RP1 Plus Cemiplimab Misses Response End Points in Locally Advanced or Metastatic CSCC

The combination of RP1 and cemiplimab-rwlc (Libtayo) provided a numerical, but not statistically significant, improvement in response rates vs cemiplimab alone in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), missing the primary end points of the phase 2 CERPASS trial (NCT04050436).¹

Data from the initial primary analysis of the trial showed that the RP1 doublet elicited a complete response (CR) rate of 38.1% vs 25% with cemiplimab alone in these patients (n = 211; P = .040), which missed the threshold for statistical significance (P ≤ .025). In the subgroup of patients with locally advanced disease (n = 83), the CR rates with RP1/cemiplimab and single-agent cemiplimab were 48.1% and 22.6%, respectively.

The objective response rate (ORR) achieved with RP1 plus cemiplimab was 52.5% compared with 51.4% with cemiplimab alone (P = .692). Although the RP1 doublet boosted duration of response (DOR) vs the monotherapy (HR, 0.45), data were immature. Further follow-up are needed.

“The overall data from the CERPASS study indicate that treatment with RP1 in combination with cemiplimab led to clinically meaningful activity with a higher rate of CRs and favorable DOR vs cemiplimab alone,” Philip Astley-Sparke, chief executive officer of Replimune Group, Inc., stated in a press release.

The randomized, controlled, open-label, phase 2 study enrolled patients with histologically confirmed locally advanced or metastatic CSCC who were not candidates for or who had refused radiotherapy or surgery.² They were required to have at least 1 measurable lesion, an ECOG performance status of 0 or 1, and a life expectancy of longer than 12 weeks.

They could not have had prior receipt of oncolytic viral therapy, PD-1 or PD-L1 inhibitors, or immune-modulating drugs. Those with active substantial herpes infections or complications, untreated brain metastases, or who had ongoing or recent autoimmune disease, were excluded.

Study participants were randomly assigned 2:1 to receive RP1 plus cemiplimab or cemiplimab alone. The first dose of RP1 was 1 x 10⁶ PFU/mL on day -21 and at 1 x 10⁷ PFU/mL for subsequent doses. The RP1/cemiplimab combination was given on days 1, 22, and 43 of cycles 1 and 2; and day 1 of cycle 3; cemiplimab alone was then given on days 22 and 43 of cycle 3 and days 1, 22, and 43 of cycles 4 through 12. Re-initiation of RP1 could occur at any time during the 108-week treatment period after RP1 had been stopped for 12 weeks.

In addition to ORR and CR rates serving as the trial’s primary end points, and secondary end points included DOR, safety, progression-free survival (PFS), and overall survival (OS). Investigators will perform biomarker analyses to examine tumor-infiltrating lymphocytes, PD-L1 expression, tumor mutational burden, and anti–HSV-1 antibodies. They will also assess RP1 biodistribution and shedding.

“There was also an imbalance in baseline tumor burden across the treatment groups which may have impacted the number of responses seen,” according to the press release issued by Replimune.¹ “A significantly greater number of patients with high baseline tumor burden (larger than 10 cm in total diameter) were treated in the RP1-plus-cemiplimab group as compared with the cemiplimab-alone group.”

Specifically, 23% of those in the doublet arm had high tumor burden at baseline vs 12.5% of those in the monotherapy arm. Data from a prespecified analysis indicated that those with a total tumor burden of 10 cm or smaller experienced a CR rate of 43% with RP1 plus cemiplimab vs 27% with single-agent cemiplimab. In those with a tumor burden of larger than 10 cm, the CR rates were 21.9% and 11.1%, respectively.

Treatment-related adverse effects (TRAEs) linked with the RP1 combination were mostly transient grade 1 or 2 effects vs the monotherapy. These effects included fatigue, pyrexia, pruritus, nausea, hypothyroidism, chills, diarrhea, asthenia, infusion-related reaction, rash, maculopapular rash, and vomiting.

Grade 3 adverse effects occurred in 16.5% of patients in the doublet arm. Two patients each experienced maculopapular rash, fatigue, and immune-mediated hepatitis. One patient each experienced grade 4 immune-mediated myocarditis and myocarditis. No grade 5 TRAEs were reported.

References

1. Replimune shares initial primary analysis results from CERPASS clinical trial in advanced cutaneous squamous cell carcinoma and presents new data from IGNYTE clinical trial of RP1 in anti-PD1 failed melanoma and non-melanoma skin cancers. News release. Replimune Group, Inc. December 5, 2023. Accessed December 13, 2023. https://ir.replimune.com/news-releases/news-release-details/replimune-shares-initial-primary-analysis-results-cerpass
2. Haydon AM, Khushalani NI, Robert C, et al. A randomized, controlled, open-label, phase 2 study of cemiplimab ± RP1 in patients with advanced cutaneous squamous cell carcinoma (CERPASS). J Clin Oncol. 2022;40(suppl 16):TPS9593. doi:10.1200/JCO.2022.40.16_suppl.TPS9593