Approaches to Potentiate Immune Response in Patients Who Do Not Respond to Anti–PD-1 Therapy for Melanoma

Get Permission

A sizable proportion of patients with advanced melanoma will experience disease progression on anti–PD-1 therapy, and the optimal treatment of such patients represents an unmet need. Two studies presented at the American Association for Cancer Research (AACR) Annual Meeting 2022 explored separate approaches designed to improve responses to immunotherapy in patients with melanoma who experienced disease progression or were refractory to anti–PD-1 therapy.

The first study evaluated the combination of ipilimumab plus nivolumab vs ipilimumab alone in patients with metastatic or unresectable melanoma who failed to respond to anti–PD-1 therapy.1 The second study looked at the efficacy of intratumoral injections of BO-112 (double-stranded, synthetic RNA) combined with pembrolizumab in patients with advanced melanoma whose disease was refractory to anti–PD-1–based therapy.2

The first study showed modest gains in progression-free survival, and the second study demonstrated activity in terms of response rates. The combination of ipilimumab plus nivolumab is a reasonable option in this setting, but further study is needed to evaluate BO-112 plus pembrolizumab.

SWOG Study: S1616

In this phase II clinical trial, the combination of ipilimumab plus nivolumab significantly improved progression-free survival vs ipilimumab alone, but the absolute gain in progression-free survival was small. However, the response rate was triple with the combination.

“In this trial enrolling patients with advanced melanoma and primary resistance to PD-1 inhibitors, progression-free survival was significantly improved by the combination vs ipilimumab alone. The objective response rate was 28% with the combination vs 9% with ipilimumab alone,” said Ari M. VanderWalde, MD, MPH, MBioeth, of The West Clinic, Germantown, Tennessee.

Ari M. VanderWalde, MD, MPH, MBioeth

Ari M. VanderWalde, MD, MPH, MBioeth

“Appropriate sequencing and combinations of immune therapy remain unknown 6 years after approval of these drugs. The combination of ipilimumab and nivolumab may be too toxic for routine use in all patients, given the high rate of response to checkpoint inhibitors. However, for those who do not respond, we wanted to evaluate the use of this combination,” he explained.

From July 2017 to July 2020, the study randomly assigned 91 patients at 35 sites in 15 states who had disease progression after PD-1/PD-L1 inhibitor therapy to treatment with ipilimumab at 3 mg/kg every 3 weeks for four doses vs the same dose of ipilimumab plus nivolumab at 1 mg/kg every 3 weeks for 4 doses and then nivolumab at 480 mg every 4 weeks. Tumor assessment was every 12 weeks for 12 months. Treatment was continued while clinical benefit persisted. The plan was to follow overall survival for 2 years.

At baseline, both treatment arms were well balanced for demographic and disease characteristics, except for more patients in the nivolumab-plus-ipilimumab arm having received no prior adjuvant therapy (84% vs 74% for ipilimumab alone).

At a median follow-up of 28.3 months, median progression-free survival was statistically significant in favor of the combination: 3 months vs 2.7 months for ipilimumab alone (P = .037). The 6-month progression-free survival rate was 34% vs 13%, respectively. The combination was superior in terms of progression-free survival across all subgroups, including age, sex, performance status, stage, lactate dehydrogenase (LDH) level, prior adjuvant therapy, and duration of prior anti–PD-1/PD-L1 therapy.

The median duration of response was 18.9 months with the combination and not reached with ipilimumab alone. Subsequent therapies after disease progression were not significantly different between the treatment arms. At a median follow-up of 27 months, overall survival is not significantly different, but it was numerically higher in the combination arm.

Adverse events were experienced by almost all patients: 93% with the combination arm and 87% with ipilimumab alone. Grade 3 or 4 treatment-emergent adverse events were reported in 56% of the combination arm and 31% of the ipilimumab arm. A total of 23 patients and 16 patients, respectively, were unable to receive all cycles of therapy. “In general, toxicities were consistent with what is known,” Dr. VanderWalde said.

“An exploratory analysis showed that the combination increased intratumoral CD8-positive cells in the tumor microenvironment. Nivolumab plus ipilimumab is an appropriate next-line treatment in patients without a response to anti–PD-1 alone,” he stated.


The phase II SPOTLIGHT-203 trial evaluated the combination of intratumoral BO-112 plus pembrolizumab in patients with advanced melanoma resistant to anti–PD-1–based therapies. The final analysis of the study showed that the combination achieved an objective response rate of 25% and a disease control rate of 65%. Responders included those with BRAF-mutated and wild-type melanoma, mucosal histology, and secondary anti–PD-1 resistance.

Median progression-free survival was 3.8 months in the intent-to-treat population and was not reached when excluding those with acral melanoma and those with very high LDH levels. Response was observed in both injected and noninjected lesions. The combination was reported to have good tolerability.

Iván Márquez-Rodas, MD, PhD

Iván Márquez-Rodas, MD, PhD

“These results justify further study of this combination in randomized clinical trials,” said Iván Márquez-Rodas, MD, PhD, of the Hospital General Universitario Gregorio Marañon, Madrid.

“Up to 70% of patients will eventually experience disease progression after anti–PD-1/PD-L1 therapy. There is no standard of care for this situation, making second-line treatment an unmet need,” Dr. Márquez-Rodas explained.

BO-112 is a synthetic nanoplexed double-stranded RNA that activates TLR3, RIG-1, and MDA5. Preclinical studies suggest that BO-112 can mimic a viral infection and induce an immune response. A first-in-human trial showed that BO-112 plus anti–PD-1 therapy was safe, with a response rate of 20%, suggesting the combination may overcome anti–PD-1 resistance.

The SPOTLIGHT-203 trial enrolled 42 patients with unresectable stage III to IV melanoma with confirmed progressive disease on one prior line of anti–PD-1 therapy. Patients were treated with BO-112 given intratumorally every week for 7 weeks and then BO-112 every 3 weeks in combination with systemic pembrolizumab at 200 mg intravenously every 3 weeks. Treatment was continued until progressive disease, unacceptable toxicity, or death; up to 2 years; or if the lesion became uninjectable.

At baseline, 71% had cutaneous melanoma, 21% had acral melanoma, and 7%, had mucosal melanoma. A total of 83% had BRAF wild-type disease. The median age of patients was 65 years.

Best overall response rate was 25%; complete response rate was 10%, partial response rate was 15%, and 40% had stable disease. A subgroup analysis found the greatest benefit in those with cutaneous and mucosal melanomas, whereas patients with acral melanoma and an elevated LDH level had no benefit.

At a median follow-up of 4.1 months, the median duration of response was not reached.

The treatment was generally well tolerated. A total of 5% had grade 3 or 4 adverse events. No treatment-related deaths were reported, and there were no treatment discontinuations due to adverse events. The most common adverse events were fever, asthenia, and flu-like symptoms. 


DISCLOSURE: Dr. VanderWalde reported financial relationships with Caris Life Sciences, George Clinical, Elsevier, Bristol Myers Squibb, and Mirati Therapeutics. Dr. Márquez-Rodas has served as a consultant or advisor to Amgen, Bioncotech, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, and Roche; and has received reimbursement for travel, accommodations, and expenses from Bristol Myers Squibb and MSD.


1. Vanderwalde AM, Moon J, Kendra K, et al: S1616: Ipilimumab plus nivolu­mab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. AACR Annual Meeting 2022. Abstract CT013. Presented April 12, 2022.

2. Marquez-Rodas I, Dutriaux C, Saiag P, et al: Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: Final results of SPOTLIGHT-203 phase 2 study. AACR Annual Meeting 2022. Abstract CT014. Presented April 12, 2022.

Related Articles

Mario Sznol, MD, and Stefania Scala, MD, on Improving Responses to Immunotherapy in Patients With Melanoma

Invited study discussant of the use of ipilimumab plus nivolumab in resistant melanoma, at the AACR Annual Meeting 2022, Mario Sznol, MD, of Yale University Cancer Center, indicated that the substantial increase in progression-free survival at 6 months was not maintained. “The durable...