Adjuvant Therapy for Melanoma: Who, What, When?

Jeffrey Weber, MD, PhD

Melanoma has a high cure rate when diagnosed and treated at an early stage, but patients with high-risk melanomas, including stage III disease, remain at increased risk of recurrence and mortality even after definitive surgical treatment. Adjuvant therapy has the potential to improve long-term outcomes in these patients but remains underutilized. In a study presented at the 2018 American Society of Clinical Oncology Annual Meeting, less than 29% of patients with stage III melanoma received adjuvant therapy.¹ This may not be surprising: until recently, the only FDA-approved adjuvant treatment option in this setting was interferon (IFN)-α, a drug with variable efficacy and treatment-limiting toxicities.² The advent of checkpoint inhibitors and targeted agents have given oncologists more to work with.

“There has been a lot of action and research and development in the adjuvant field in melanoma within the last year, with 3 very impressive trials and multiple new approvals,” moderator Jeffrey S. Weber, MD, PhD, said during a recent OncLive Peer Exchange^® on the evolving armamentarium in advanced melanoma.

Stage III Melanoma: Who's Resectable?

More patients than ever before may now be good candidates for adjuvant therapy and derive long-term benefits from it, but new data and expanding treatment options have led to many new questions on how to optimize treatment. During the Peer Exchange, a group of melanoma experts shared their insights on who should undergo completion lymph node dissection, which molecular testing and adjuvant treatments to consider, what staging challenges need to be overcome, and when to implement and stop adjuvant therapy.Stage III melanoma is now known to be a heterogenous entity, and the panel noted that not all patients with this disease should receive a completion lymph-node dissection, unlike previously thought. “In the stage III setting, we really have to divide patients into the ones who have microscopic disease in their lymph nodes versus the patients who present with bulky disease and macroscopic disease,” Robert Andtbacka, MD, CM, said, noting that 2 recent studies have shown that patients with microscopic disease can do just as well with ultrasound follow-up.^3,4

In the MSLT-II, the larger of the 2 trials discussed and one in which Andtbacka is an investigator, completion lymph-node dissection did not lead to improvement in melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis.3 At a median follow-up of 43 months, the mean 3-year rate of melanoma-specific survival in the per-protocol analysis was almost identical between the dissection and observation groups, at 86% ± 1.3% and 86% ± 1.2%, respectively, though the rate of disease-free survival was somewhat higher at 68 ± 1.7% versus 63 ± 1.7%, respectively.3 In the multicenter, randomized DeCOG-SLT trial, no benefit was observed with dissection versus observation for distant metastasis- free survival, recurrence-free survival, or overall survival after a median follow-up of 72 months among 473 patients with a positive sentinel node.⁴

BRAF, PD-L1, or Both: What to Test?

“One of the caveats with both of these studies was that the amount of tumor in the sentinel lymph node was fairly small. When we think about these patients, we have to remember that most patients had only 1 positive sentinel lymph node,” Andtbacka said. He explained that in his practice, he has found the ultrasound approach to be viable for patients with a low disease burden in their sentinel lymph nodes and that more than half of these patients prefer ultrasound over receiving surgery. In general, he said, he reserves complete lymph-node resection for patients with more extensive disease in their lymph node basin or with melanoma in multiple lymph nodes and that these are the patients with whom he also discusses adjuvant therapy, because of their high risk of local and distant recurrence.Approximately 50% of advanced melanomas are known to harbor BRAF gene mutations,⁵ and in patients with BRAF V600—mutated melanoma, targeted therapy with BRAF and MEK inhibitors is associated with significant long-term benefit. The panel agreed that obtaining BRAF mutation status early is important. “We now try to do [BRAF testing] on the majority of patients, because of the decisions to be made in the adjuvant setting,” Omid Hamid, MD, said.

He explained that although mutational analysis does not affect immediate management, having that information available ensures timely treatment if there is a metastatic recurrence. “With the patient, we discuss that most of the data will be used in the case of metastatic disease,” he said. The panel noted some challenges with BRAF gene testing. “One of the challenges of testing for the BRAF gene in the stage III setting, especially stage IIIa, is that patients may have some primaries and only microscopic disease in the sentinel lymph nodes, so the availability of tissue is a very important aspect,” Hussein A. Tawbi, MD, PhD, said.

Jason J. Luke, MD, explained that having the molecular analysis early in the process is crucial to selecting adjuvant therapy. “There’s all of this great data from BRAF and MEK, but if you don’t know whether or not the patient has a BRAF mutation, you really can’t make [the decision about follow-up treatment]. That’s something in which our community needs to sort of reach back with our pathology and our surgery groups, to expedite getting that information,” he said.

Challenges of Tumor Staging

In contrast, testing for PD-L1 is not routine among the panel. “PD-L1 positivity is associated with higher response rates, but PD-L1—negative patients still respond, so we really don’t use that to make determinations of whether we should treat our patients or not,” Tawbi explained. He noted that although his practice tests patients who are enrolled into clinical trials for PD-L1 positivity, this marker is not used for clinical decision making in the adjuvant setting.Defining stage III tumors has posed a challenge to clinicians because of the significant heterogeneity among patients in these groupings, which has led to major differences in prognosis across the stage III subtypes (ie, IIIA, IIIB, IIIC): 5-year melanoma-specific survival rates range from 93% for stage IIIa disease to 32% for stage IIID cancer The panel discussed new staging criteria outlined in the American Joint Committee on Cancer (AJCC) Staging Manual, Eighth Edition, which redefined stage III subtypes based on tumor thickness, ulceration status, number of tumor-involved lymph nodes, and the presence or absence of non-nodal regional metastasis.6 “The way that I look at this, the old stage IIIA is the new stage IIIA and IIIB. That sort of splits the patient population. We now have the new stage IIIa [category] with the thinner tumors—less than 2 mm,” Andtbacka said.

The new AJCC criteria have also added a fourth category, stage IIID, which encompasses tumors >4 mm with ulceration and the following nodal findings: ≥4 clinically occult nodes; ≥4 nodes, at least 1 of which was clinically detected or the presence of any number of matted nodes; or ≥2 clinically occult or clinically detected and/ or presence of any number of matted nodes.⁶ These revised criteria aim to provide more accurate staging, enabling more effective use of monotherapies and combination therapies, and to assist clinicians in better informing patients about their treatment options, including enrollment into clinical trials.6 The new AJCC staging system was formally implemented nationwide on January 1, 2018,6 so its impact, particularly with regard to treatment decision making, clinical trial enrollment, and overall outcomes has yet to be determined.

Although subtyping of stage III tumors has improved, the panelists noted that there is currently an unmet need among patients with stage II melanoma, particularly those with stage IIC disease, which is another high-risk subtype. Many clinical trials have excluded these patients, but in the BRIM8 trial, which included patients with stage IIC melanoma in a combined cohort with stage IIIA and IIIB melanoma (cohort 1), adjuvant vemurafenib (Zelboraf) was shown to have a biologic effect; however, BRIM8 was not considered a positive study because it did not meet its primary endpoint of diseasefree survival in stage IIIC disease (cohort 2).⁷

Adjuvant Treatments: What to Select and When to Implement

“[Nevertheless] that tells us that we need to test some of these drugs in stage II patients,” Michael A. Postow, MD, said, noting that a lot of patients who recur or develop stage IV disease do not have prior stage III disease, but do have stage II or even stage I disease. He mentioned that some upcoming adjuvant studies of PD-1 drugs, such as pembrolizumab (Keytruda), are now including higher-risk stage II melanoma, which he hopes will have a significant impact on disease management.The panelists deemed 3 large randomized adjuvant therapy trials to be practice changing in the field of melanoma (Table).^8-10 “[Based on these trial results], we now have a win for pembrolizumab over observation, a win for nivolumab over ipilimumab, and a win for dabrafenib and trametinib over observation alone,” Postow said. He pointed out, however, that these trials had slightly different populations and that there are no head-to-head data to compare these approaches with one another. “It’s impossible to really tell the difference between nivolumab and pembrolizumab in the adjuvant setting… [and] it’s really hard to say whether dabrafenib and trametinib [combined] are better than PD-1,” he noted. Consequently, treatment decision making remains challenging and more data are needed to provide better guidance.

The panelists also discussed when to initiate adjuvant therapy, with Weber asking what hazard ratio the panelists would need to see to consider it for patients with stage IIIa disease. Luke said that he was impressed by the hazard ratios for both targeted therapy and immunotherapy and that he leans toward treating most patients with stage IIIA melanoma who haven’t had a complete lymph-node dissection. Hamid and Andtbacka agreed. “The KEYNOTE-054 data clearly look at the stage IIIA patients and show a significant hazard ratio for them. That makes me feel more confident in speaking to the IIIA patients and offering them adjuvant therapy,” Hamid said.

Andtbacka stated that the MSLT-II and DeCOG-SLT studies lend further evidence to treating these patients. “If you look at [these studies], we know that for about 25% of patients, maybe even more, if they had thicker tumors and more disease in the sentinel lymph node, they [would] have additional lymph nodes with melanoma in them. I think that we know that there’s a patient population that clearly has disease that has not been taken out, which strengthens the reason for us to treat these patients,” he said.

Table. Practice-Changing, Phase III, Adjuvant Therapy Trials in Melanoma

Toxicity in the Adjuvant Setting

It is yet unclear whether patients classified as stage IIIA using the new AJCC staging criteria will benefit from adjuvant therapy, as they have a low risk of relapse and death from disease over 5 years. Andtbacka said that if a patient has a small amount of disease in the sentinel node, he will usually observe the patient but that the option to treat should be discussed with the patient and the healthcare team. Such discussions should address the risks and benefits, cost issues, and whether it is better to treat now or wait, he noted. Little clarity exists on the latter issue but data from several studies are expected to provide some answers.The panelists agreed that there should be a much lower toxicity threshold for discontinuing therapy in the adjuvant setting than in the malignant setting. “We have to really think about the impact on patients who are otherwise surgically cured,” Tawbi said, noting the importance of considering long-lasting toxicities. “If you have young patients who develop new endocrinopathies following PD-1 monotherapy, for the rest of their lives they’ll have hypothyroidism or secondary adrenal insufficiency. That may have different implications 20 or 30 years down the line than for a patient with metastatic disease,” Postow explained. Therefore, although treatment-related toxicities in the adjuvant setting are similar to those that have been observed in the metastatic setting, the panelists emphasized that clinicians really need to think about the long-term implications of these treatments in their adjuvant therapy candidates.

Despite some caveats, the panelists agreed that adjuvant therapy should be considered the new standard of care for stage III disease, particularly in the community setting. “[Clinicians] should be offering it to almost every patient with stage III, which is really a change from the historical practice, where options were perhaps not so tolerable,” Luke concluded.

References

1. Cowey CL, Ghate SR, Rhodes WC, et al. Adjuvant therapy utilization among stage III melanoma patients. J Clin Oncol. 2018;36(suppl; abstr e21574). abstracts.asco.org/214/Abst- View_214_216343.html.
2. Ascierto PA, Palmieri G, Gogas H. What is changing in the adjuvant treatment of melanoma? Oncotarget. 2017;8(67):110735- 110736. doi: 10.18632/oncotarget.22988.
3. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222. doi: 10.1056/NEJMoa1613210.
4. Leiter UM, Stadler R, Mauch C, et al. Final analysis of DECOG-SLT trial: survival outcomes of complete lymph node dissection in melanoma patients with positive sentinel node. J Clin Oncol. 2018;36(suppl; abstr 9501). abstracts.asco.org/214/Abst- View_214_216115.html.
5. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31(1):24-38. doi: 10.1038/modpathol. 2017.104.
6. Keung EZ, Balch CM, Gershenwald JE, Halpern AC. Key changes in the AJCC eighth edition melanoma staging system. The Melanoma Letter. 2018;36(1). skincancer.org/publications/the-melanoma- letter/2018-vol-36-no-1/ajcc-staging-system. Published January 1, 2018. Accessed September 12, 2018.
7. Maio M, Lewis K, Demidov L, et al; BRIM8 Investigators. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2018;19(4):510-520. doi: 10.1016/S1470-2045(18)30106-2.
8. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. doi: 10.1056/NEJMoa1708539.
9. Weber JS, Mandala M, Del Vecchio M, et al. Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: updated results from a phase III trial (CheckMate 238). J Clin Oncol. 2018;36(suppl; abstr 9502). abstracts.asco.org/214/AbstView_214_214567.html.
10. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;