Real-World Data Show Survival Benefit for Adjuvant Immunotherapy in Stage III Melanoma

Along With Disparities in Terms of Who Actually Receives the Treatment

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Although ipilimumab is approved as adjuvant therapy for stage III melanoma and has been shown to improve survival when given after complete resection, a little more than one-third of eligible patients received adjuvant immunotherapy after the drug’s approval for this indication, according to early data from a “real-world” analysis presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.1

Justin T. Moyers, MD

Justin T. Moyers, MD

Of note, the study found that receiving adjuvant immunotherapy trended toward improved survival in patients with stage III melanoma at this early time point. Furthermore, patients with stage IIIC disease had significantly improved overall survival compared with those who did not receive adjuvant immunotherapy: 32 months vs 28 months.

“Patients with stage III melanoma tend to have a poor prognosis, even after curative-intent surgery,” said Justin T. Moyers, MD, Fellow at Loma Linda University in California. “This first early analysis of the National Cancer Database in the era of adjuvant immune checkpoint inhibitor therapy shows that adjuvant immunotherapy in resected stage IIIC melanoma yielded a superior survival advantage. Based on our findings, immunotherapy after resected stage III melanoma appears to reveal a trend for real-world 24-month survival advantage compared with no therapy, supporting the role of adjuvant immunotherapy in the real-world setting.”

Immunotherapy after resected stage III melanoma appears to reveal a trend for real-world 24-month survival advantage compared with no therapy.
— Justin T. Moyers, MD

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Another important finding of the analysis was that patients with improved socioeconomic status were more often treated with immunotherapy. “There was a trend toward a decrease in receipt of immunotherapy for those with lower income and high school graduation rates, but this was not statistically significant,” Dr. Moyers said.

Study Details

As background, ipilimumab was shown to improve progression-free survival as adjuvant therapy after surgical resection for stage III melanoma and was approved for this indication by the U.S. Food and Drug Administration (FDA) in 2015. Dr. Moyers and colleagues wanted to determine the percentage of patients actually receiving adjuvant immunotherapy following this approval as well as to compare the survival rate of those receiving it with those who did not.

The researchers used the National Cancer Database to identify patients with stage III melanoma diagnosed in 2015 and 2016. The database includes all newly diagnosed cancer cases in the United States and is a joint project of the American Cancer Society and the American College of Surgeon’s Commission on Cancer. They also analyzed survival for cases diagnosed in 2015. Those who had surgery to the primary site were included; systemic therapy prior to surgery was an exclusion criterion.

Between 2015 and 2016, 583,212 patients with confirmed melanoma were identified, and 9,526 were diagnosed with stage III melanoma. After exclusion criteria were applied, the study sample was 8,160 patients with stage III disease who underwent surgery. The survival analysis included 4,094 patients diagnosed in 2015, and the treatment pattern analysis for 2015 to 2016 included 8,160 patients. The mean patient age was 63 years.

Adjuvant immunotherapy was not received by 72.3% of the total sample and was given to 27.7%. Patients who were given adjuvant immunotherapy tended to be younger and have fewer comorbidities.

“The specific type of immunotherapy was not recorded in the National Cancer Database; however, based on the practice pattern and chronologic approval data of different -immunotherapy agents, certain deductions can potentially be made,” Dr. Moyers noted.

Key Findings

Median overall survival was not reached in either group. In the survival analysis, the 24-month survival rate did not significantly differ from that in those who received immunotherapy vs those who did not (83% vs 80%, respectively), but at this early timepoint, the percentages favored receipt of immunotherapy. Dr. Moyers said that longer follow-up is needed to see whether the survival curves continue to diverge.

However, overall survival for patients with stage IIIC melanoma was significantly improved with adjuvant immunotherapy: at 24 months, 70% of patients who received adjuvant immunotherapy were alive vs 59% in the group that did not receive it (P < .01).

In a separate analysis of treatment patterns, 8,160 patients were included, and 2,260 (28%) received adjuvant immunotherapy after surgery. Increased comorbidity scores, lower income, lower rate of high school graduation, and Medicare as the primary payer were all associated with a lower likelihood of receiving adjuvant immunotherapy.

Limitations of the study include a lack of disease-specific survival and recurrence/progression-free survival data. Some demographic data are derived from zip codes where patients lived at the time of diagnosis. Also, it is possible that some patients whose disease progressed early after surgery received immunotherapy.

Additional Commentary

At a premeeting press briefing, AACR President Antoni Ribas, MD, of UCLA School of Medicine, Jonsson Comprehensive Cancer Center, Los Angeles, commented on the study: “The study included more than 8,000 patients with resected melanoma at high risk for relapse treated in the real world and included in the National Cancer Database. The study was conducted between 2015 and 2016—the first year an immune checkpoint inhibitor was approved for this indication. In the study, slightly more than one-third of patients did get an immune checkpoint inhibitor, and these patients did better than those who did not. Patients covered by Medicare and those who had higher comorbidity scores were less likely to receive adjuvant immunotherapy, and there was a trend for those with lower income and lower rates of high school graduation being to be less likely to receive it.”

These data highlight the negative impact of socioeconomic background on access to state-of-the-art therapy in clinical trials and in the real world.
— Antoni Ribas, MD

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“The trend was that people with lower socioeconomic status did not receive treatment that had been demonstrated to have a proven benefit in two randomized trials, leading to the FDA approval of adjuvant anti–PD-1 therapy for stage III melanoma. Together, these data highlight the negative impact of socioeconomic background on access to state-of-the-art therapy in the real world,” Dr. Ribas stated.

“At present, the standard of care for adjuvant immunotherapy is primarily that patients with stage IIIB and stage IIIC melanoma will be offered adjuvant immunotherapy,” said Laleh Melstrom, MD, Assistant Professor in the Department of Immuno-Oncology at the City of Hope, Duarte, California. “This abstract retrospectively reviewed patients who received adjuvant immunotherapy after the approval of ipilimumab. Since then, further trials have also showed prolonged survival with pembrolizumab in this setting. The benefit of pembrolizumab is a better toxicity profile.”

Dr. Melstrom continued: “There are trials showing prolonged survival in patients with stage IIIB and stage IIIC melanoma receiving adjuvant immunotherapy. The unique aspect of this study is that it reports on retrospective data outside of a clinical trial. I suspect that if we were to review 2019 data, a much larger proportion of patients with stage IIIB and IIIC disease would have received adjuvant immunotherapy than reported in this trial for the years 2015 to 2016. At present, ongoing trials are evaluating the utility of perioperative immunotherapy for patients with stage IIIC melanoma.”

Laleh Melstrom, MD

Laleh Melstrom, MD

“Of course, this study highlights access to care as an issue as well,” Dr. Melstrom added. “Other reasons for not using adjuvant immunotherapy could be high toxicity, a delay in adopting this practice, and the fact that ipilimumab is not approved for stage IIIA melanoma.”

When asked whether adjuvant immunotherapy is worth the cost in this setting, Dr. Melstrom replied: “As these therapies prolong survival, the answer has to be yes—particularly for patients with stage IIIC melanoma, who often experience recurrence in distant sites.” 

DISCLOSURE: Dr. Moyers has received travel compensation from Astellas Pharmaceuticals. Dr. Ribas reported financial relationships with Amgen, Chugai, Genentech, Merck, Novartis, Sanofi, Advax, Arcus, Highlight, Compugen, CytomX, Five Prime, RAPT, ImaginAB, Isoplexis, Kite-Gilead, Merus, Rgenix, Lutris, PACT Pharma, and Tango Therapeutics. Dr. Melstrom reported no conflicts of interest.


1. Moyers JT, Chong EG, Mitchell J, et al: Immunotherapy in resected stage III melanoma: An analysis of the National Cancer Database. 2020 AACR Virtual Annual Meeting II. Abstract 4338.