Second-Line Nivolumab Plus Ipilimumab Improves PFS in Advanced Melanoma

Ari VanderWalde, MD, MPH

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated a statistically significant improvement in progression-free survival (PFS) vs ipilimumab alone as second-line therapy in previously treated patients with stage III unresectable or stage IV melanoma, according to findings from the phase 2 SWOG S1616 trial (NCT03033576) that were presented during the 2022 AACR Annual Meeting.

At a median follow-up of 28.3 months, the median PFS was 3.0 months (90% CI, 2.8-5.3) with the combination vs 2.7 months (90% CI, 2.5-2.9) with ipilimumab alone (HR, 0.63; 90% CI, 0.41-0.97; P = .037). The estimated 6-month PFS rates were 34% (90% CI, 25%-44%) and 13% (90% CI, 4%-27%), respectively.

“Subgroups that appear to have done particularly well with the combination therapy include patients with stage IV disease, patients with no prior adjuvant therapy, and patients who received less than 6 months of anti–PD-1 therapy prior to enrollment,” lead study author Ari VanderWalde, MD, MPH, vice president of Clinical Development, Precision Oncology Alliance, Caris Life Sciences, and research faculty at the West Cancer Center & Research Institute, said in the presentation.

The optimal use of immunotherapy is not well defined in melanoma. Available frontline options, such as the combination of ipilimumab and nivolumab, may be too toxic for all patients, and although PD-1 inhibitors have a high response rate, patients will ultimately develop resistance.

As such, the SWOG S1616 trial was designed to understand whether treatment with a CTLA-4 inhibitor alone or in combination with continued PD-1 inhibition can couldreverse primary resistance to PD-1/PD-L1 inhibition in metastatic melanoma.

The study enrolled patients with unresectable stage III or IV melanoma with disease progression on prior PD-1/PD-L1 inhibition. Patients must have achieved a confirmed partial response (PR) or complete response (CR) prior to progression. Patients who progressed on a PD-1/PD-L1 inhibitor in the adjuvant setting were not excluded from enrollment.

Additional eligibility criteria stipulated that patients must have measurable disease per RECIST version v1.1 criteria; a Zubrod performance status of 2 or belowlower; no prior exposure to a CTLA-4 inhibitor;, no history of clinically significant autoimmune disease; and no active central nervous system metastases.

Patients underwent a pretreatment biopsy and were randomized 1:3 to 3 mg/kg of ipilimumab every 3 weeks for 4 doses (n = 24) or the same schedule of ipilimumab plus 1 mg/kg of nivolumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks (n = 70). Additional blood samples and biopsies were taken on days 28 through 35.

Patients underwent tumor assessment every 12 weeks for 1 year. Treatment was continued with clinical benefit, and patients were followed for 2 years.

PFS served as the primary end point of the study. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and the difference in T-cell infiltrate between on-study biopsy samples of responders vs nonresponders.

Between July 2017, and July 2020, 91 eligible patients were treated across 35 sites in the United States.

A total of 23 patients received ipilimumab and 68 received ipilimumab plus nivolumab.

The study arms were well balanced for significant baseline factors. Most patients were male, White, had a performance status of 0, less than 6 months of prior PD-1 therapy, no prior adjuvant therapy, and prior PD-1 therapy only for metastatic disease.

Additional results demonstrated that the ORR was 9% (n = 2; 90% CI, 2%-25%) with ipilimumab alone vs 28% (n = 19; 90% CI, 19%-38%) with the combination (P = .05). In the ipilimumab arm, there were 0 CRs, 2 PRs (9%), 3 cases of stable disease (13%), and 18 cases of progressive disease (78%). In the combination arm, there were 6 CRs (9%), 13 PRs (18%), 14 cases of stable disease (20%), and 35 cases of progressive disease (51%); 1 patient was not evaluable for response.

The median duration of response was not reached (NR) with ipilimumab vs 18.9 months with the combination. Response was ongoing in 9% of patients on ipilimumab (100% of responders) vs 12% of patients on the combination (42% of responders).

Post-progression therapy for patients from both arms included pembrolizumab (Keytruda; n = 6; 8%), a PD-1 inhibitor (n = 5; 6%), ipilimumab (n = 6; 8%), another immunotherapy (n = 16; 21%), targeted therapy (n = 12; 15%), cytotoxic chemotherapy (n = 4; 5%), and radiation (n = 12; 15%). No significant differences were seen in post-progression therapy between treatment arms; any differences were above the threshold for significance (P ≥ .2).

At a median follow-up of 27.3 months, the median OS was 21.7 months (90% CI, 15.4-32.4) with the combination vs 25.7 months (90% CI, 8.1-NR) with ipilimumab, failing to reach the threshold for statistical significance (HR, 0.93; 90% CI, 0.54-1.60; P = .408). The 12-month OS rates were 63% (90% CI, 52%-72%) and 57% (90% CI, 38%-71%), respectively.

Regarding safety, any-grade adverse effects (AEs) were reported in 87% (n = 20) of patients on ipilimumab vs 93% (n = 63) of patients on the combination. Grade 1 through 3 AEs occurred in 74% (n = 17) of patients in the ipilimumab arm vs 85% (n = 58) of patients in the combination arm. Grade 4 and 5 AEs occurred in 13% (n = 3) of patients vs 7% (n = 5) of patients, respectively.

Grade 3 or greater higher AEs that occurred in at least 5% of patients in the ipilimumab and/or combination arms, respectively, included diarrhea (13% each), aspartate aminotransferase increase (7% each), alanine aminotransferase (7% each), rash (4% vs 6%), fatigue (4% vs 6%), anemia (0% vs 6%), hypotension (0% vs 6%), and hyponatremia (4% vs 6%).

A total of 16% (n = 4) and 23% (n = 16) of patients in the ipilimumab and combination arms, respectively, did not complete all 4 doses of ipilimumab because of an AE.

Correlative analysis demonstrated that the combination led to an increase in CD8+ cells in the tumor and at the boundary in responsive tumors.

“Nivolumab plus ipilimumab is an appropriate next-line treatment in patients without response to anti–PD-1 alone,” VanderWalde concluded.

Reference

VanderWalde A, Moon J, Bellasea S, et al. Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT013.