Considerations for adjuvant immunotherapy in stage II melanoma: KEYNOTE-716 and beyond

The utility of adjuvant programmed cell death protein 1 (PD-1) inhibition in cutaneous melanoma patients was first established by KEYNOTE-054 and Checkmate-238, where both nivolumab and pembrolizumab improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected high-risk stage III disease (1,2). Stage II disease, however, remains a significant cause of melanoma morbidity and mortality. The incidence of stage II disease is double that of stage III disease. About 7% of all newly diagnosed melanoma is stage IIB or IIC, which refer to tumors that are thick and/or ulcerated but remain lymph node negative (T3bN0-T4bN0) (3). The 10-year melanoma-specific survival (MSS) for patients with stage IIB–IIC tumors ranges from 75–83%. The 5-year MSS for patients with T4b tumors is 82%, which is similar to the 5-year MSS for patients with N1 (and thus stage III) disease (4). The risk of recurrence is high in patients with stage IIB–IIC disease; 2-year recurrence risk was 20–30% in a large prospective trial (5), and 10-year RFS was 33–49% for patients with stage IIC disease and 56% in stage IIB in a large German cohort (6), highlighting a need for effective preventative therapies.

KEYNOTE-716 is a practice-changing trial that sought to expand the application of adjuvant immune checkpoint inhibition to the stage II setting. It is a multicenter, double-blind placebo-controlled phase III randomized control trial that studied the benefit of one year of adjuvant pembrolizumab for completely resected stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma (7,8). The trial included 976 patients who were randomly assigned to pembrolizumab or placebo every 3 weeks for 17 cycles until disease recurrence or unacceptable toxicity. In part 2 of the study, eligible patients with disease recurrence could either be rechallenged with or crossover to receive pembrolizumab. The primary endpoint of the study was RFS, and the secondary endpoints included DMFS and overall survival (OS).

The third interim analysis took place after a median follow-up of 27.4 months, at which time median RFS was 37.2 months for the pembrolizumab arm and not reached for the placebo arm (8). The risk of recurrence was significantly lower with pembrolizumab (HR 0.64, 95% CI: 0.50–0.84), confirming the benefit with pembrolizumab that was observed at the first and second interim analyses. The RFS benefit with pembrolizumab was consistent across T stage subgroups (T3b, T4a, T4b), though for the T4b subgroup the HR for recurrence was 0.76 with a 95% CI of 0.51–1.13. Twenty-four-month RFS was 81% in the pembrolizumab arm and 73% for the placebo arm. In an updated analysis, median DMFS was not reached in either group but was significantly improved in the pembrolizumab arm (HR 0.64, 95% CI: 0.47–0.88, P=0.0029) (7). Twenty-four-month DMFS was 88% for the pembrolizumab group and 82% for the placebo group. Subgroup analysis for DMFS demonstrated a mostly consistent benefit with pembrolizumab with HR <1 across all subgroups, but the confidence interval crosses the threshold of 1 in patients with T3b and T4b disease, age <65, female patients, and patients from the US (7). These findings are consistent with preliminary results that were recently presented from CheckMate-76K, which is a randomized phase III trial that studied the benefit of one year of adjuvant nivolumab compared to placebo in 760 patients with completely resected stage IIB and IIC melanoma (9). After a median follow-up of 16 months, one year of adjuvant nivolumab improved both one-year RFS (89% with nivolumab vs. 79% with placebo; HR 0.42, 95% CI: 0.30–0.59) and one-year DMFS (92% with nivolumab vs. 87% with placebo; HR 0.47, 95% CI: 0.30–0.72) (9). The benefit of nivolumab was observed across prespecified subgroups including T category and disease stage.

As expected in a placebo-controlled trial, the rate of adverse events in KEYNOTE-716 was significantly higher among patients treated with pembrolizumab. Treatment-related adverse events (TRAEs) occurred in 83% of patients treated with pembrolizumab, compared to 53% of patients in the placebo group (7,8). Grade 3 TRAEs were also higher with pembrolizumab (17% vs. 5%), with the most common side effects being hypertension, diarrhea, autoimmune hepatitis, and rash. Ten percent of patients treated with pembrolizumab experienced a treatment-related serious adverse event (most commonly adrenal insufficiency, colitis, autoimmune hepatitis), compared to just 2% in the placebo arm (7). Treatment-related endocrinopathies occurred in 24% of patients who received pembrolizumab compared to 3% in the placebo group (8). For most of these patients, these endocrine disorders were permanent; at the time of the second interim analysis, almost 20% of patients treated with pembrolizumab received long-term hormone replacement therapy for treatment-related hypothyroidism, adrenal insufficiency, thyroiditis, hypophysitis, or type 1 diabetes (8). Importantly for KEYNOTE-716, 17% of patients assigned to the pembrolizumab group discontinued treatment due to an adverse event compared to 5% of patients assigned to placebo, while a slightly higher percentage of patients in the pembrolizumab group (8% vs. 5%) withdrew from the study with no specific reason for treatment discontinuation. This has implications on patient censoring in the trial and may have inflated the magnitude of RFS benefit observed with pembrolizumab. Preliminary results from CheckMate-76K showed a similar toxicity profile; among patients who received adjuvant nivolumab, there was an increased rate of TRAEs (83% vs. 54%), increased frequency of Grade 3–4 TRAEs (10% vs. 2%), a higher rate of immune-mediated adverse events (41% vs. 17%), and higher treatment discontinuation rates due to an adverse event (17% vs. 3%) compared to placebo (9).

Considering the efficacy observed in KEYNOTE-716, pembrolizumab received Food and Drug Administration (FDA) approval for adjuvant treatment of stage IIB or IIC melanoma in December 2021. While the results of the trial are certainly promising and strongly support the consideration of adjuvant pembrolizumab for all patients with resected stage IIB and IIC disease, many questions remain unanswered. For instance, it is still unclear whether upfront adjuvant immune checkpoint inhibition is superior to treatment at the time of recurrence. The latter approach may increase patients’ time off treatment and for some patients may reduce unnecessary exposure to toxicities. Bearing in mind that median OS of metastatic melanoma is now over 5 years with dual checkpoint inhibitor therapy (10) and that many patients with metastatic disease can now be treated with curative intent, the benefit of universal upfront adjuvant therapy appears more questionable, as a “watch and wait” strategy may still lead to the same outcome for some patients even if they develop metastatic recurrence. Since patients in the placebo arm of KEYNOTE-716 were allowed to crossover to receive pembrolizumab at the time of distant recurrence, pending OS analyses from the trial will be informative.

Although pembrolizumab is generally well-tolerated, the increased rate of TRAEs and serious adverse events observed in KEYNOTE-716 is not negligible. In particular, the high rate of treatment-related endocrinopathies should be considered and discussed with patients, as most of these disorders were permanent and required long-term hormone replacement therapy. For both patients and their providers, the willingness to accept toxicity risk (especially permanent toxicity risk) and continue treatment through low grade toxicities is likely much lower in the adjuvant setting, where patients are presumably disease-free, than in the recurrent or metastatic disease settings.

In addition to treatment-related toxicity, financial toxicity is an important consideration when deciding to offer a year of adjuvant immunotherapy to all patients with stage IIB/IIC disease. With a current list price of $10,683.52 for each indicated dose of Keytruda when given every 3 weeks, 17 cycles of adjuvant pembrolizumab would cost over $180,000 per patient (11,12). Meanwhile, based on a 2-year RFS of 81% in patients treated with pembrolizumab compared to 73% in patients treated with placebo, the number needed to treat (NNT) is 12.5, meaning that on average 12.5 patients would need to have received pembrolizumab in order to prevent one recurrence after 2 years. The NNT is even higher—16.7—to prevent a distant metastasis at 2 years.

Given the medical and financial toxicities, length of adjuvant treatment, and relatively high NNT to prevent one recurrence or distant metastasis, there is incentive to improve selection criteria and identify patients within the broad category of stage IIB/IIC disease who are more likely to benefit from adjuvant anti-PD-1 therapy. However, individualized risk/benefit assessments can be difficult to make in the absence of predictive biomarkers. programmed cell death ligand 1 (PD-L1) status, for instance, has not been shown to be a useful biomarker for patient selection in the adjuvant setting thus far. In KEYNOTE-054, patients with high-risk stage III melanoma benefitted from adjuvant pembrolizumab regardless of PD-L1 status (1), and PD-L1 status was not reported in KEYNOTE-716. BRAF mutation status was also not reported in KEYNOTE-716, though prior studies have shown benefit with pembrolizumab in patients with stage III melanoma regardless of BRAF mutation status (1). Gene expression profiling (GEP) has demonstrated a predictive role in identifying patients at higher risk of metastasis, but its role in considering patients for adjuvant therapy was not studied in either KEYNOTE-716 or CheckMate-76K (13,14). The role of GEP is being tested prospectively in the NivoMela trial (NCT04309409), a multicenter randomized phase III study in patients with resected stage IIA–IIC melanoma that uses the MelaGenix GEP score to identify patients at high risk for relapse and randomizes these high-risk patients to either adjuvant nivolumab or observation. This is an ongoing trial and data has not yet been presented. Further studies like this are needed to identify better biomarkers and test them in a prospective setting; if successful, these efforts would refine our current treatment paradigm and advocate for additional treatment for patients who are most likely to benefit from adjuvant PD-1 therapy while de-escalating treatment for others.

These questions and considerations are especially important as the landscape of adjuvant systemic therapy for stage IIB–IIC melanoma continues to evolve. For instance, the placebo-controlled COLUMBUS-AD trial (NCT05270044) is evaluating the role of adjuvant encorafenib and binimetinib for BRAF-mutated stage IIB–IIC tumors. If approved, these agents will expand adjuvant treatment options but also raise additional questions about best practices for patient and treatment selection. Furthermore, as treatment with curative intent moves towards a neoadjuvant approach, it is not yet clear how the impact of KEYNOTE-716 will change. Results from the SWOG 1801 study, which were presented at ESMO 2022, identified a benefit with neoadjuvant pembrolizumab for patients with resectable stage IIIB–IV melanoma, as patients who received 2 doses of neoadjuvant pembrolizumab had improved event-free survival compared to patients who received all 17 cycles in the adjuvant setting (15). The neoadjuvant treatment approach has the potential benefit of identifying treatment effect and pathological response on surgical specimens, which could subsequently influence adjuvant treatment decisions. Whether the benefit of neoadjuvant therapy extends to the stage II setting remains untested.

Stage IIB–IIC melanoma represents a group of high-risk early stage tumors that warrant further attention in the perioperative setting. While one year of adjuvant pembrolizumab is now FDA-approved for stage IIB–IIC melanoma based on the RFS benefit observed in KEYNOTE-716, additional studies are needed to further distinguish between patients who are most likely to benefit from adjuvant therapy and patients who would only incur medical and financial toxicity without a survival benefit. Identifying better biomarkers and exploring the benefit of neoadjuvant therapy for stage IIB–IIC tumors will be important for advancing truly personalized medicine for early-stage melanoma.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-839/coif). RDC reports research funding to Columbia University from Amgen, Astellis, AstraZeneca, BioMed Valley, Bolt, Bristol-Myers Squibb, Corvus, Cstone, Foghorn, Ideaya, Immatics, Immunocore, InxMed, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron, Roche/Genentech, received consulting fees from Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics and Trisalus, payments or honoraria from PER, involved on Clinical/Scientific Advisory Boards for Celldex, Aura Biosciences, Chimeron and Rgenix, and received stock or stock options from Aura Biosciences, Chimeron, Rgenix. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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