FDA Issues CRL to Cosibelimab in Metastatic or Locally Advanced CSCC


The FDA has issued a complete response letter which will delay the potential approval of cosibelimab for patients with cutaneous squamous cell carcinoma.

  • The FDA rejected the biologics license application (BLA) for cosibelimab (formerly CK-301) due to inspection findings at the drug's manufacturing facility.

  • No concerns were raised about the drug's safety, efficacy, or labeling.

  • Checkpoint Therapeutics believes they can address the FDA's feedback and resubmit the BLA for approval in 2024. They are collaborating with the manufacturer to resolve the manufacturing issues.

A complete response letter (CRL) has been issued by the FDA to the BLA seeking the approval of cosibelimab for patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not eligible for curative surgery or radiation, according to Checkpoint Therapeutics, Inc.1

The CRL was issued following a multi-sponsor inspection of Checkpoint’s third-party contract manufacturing organization. In the CRL, no concerns regarding the clinical data package, safety, or labeling of the drug were flagged; however, findings that arose during that inspection were cited as “approvability issues” to be addressed in the resubmission.

“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,” said James Olivero, president and chief executive officer of Checkpoint Therapeutics, 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.”

The FDA accepted the BLA of cosibelimab for filing in March 2023 and subsequently, a decision date of January 3, 2024, was set under the Prescription Drug User Fee Act.2 Findings from a registration-enabling phase 1 trial titled Study CK-301-101 (NCT03212404) supported this regulatory decision as cosibelimab generated a confirmed objective response rate (ORR) of 47.4% (95% CI, 36.0%-59.1%) by independent central review and RECIST v1.1 criteria in the cohort of 78 patients with metastatic CSCC.3,4

In the open-label, multicenter, dose-escalation trial, patients were enrolled across study sites in Australia, France, New Zealand, Poland, Russia, South Africa, Spain, Thailand, and Ukraine and given intravenous cosibelimab alone for 28-day cycles.

Enrollment in phase 1 of the study was open to patients aged 18 years and older with histologically confirmed metastatic CSCC that was not amenable to surgery. Patients must have also had an ECOG performance status of 0-1 and had a life expectancy of longer than 3 months. Once enrolled, they were treated with intravenous cosibelimab at 800 mg every 2 weeks until confirmed complete response (CR), progressive disease (PD), unacceptable toxicity, or clinical deterioration. After treatment, they entered follow-up.

The co-primary end points of the study were dose-limiting toxicities, the number of patients who have treatment-emergent adverse events, and the confirmed ORR. The secondary end points included confirmed best ORR, duration of response (DOR), overall survival, pharmacokinetics, and the number of patients with anti-cosibelimab antibodies.

The trial previously met its primary end point for the metastatic CSCC cohort and data were presented at the 2022 American Society of Clinical Oncology Annual Meeting. According to these data, robust and durable reductions in target lesions were reached at the data cutoff date of November 18, 2021.3,4

At a median follow-up of 15.3 months (95% CI, 12.0-20.5), 7.7% of patients who responded to cosibelimab had achieved a CR, 39.7% reached a partial response, and 15.4% had stable disease. Further, 26.9% of patients experienced PD. The median DOR was not reached at this time (range, 1.4-31.8 months); however, the Kaplan-Meier estimated DOR probability rate was 88.1% (95% CI, 71.3%-95.4%) at 6 months, and the estimated DOR probability rate at 24 months was 72.5% (95% CI, 51.6%-85.5%). Additionally, 75.7% of patients were still responding to treatment at the data cutoff.

For safety, treatment-related AEs (TRAEs) were observed in 70.5% of patients. A total of 9.0% of patients had at least 1 TRAE that was grade 3 or higher, and no grade 4 or 5 TRAEs were observed. The most common TRAEs were fatigue (11.5%), rash (10.3%), and diarrhea and pruritus (6.4% each).

Serious AEs deemed treatment-related were observed in 3.8% of patients. One patient discontinued treatment with the study drug due to pemphigoid, which was considered to potentially be associated with the cosibelimab. Moreover, 3 patients died due to their AEs, including 2 patients who had COVID-19 and 1 patient who experienced cardiac arrest, but no deaths were linked with cosibelimab.

In July 2023, long-term data showed that at the data cutoff date of January 2023, the ORR in the locally advanced disease cohort treated with cosibelimab was 55% (95% CI, 36%-73%).5 The CR rate was 23% in this cohort, responses were ongoing in 82% of patients, and at this time, the median DOR still had not yet been reached.

In the metastatic disease cohort, treatment with cosibelimab led to an ORR of 50% (95% CI, 39%-62%) and the CR rate was 13%. Sixty-nine percent of patients had ongoing responses and the median DOR was still not yet reached.

  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://tinyurl.com/5djvexw5
  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://tinyurl.com/bdfwbda7
  3. Checkpoint Therapeutics 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://tinyurl.com/2ya2xfwz
  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 cosibelimab longer-term results demonstrating substantial increases in complete response rates in advanced cutaneous squamous cell carcinoma. News release. Checkpoint Therapeutics, Inc. July 27, 2023. Accessed December 18, 2023. https://tinyurl.com/yr5mztkx
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