Practice-Changing Advances in the Adjuvant Treatment of Melanoma

Ahmad A. Tarhini, MD, PhD

Adjuvant therapy for melanoma to lower the risk of disease recurrence and death in patients with high-risk disease who have undergone definitive surgical treatment has previously been administered primarily to patients with stage III disease, as well as a small group of patients with stage IV disease who could be rendered disease free surgically, according to Ahmad A. Tarhini, MD, PhD.

These patients have unmet treatment needs. Tarhini, director, Melanoma and Skin Cancer Program and Center for Immuno- Oncology Research, Cleveland Clinic Taussig Cancer Institute, said that toxicities, negative effects on quality of life (QoL), and inconvenient dosing schedules have contributed to the lack of uptake of adjuvant therapy for patients with melanoma.

Data presented at the recent American Association for Cancer Research meeting by Tarhini and colleagues showed that of patients with a high risk of relapse after surgery for melanoma who were eligible for adjuvant therapy in about the last decade, only 5% received adjuvant therapy.¹

Interferon (IFN) alpha has been widely used for adjuvant therapy for melanoma. However, low- and intermediate-dose IFN do not improve survival and have not consistently improved relapse-free survival (RFS). Although high-dose IFN alpha improves RFS, it does not improve overall survival (OS) and is associated with treatment-limiting toxicity. Pegylated IFN alpha-2b has an improved toxicity profile but does not affect OS and has limited effects on RFS.²

Likewise, adjuvant high-dose ipilimumab (Yervoy), a CTLA-4−blocking antibody, although improving RFS and OS, is associated with a high rate of toxicity, which has resulted in discontinuation by half of patients and a 1% treatment-related mortality rate.^2,3

Vernon K. Sondak, MD

Welcome advances in the adjuvant setting that are addressing the unmet need for more effective and tolerable therapeutic options include the FDA approval of the immunotherapy nivolumab (Opdivo), a PD-1−blocking antibody, in December 2017,^4,5and the approval of the combination of the targeted kinase inhibitors dabrafenib (Tafinlar)6 plus trametinib (Mekinist)7 in the adjuvant setting for patients with BRAF-mutant melanoma in April 2018.

Encouraging results were also recently reported from studies of the immunotherapy pembrolizumab (Keytruda), another anti— PD-1 antibody,^8-10in the adjuvant setting.

“What we’ve seen in the last year or so has been little short of a revolution in adjuvant therapy in melanoma. It has been transformative, it’s practice-changing, paradigm-shifting,” said Vernon K. Sondak, MD, chair, Department of Cutaneous Oncology, Moffitt Cancer Center, in an interview with Targeted Therapies in Oncology™. “We have moved into an era of very active adjuvant therapies with very acceptable toxicity profiles.”

ADJUVANT IMMUNOTHERAPIES

The basis of the approval of adjuvant nivolumab for melanoma was the results of the randomized, double-blind phase III CheckMate 238 trial of patients with completely resected stage IIIb/c or stage IV melanoma.^4,12In this trial, patients 15 years and older were randomly assigned to receive intravenous infusions of nivolumab 3 mg/kg every 2 weeks (n = 453) or ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 12 weeks beginning at week 24 for up to 1 year (n = 453). Patients were treated up to 1 year or until disease recurrence, unacceptable toxicity, or withdrawal of consent.¹²

The primary endpoint was RFS; patients were to be assessed for recurrence by imaging every 12 weeks for 2 years, then every 6 months, for a total of 5 years. Secondary endpoints included OS, safety, adverse event (AE) profiles, RFS according to PD-L1 status, and health-related QoL. An exploratory endpoint was distant metastasis-free survival (MFS).

At a minimum follow-up of 18 months, the results of a prespecified interim analysis showed that the 12-month RFS for the nivolumab group was 70.5% (95% CI, 66.1%-74.5%) compared with 60.8% (95% CI, 56.0%-65.2%) for those assigned to receive the CTLA-4 inhibitor (HR for disease recurrence or death, 0.65; 97.56% CI, 0.51-0.83; P <.001). The median RFS was not reached in either treatment group.

Although not adjusted for multiple analyses (TABLE 1), a prespecified subgroup analysis of RFS by PD-L1 expression showed a 1-year RFS of 81.9% (95% CI, 74.7%-87.2%) in the nivolumab group in patients with PD-L1 expression &ge;5% in tumor cells compared with 73.8% (95% CI, 65.9%-80.1%) in the ipilimumab group.

Treatment-related grade 3/4 AEs occurred in 14.4% of patients receiving nivolumab versus 45.9% receiving ipilimumab; serious AEs occurred in 17.5% versus 40.4%, respectively; and discontinuation due to any AE occurred in 9.7% versus 42.6%. Two deaths attributed to toxicity occurred in patients receiving ipilimumab over 100 days post treatment versus none in the nivolumab group.

This study&rsquo;s findings showed that after resection of stage IIIb/c or stage IV melanoma, adjuvant nivolumab prolonged RFS, with a lower rate of grade 3/4 AEs compared with adjuvant ipilimumab. Additional results are pending further follow-up.

Pembrolizumab was studied in EORTC 1325 (KEYNOTE-054), a phase III, double-blind trial in patients 18 years and older with completely resected stage III melanoma. Patients received pembrolizumab 200 mg (n = 514) or placebo (n = 505) every 3 weeks for 18 doses or until disease recurrence or unacceptable toxicity. The primary endpoints included RFS in the overall intent-to-treat (ITT) population and in the subgroup of patients with PD-L1—positive disease.¹⁰

At the interim analysis, positive results were seen in the ITT population, leading to the interim analysis of RFS becoming the final analysis. At a median follow-up of 15 months, the 1-year RFS rate in the pembrolizumab group was 75.4% (95% CI, 71.3%-78.9%) versus 61.0% (95% CI, 56.5%-65.1%) in the placebo group in the overall ITT population (HR for recurrence or death, 0.57; 98.4% CI, 0.43-0.74; P <.001). At 18 months, the estimated RFS rate was 71.4% (95% CI, 66.8%-75.4%) in the pembrolizumab arm versus 53.2% (95% CI, 47.9%-58.2%) in the placebo arm.

In the subgroup of 853 patients with PD-L1—positive tumors, the 1-year RFS rate in the pembrolizumab group was 77.1% (95% CI, 72.7%-80.9%) versus 62.6% (95% CI, 57.7%-67.0%) in the placebo group (HR, 0.54; 95% CI, 0.42-0.69; P <.001).

In the pembrolizumab group, 13.8% discontinued treatment due to AEs compared with 2.2% from the placebo group. Discontinuation due to disease recurrence occurred in 21.4% of the pembrolizumab group versus 35.7% in the placebo group. Treatment-related grade 3 to 5 AEs were reported in 14.7% of the pembrolizumab group versus in 3.4% in the placebo group, with 1 treatment-related death in the pembrolizumab group. No new toxicity signals were associated with pembrolizumab treatment. Further analysis of distant MFS and OS, both secondary endpoints, are ongoing.

When initiated, these trials called for complete lymph-node dissection, which is no longer considered mandatory. Whether these trial results apply to patients not undergoing a complete lymph node resection is not known. The most recent nivolumab prescribing information indicates its use in patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection in the adjuvant setting.⁵

ADJUVANT TARGETED KINASE INHIBITORS

Two targeted kinase inhibitors were tested in combination in a double-blind, placebo-controlled phase III trial in patients with stage III BRAF-mutated melanoma that had been completely resected, including lymphadenectomy.¹¹Dabrafenib and trametinib target 2 kinases in the RAS/RAF/MEK/ERK pathway.^6,7Dabrafenib inhibits some mutated BRAF kinases, including BRAF V600E, BRAF V600K, and BRAF V600D. Dabrafenib is currently indicated as a single agent in patients with unresectable or metastatic melanoma with BRAF V600E mutation, and in combination with trametinib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test for both. Although it also inhibits some wild-type BRAF and other kinases, dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma.⁶

Trametinib, a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity, is currently indicated as a single agent for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test and, as noted above, in combination with dabrafenib for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. Trametinib is not indicated for the treatment of melanoma that has progressed on prior BRAF inhibitor therapy.¹⁰

The combination recently received FDA approval based on the results of the phase III COMBI-AD trial (see page 6), in which patients 18 years and older with completely resected, stage III melanoma with BRAF V600E or V600K mutations were randomly assigned to oral dabrafenib 150 mg twice daily plus oral trametinib 2 mg once daily (n = 438) or to matched placebo tablets (n = 432) for 12 months or until disease recurrence, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was RFS. Secondary endpoints included OS, distant MFS, freedom from relapse, and safety (TABLE 2).¹¹

In the primary analysis at a median follow-up of 2.8 years, the estimated 3-year RFS rate was 58% in the dabrafenib-plus-trametinib combination therapy group versus 39% in the placebo group (HR for relapse or death, 0.47; 95% CI, 0.39-0.58; P <.001). The 3-year OS was 86% for the combination versus 77% for placebo (HR for death, 0.57; 95% CI, 0.42-0.79; P = .0006). However, OS results did not cross the prespecified significance threshold for between-group differences for the first interim analysis of 2-sided P = .000019. Rates of distant metastasis or death were lower for the combination than the placebo (25% versus 35%; HR, 0.51; 95% CI, 0.40-0.65; P <.001); results for freedom from relapse were similar.¹¹

Most patients in both groups experienced at least 1 AE. Discontinuations related to AEs occurred in 26% of the combination group compared with 3% in the placebo group. Serious AEs were reported in 36% and 10%, respectively. There were no new safety signals for dabrafenib plus trametinib compared with AEs previously observed for the combination in patients with metastatic melanoma.¹¹

Vemurafenib (Zelboraf) is another orally dosed inhibitor of several kinases, including some mutated forms of BRAF (ie, BRAF V600E). Vemurafenib is currently indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDA-approved test. It is not indicated for the treatment of patients with wild-type BRAF melanoma.¹³

Vemurafenib was studied in BRIM8, a double-blind, randomized, placebo-controlled phase III trial in patients 18 years and older who had stage IIc or IIIa/b/c BRAF V600 mutation&minus;positive fully resected melanoma. Patients were randomly assigned to vemurafenib 960 mg twice daily or matching placebo for 52 weeks. The primary endpoint was disease-free survival (DFS) in the ITT population. Cohort 1 included patients with stage IIc, IIIa, or IIIb disease (n = 93 in the vemurafenib group, n = 91 in the placebo group).

Cohort 2 included patients with stage IIIc disease (n = 157 in the vemurafenib group, n = 157 in the placebo group).¹⁴

At a median follow-up of 33.5 months for cohort 2, the median DFS was 23.1 months (95% CI, 18.6- 26.5) in the vemurafenib group versus 15.4 months (95% CI, 11.1-35.9) in the placebo group (HR, 0.80; 95% CI, 0.54-1.18; log-rank P = .26). At a median follow-up of 30.8 months for cohort 1, the median DFS was not reached in the vemurafenib group but was 36.9 months in the placebo group (HR, 0.54; 95% CI, 0.37-0.78; log-rank P = .0010). This result was considered not to be significant because it was prespecified for cohort 2 to show a significant DFS benefit before the results of cohort 1 could be considered significant.¹⁴

The safety profile of vemurafenib was consistent with that reported in other studies. Grade 3/4 AEs occurred in 57% of patients in the vemurafenib group and 15% of patients in the placebo group. Serious AEs were reported in 16% and 10%, respectively, with the most common being basal cell carcinoma in 3% of patients in each group. The authors concluded that although 1 year of adjuvant vemurafenib was well tolerated, given that the study did not meet its primary endpoint, the current regimen of vemurafenib is not optimal despite a numerical benefit seen in cohort 1.¹⁴

LOOKING AHEAD

An editorial accompanying the BRIM8 trial results commented that the study was initiated before it was known that the addition of a MEK inhibitor in metastatic melanoma would improve OS.¹⁵The duration of adjuvant therapy may be important, since even in the highest stage (stage III), vemurafenib is favored in DFS for the first year, and converges with placebo at year 2. Therefore, patients with higher-risk disease may benefit from lengthier treatment. A longer duration of dabrafenib plus trametinib might also be more effective than the 1 year administered in the COMBI-AD study.

It is not known if melanoma recurring after adjuvant vemurafenib or combination dabrafenib plus trametinib is resistant to BRAF and MEK inhibition or if retreatment might be effective. Because the recent adjuvant trials, other than BRIM8, have not included patients with stage IIc melanoma, no conclusions can be drawn about the efficacy of treatment for high-riskstage II disease, which represents an unmet need.

Sondak commented that he thinks is it possible that some patients with high-risk stage II melanoma, in addition to those with stage III or resected stage IV disease, might benefit from adjuvant therapy. &ldquo;Now, we don&rsquo;t know that and exactly who those people are, whether the costs will outweigh the benefits in that group, but it is clearly an important question for us to start asking,&rdquo; he said.

Commenting on the use of adjuvant therapy earlier than stage III, Tarhini said, &ldquo;I would not expect it, and I would not advise it based on the current data.&rdquo; He recommends that treatment be consistent with the eligibility criteria of clinical studies for FDA approval and with the FDA-approved indications.

With the recent data from the studies of nivolumab, pembrolizumab, and dabrafenib plus trametinib as adjuvant therapy in the high-risk population, Tarhini said, &ldquo;the field has entirely changed in terms of the options available. First, the clinical activity that&rsquo;s being seen is consistent across all 3 studies. There is significant improvement in reducing the risk of relapse. The toxicity profile is much more favorable when compared to ipilimumab at 10 mg/kg but also to high-dose IFN alpha.&rdquo;

The improved efficacy, toxicity profile, and the impact on QoL of these regimens should improve uptake in the adjuvant setting. An additional factor in their favor is that nivolumab, pembrolizumab, dabrafenib, and trametinib have been used in nonadjuvant settings and other indications. Clinicians are already familiar with their use.

Sondak said that with new adjuvant therapy options for melanoma approved or in development, questions that need to be asked include which therapy to use, for how long, and when (ie, before or after surgery). These are &ldquo;completely different questions than we were asking just a couple of years ago.&rdquo;

He also suggested that neoadjuvant therapy for melanoma (ie, giving the treatments before surgery) adds important advantages. In addition to making surgery easier, the response can be quantified in individual patients with measurable disease at presentation. &ldquo;Neoadjuvant therapy brings in its own different risks and its own different needs. In our hands, we&rsquo;ve been very excited about neoadjuvant BRAF/MEK inhibition, and we&rsquo;ve been a little more cautious with neoadjuvant immunotherapy. Neoadjuvant therapy is going to be very important in the near future, extending the benefits of current adjuvant therapy in a new population,&rdquo; he said.

Other questions that remain to be answered include whether additional combinations would benefit patients with high-risk disease, and if the increased toxicity is worth the benefit in some groups. Answering all of these questions will require more clinical trials. &ldquo;That is one thing we do know. As good as these new adjuvant therapies are, they are not working for everybody. They are not completely obliterating melanoma in every patient,&rdquo; Sondak said. &ldquo;It&rsquo;s definitely an extremely exciting time, with important studies and work still to go.

References:

1. Tarhini A, Gupte-Singh K, You M, et al. Use of adjuvant interferon alfa-2b or ipilimumab 10 mg/kg for high-risk patients with melanoma, and associated adverse events and duration of therapy. Presented at: 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract 3641. abstractsonline.com/pp8/#!/4562/ presentation/7610.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Melanoma. Version 2.2018. NCCN website. nccn.org/professionals/ physician_gls/pdf/melanoma.pdf.
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4. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. US Food & Drug Administration website. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm. Published December 20, 2017. Accessed April 20, 2018.
5. Opdivo (nivolumab) injection, for intravenous use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2018. https://packageinserts.bms. com/pi/pi_opdivo.pdf.
6. Tafinlar (dabrafenib) capsules, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/tafinlar.pdf.
7. Mekinist (trametinib) tablets, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2018. www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/mekinist.pdf.
8. Merck&rsquo;s KEYTRUDA (pembrolizumab) significantly improved recurrence-free survival compared to placebo as adjuvant therapy in patients with stage 3 resected high-risk melanoma (EORTC1325/KEYNOTE-054). Kenilworth, NJ: Merck; January 8, 2018. www.mrknewsroom.com/news-release/oncology/mercks-keytruda-pembrolizumab-significantly-improved-recurrence-free-survival-. Accessed April 20, 2018.
9. Keytruda (pembrolizumab) for injection, for intravenous use [prescribing information]. Whitehouse Station, NJ: Merck & Co., Inc; 2017. www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
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12. Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi: 10.1056/NEJMoa1709030.
13. Zelboraf (vemurafenib) tablet for oral use [prescribing information]. South San Francisco, CA: Genentech USA, Inc; 2017. www.gene.com/download/pdf/zelboraf_prescribing.pdf.
14. 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.
15. Warner AB, Postow MA. The brim of uncertainly in adjuvant treatment of melanoma. Lancet Oncol. 2018;19(4):436-437. doi: 10.1016/S1470-2045(18)30150-5.