RP1 Plus Nivolumab Is Active, Safe in Advanced Melanoma After Progression on Anti–PD-1 Therapy

The combination of the HSV-1–based oncolytic immunotherapy RP1 (vusolimogene oderparepvec) and nivolumab (Opdivo) generated responses and had a favorable safety profile in patients with advanced melanoma whose disease progressed on or after prior anti–PD-1 therapy, according to data from the phase 2 IGNYTE trial (NCT03767348).¹

Findings presented at the 2024 SITC Annual Meeting demonstrated that at a median follow-up of 15.4 months (range, 0.5-47.6), patients treated with RP1 plus nivolumab (n = 140) achieved a confirmed overall response rate (ORR) of 33.6% (95% CI, 25.8%-42.0%) per modified RECIST (mRECIST) 1.1 criteria by blinded independent central review (BICR) assessment. This comprised a complete response (CR) rate of 15.0% and a partial response (PR) rate of 18.6%; the stable disease (SD) and progressive disease (PD) rates were 29.3% and 30.7%, respectively.

Data from sensitivity analysis using RECIST 1.1 criteria showed the confirmed ORR was 32.9% (95% CI, 25.2%-41.3%), which included a CR rate of 15.0%, a PR rate of 17.9%, an SD rate of 22.1%, and a PD rate of 38.6%.

“RP1 combined with nivolumab after confirmed progression on anti–PD-1 therapy alone or in combination with anti–CTLA-4 [therapy] demonstrated a clinically meaningful rate and duration of response [DOR],” Michael K. Wong, MD, PhD, FRCPC, of The University of Texas MD Anderson Cancer Center in Houston, said during a presentation of the data.

Regarding safety, most adverse effects (AEs) were grade 1 or 2. No specific grade 3 AEs occurred in more than 5% of patients, and 5 total grade 4 AEs occurred across the study. No fatal AEs were reported.

IGNYTE Design and Patient Characteristics

The study enrolled patients at least 18 years of age with advanced cutaneous melanoma that had progressed following anti–PD-1 therapy.^1,2 Patients needed to have measurable disease, adequate organ function, and an ECOG performance status of 0 or 1. No prior treatment with an oncolytic therapy was allowed.¹

Enrolled patients received RP1 alone at 1 x 10⁶ pfu/mL at the start of the first 2-week cycle. In cycles 2 to 8, RP1 was administered at 1 x 10⁷ pfu/mL in combination with 240 mg of nivolumab once every 2 weeks. Nivolumab was then given alone at 240 mg in cycle 9 before being administered at 480 mg once every 4 weeks in cycles 10 through 30.

RP1 was injected into superficial and/or deep/visceral tumors; injections into superficial and deep/visceral tumors were allowed on the same day, and injections for deep/visceral sites were guided by ultrasound or CT scan. The volume of RP1 was dependent on lesion size, and multiple tumors were allowed to be injected with up to 10 mL of RP1. “Generally, injections are made from larger to smaller lesions,” Wong said.

Safety and BICR-assessed efficacy per mRECIST 1.1 criteria served as the trial’s primary end points. Secondary end points included investigator-assessed ORR; BICR- and investigator-assessed duration of response (DOR), CR rate, disease control rate, and progression-free survival (PFS); and 1- and 2-year overall survival (OS).

Wong noted that investigators aimed to enroll a population that reflected real-world patients with advanced melanoma that progressed following anti–PD-1 therapy. Patients had a median age of 62 years (range, 21-91), and the majority were male (67.9%), had BRAF wild-type disease (62.1%), and had a lactate dehydrogenase level no higher than the upper limit of normal (65.7%). Patients had either stage IIIB/IIIC/IVM1A (51.4%) or IVM1B/C/D (48.6%) disease. Additionally, 56.4% of patients had a negative PD-L1 expression below 1%, 31.4% had a PD-L1 expression of at least 1%, and PD-L1 expression was unknown in 12.1% of patients.

Prior anti–PD-1 therapy was given to 25.7% of patients in the adjuvant setting, and 74.3% of patients received anti–PD-1 therapy in any other setting. Furthermore, 43.6% of patients received anti–PD-1 therapy in combination with anti–CTLA-4 therapy, and 2.9% of patients had sequential treatment with anti–PD-1 and anti–CTLA-4 therapy. Prior BRAF/MEK therapy was given to 12.1% of patients. Most patients (65.7%) were classified as having primary anti–PD-1 resistance, and the remainder (34.3%) had secondary resistance.

Additional Efficacy and Safety Data

Findings also showed that patients achieved a median DOR of 21.6 months (range, 1.2+ to 43.5+), and the 12-month DOR rate was 70.5%.

ORRs were consistent across subgroups, including those who received prior single-agent anti–PD-1 therapy (n = 75; ORR, 38.7%), patients who received prior anti–PD-1 and anti–CTLA-4 therapy (n = 65; 27.7%), patients with stage IIIB to IVA disease (n = 72; 40.3%), those with stage IVB to IVD disease (n = 68; 26.5%), patients with primary anti–PD-1 resistance (n = 92; 35.9%), those with secondary anti–PD-1 resistance (n = 48; 29.2%), patients given prior anti–PD-1 therapy in the adjuvant setting (n = 36; 44.4%), and those given prior anti–PD-1 therapy outside the adjuvant setting (n = 104; 29.8%).

Responses were observed in both injected and noninjected lesions. Among lesions injected with RP1 (n = 79), any reduction was observed in 98.7% of lesions, including 54.4% that had a reduction of 100% and 39.2% that had a reduction of at least 30% and less than 100%. In noninjected lesions (n = 123), any reduction was observed in 96.7%, including a 100% reduction in 40.7% of lesions and a reduction of at least 30% and less than 100% in 39.0% of lesions. Notably, 85.0% of all lesions underwent a reduction of at least 30%.

“Tumor reduction [was] seen in 53 out of 60 noninjected visceral organ lesions,” Wong explained. “Injected and noninjected lesions responded with similar frequency, depth, and duration.”

In patients with noninjected lesions in visceral organs (n = 47), responses were observed in these organs, including those distant from the injection site. Any reduction was observed in 96.6% of lung lesions (n = 29), 100% of liver lesions (n = 15), 33.3% of adrenal lesions (n = 3), 100% of ovary lesions (n = 1), 83.3% of spleen lesions (n = 6), 100% of pleura lesions (n = 2), 33.3% of brain lesions (n = 3), and 0% of pancreas lesions (n = 1).

The median PFS was 3.7 months (95% CI, 3.4-5.0), and the 12-month PFS rate was 32.8%. The median OS was not reached, and the 1-, 2-, and 3-year OS rates were 75.3%, 63.3%, and 54.8%, respectively.

Additional safety data showed that any-grade treatment-related AEs (TRAEs) occurred in 89.4% of patients (n = 141), and grade 3 or 4 TRAEs were observed in 12.8% of patients. TRAEs reported in at least 5% of patients included fatigue (any grade, 32.6%; grade 3/4, 0.7%), chills (31.9%; 0%), pyrexia (30.5%; 0%), nausea (22.0%; 0%), flu-like illness (17.7%; 0%), injection-site pain (14.9%; 0%), diarrhea (14.2%; 0.7%), vomiting (13.5%; 0%), headache (12.8%; 0%), pruritus (12.8%; 0%), asthenia (9.9%; 0.7%), arthralgia (7.1%; 0.7%), decreased appetite (6.4%; 0.7%), myalgia (6.4%; 0%), cough (5.7%; 0%), rash (5.7%; 0%), injection-site reaction (5.0%; 0%), and vitiligo (5.0%; 0%).

Pharmacokinetic Data and Next Steps for RP1 Plus Nivolumab

Findings from the study showed that the combination of RP1 and nivolumab led to increases in T-cell infiltration and PD-L1 expression. At day 43, CD8-positive T-cell scores increased in 47% of evaluable patients (n = 78), and PD-L1 expression was boosted in 57% of patients (n = 68). Investigators also observed changes in interferon gene expression signatures associated with the induction of an inflamed tumor phenotype.

The combination of RP1 and nivolumab is being further evaluated vs physician’s choice of therapy in patients with advanced melanoma that progressed following prior anti–PD-1 and anti–CTLA-4 therapy in the ongoing, confirmatory phase 3 IGNYTE-3 trial (NCT06264180).

References

1. Wong M, Bommareddy PK, Middleton MR, et al. Primary analysis of the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE trial of RP1 plus nivolumab, including clinical subgroup and initial biomarker data. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1504.
2. Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated September 19, 2024. Accessed November 11, 2024. https://clinicaltrials.gov/study/NCT03767348