A combination of vusolimogene oderparepvec and nivolumab elicited early clinical activity in patients with cutaneous melanoma whose disease did not response to anti-PD-1 therapy.
Mark Middleton, MD, PhD, FRCP
Patients with cutaneous melanoma whose disease did not response to anti–PD-1 therapy achieved encouraging initial responses with a combination of vusolimogene oderparepvec (RP1) and nivolumab (Opdivo) in the phase 2 IGNYTE trial (NCT03767348).1
At a median follow-up of 9.96 months, the first 75 patients enrolled on the trial achieved an overall response rate (ORR) over 36%, including a complete response (CR) rate of 20% and a partial response rate of 16.0%.2 Furthermore, 17.3% of patients had stable disease, and 42.7% experienced progressive disease. The disease control rate (DCR) was 53.3%.
The findings were consistent with previously reported data for 16 patients with melanoma who failed prior anti–PD-1 therapy, where the combination elicited an ORR of 37.5% and a DCR of 43.8%.
“The rate, depth, and durability of responses seen across a range of anti–PD1 failed melanoma settings with RP1 combined with nivolumab suggests broad utility of RP1 in this difficult to treat patient population,” Mark Middleton, MD, PhD, FRCP, professor of Experimental Cancer Medicine, consultant medical oncologist at the Oxford Cancer Centre, head of the Department of Oncology at the University of Oxford, and principal investigator on the IGNYTE study, stated in a press release.
“Based on the growing body of clinical data with RP1, I believe it has the potential to become a new treatment paradigm across multiple skin cancers, including in melanoma patients who have failed anti–PD-1 therapy. I look forward to seeing the primary analysis data from the full 125 patients in the anti–PD-1 failed cohort from the IGNYTE clinical trial, and of the registration-directed [phase 2] CERPASS clinical trial [NCT04050436] in cutaneous squamous cell carcinoma in 2023.”
RP1 is based on a proprietary new strain of herpes simplex virus engineered and genetically armed with a fusogenic protein and granulocyte-macrophage colony-stimulating factor to maximize tumor killing potency, the immunogenicity of tumor cell death, and the activation of a systemic antitumor immune response.
IGNYTE is evaluating RP1 monotherapy and in combination with nivolumab across cohorts of patients with advanced or metastatic non-neurological solid tumors without treatment options. Key overall eligibility criteria for the trial include at least 1 measurable and injectable lesion of at least 1 cm, adequate organ function, no prior treatment with an oncolytic therapy, and an ECOG performance status of 0 or 1.
In the cohort of those with melanoma who failed prior anti–PD-1 therapy, patients were required to have at least 8 weeks of prior anti–PD-1 therapy and have confirmed progression while on anti–PD-1 therapy. Anti–PD-1 therapy must have been the last therapy prior to enrollment on IGNYTE. Patients on prior adjuvant therapy must have progressed while on prior adjuvant treatment, with confirmation from a biopsy.
In the anti–PD-1 failed cutaneous melanoma cohort, patients received the first dose of RP1 at 1 x 106 cells during the first 2-week cycle. In cycles 2 through 8, patients were given RP1 at 1 x 107 cells plus 240 mg of nivolumab. In cycle 9, patients received 240 mg of nivolumab alone, and in cycles 10 to 30, nivolumab was administered at 480 mg every 4 weeks.
Radiographic imaging occurred at baseline and every 8 weeks from the first dose, plus every 12 weeks after confirmation of response. A 100-day safety follow-up was also conducted.
The co-primary end points of the trial were safety and tolerability, plus ORR. Secondary end points included duration of response, CR rate, DCR, progression-free survival (PFS), and 1- and 2-year overall survival (OS).
Among the 75 patients enrolled in the anti–PD-1 failed melanoma cohort, the median age was 60 years (range, 31-91), and 70.7% of patients were male. Regarding prior therapy, 69.3% of patients had failed anti–PD-1 therapy but not anti–CTLA-4 therapy, 29.3% of patients failed both anti–PD-1 and anti–CTLA-4 therapy, 9.3% also failed BREF/MEK inhibition, and 12.0% also failed other therapy. Notably, 34.7% of patients received prior anti–PD-1 therapy only as adjuvant therapy.
Disease stage included IIIB (4.0%), IIIC (34.7%), IVM1a (16.0%), IVM1b (18.7%), and IVM1c (26.7%). Most patients had lactate dehydrogenase at or below the upper limit of normal (65.3%) and an ECOG performance status of 0 (64.0%).
Additional data showed that 85% of responses were ongoing at data cutoff, and most responses were observed in patients who did not respond to prior anti–PD-1 therapy. A clinically meaningful ORR was seen across all subgroups analyzed, including prior adjuvant anti–PD-1 therapy only (n = 30; ORR, 50.0%), prior anti–PD-1 therapy other than adjuvant (n = 61; ORR, 29.5%), prior anti–PD-1 and anti–CTLA4 therapy (n = 31; ORR, 29.0%), stage IIIB/IIIC/IVa disease (n = 44; ORR, 45.4%), and stage IVB/IVC disease (n = 47; ORR, 27.7%).
More than 50% of patients experienced target tumor reduction, per RECIST v1.1 criteria. PFS and OS data are immature, although a plateau appears to be developing on the PFS curve, and OS data are promising.
Regarding safety data for all patients with skin cancer who have received RP1 plus nivolumab during IGNYTE (n = 187), treatment-related adverse effects (TRAEs) were generally grade 1/2. The most common any-grade TRAEs included fatigue (34.2%), chills (28.9%), pyrexia (25.1%), nausea (20.9%), influenza-like illness (13.9%), and pruritus (13.4%). One grade 5 event of immune-mediated myocarditis occurred.
“We are pleased to be providing an initial data snapshot from the first 75 patients from the IGNYTE clinical trial being conducted with registrational intent for the treatment of anti–PD1 failed cutaneous melanoma,” Philip Astley-Sparke, chief executive officer of Replimune, said.
“The data confirm the prior signal seen in anti–PD-1 failed melanoma in a smaller earlier cohort of patients, with the data from the first 75 patients in the new cohort showing an overall 36% ORR, a 20% CR rate, and clinically meaningful activity across all subgroups analyzed, including the most advanced stage IVM1b/c patients. This highly encouraging data, taken together with the compelling and durable data with RP1 we have previously shared from our prior IGNYTE cohorts, give us high confidence we will be able to realize our ambition of establishing a broad skin cancer franchise with RP1.”