1% (95% CI, 71.3%-95.4%); the estimated DOR probability rate at 24 months was 72.5% (95% CI, 51.6%-85.5%).

In terms of safety, 70.5% of patients had treatment-related AEs (TRAEs) with 9.0% experiencing at least 1 TRAE that was grade 3 or higher. No grade 4 or 5 TRAEs were reported. Moreover, 3.8% of patients experienced serious AEs that were determined to be treatment related. One patient discontinued cosibelimab because of pemphigoid, and this was considered to potentially be associated with the study drug. Three patients had AEs that proved fatal; 2 patients had COVID-19 and 1 patient experienced cardiac arrest. None of these deaths were linked with cosibelimab.

In June 2022, interim findings from the locally advanced CSCC cohort were reported.⁵ Cosibelimab was reported to have induced an ORR that substantially exceeded a clinically meaningful lower bound of the 95% two-sided confidence interval of 25%.

Most recently, in July 2023, long-term data from the trial were reported.⁶ At the data cutoff date of January 2023, the ORR achieved with cosibelimab in the locally advanced disease cohort was 55% (95% CI, 36%-73%); this included a 23% CR rate. Responses were ongoing in 82% of patients, and the median DOR still had not yet been reached. Cosibelimab induced an ORR of 50% (95% CI, 39%-62%) in the metastatic disease cohort, which included a 13% CR rate. In this group, response was ongoing for 69% of patients, and the median DOR was still not yet reached.

References

1. US Food and Drug Administration issues complete response letter for cosibelimab solely due to inspection findings at third-party manufacturer. News release. Checkpoint Therapeutics, Inc. December 18, 2023. Accessed December 18, 2023. https://ir.checkpointtx.com/news-events/press-releases/detail/111/u-s-food-and-drug-administration-issues-complete-response
2. Checkpoint Therapeutics announces FDA filing acceptance of biologics license application for cosibelimab in metastatic or locally advanced cutaneous squamous cell carcinoma. News release. Checkpoint Therapeutics, Inc. March 2, 2023. Accessed December 18, 2023. https://ir.checkpointtx.com/news-events/press-releases/detail/96/checkpoint-therapeutics-announces-fda-filing-acceptance-of
3. Checkpoint Therapetuics announces positive topline results from the registration-enabling trial of cosibelimab in metastatic cutaneous squamous cell carcinoma. News release. Checkpoint Therapeutics, Inc. January 25, 2022. Accessed December 18, 2023. https://ir.checkpointtx.com/news-events/press-releases/detail/86/checkpoint-therapeutics-announces-positive-interim-results
4. Clingan PR, Brungs D, Arnold S, et al. Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in patients with metastatic cutaneous squamous cell carcinoma. J Clin Oncol. 2022;40(suppl 16):9537. doi:10.1200/JCO.2022.40.16_suppl.9537
5. Checkpoint Therapeutics announces positive interim results from registration-enabling trail of cosibelimab in locally advanced cutaneous squamous cell carcinoma. News release. Checkpoint Therapeutics, Inc. June 16, 2022. Accessed December 18, 2023. https://ir.checkpointtx.com/news-events/press-releases/detail/86/checkpoint-therapeutics-announces-positive-interim-results
6. Checkpoint Therapeutics announces cosibelimab longer-term results demonstrating substantial increases in complete response rates in advanced cutaneous squamous cell carcinoma. News release. Checkpoint Therapeutics. July 27, 2023. Accessed December 18, 2023. https://ir.checkpointtx.com/news-events/press-releases/detail/102/checkpoint-therapeutics-announces-cosibelimab-longer-term