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Immunotherapy has been one of the most impactful innovations in 21st century oncology. This has been driven mainly by the development of immune checkpoint inhibitors targeting the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1). In melanoma, these agents have demonstrated robust activity and favorable tolerability, shifting the treatment paradigm away from classical systemic chemotherapy.1 With immunotherapy transforming the natural history of advanced melanoma, researchers have continued to press these agents into new treatment settings. 2018 was another important year for advancement in immunotherapy, as we gained further insight into long-term outcomes with these agents, as well as efficacy in novel treatment settings.
Long-term follow-up of anti-PD-1 therapies extends the survival tail
Anti-PD-1 antibodies were first approved in melanoma, based on remarkable pivotal trial data demonstrating improved overall survival (OS) compared with systemic chemotherapy. Longer follow-up of studies evaluating anti-PD-1 antibodies continue to support a persistent tail in the OS curves when using these agents.2-7 These updated analyses are summarized in Table 1.
NR, not reported
These data indicate that there is a rather large subgroup of patients who can achieve a highly durable antitumor response with anti-PD-1 therapy, with the longest follow-up suggesting that approximately one-third of patients can achieve at least 5-year OS with anti-PD-1 monotherapy. In the KEYNOTE-001 and -006 studies, these durable remissions appeared to be enriched in the subgroup of patients with no prior treatment (KEYNOTE-001 5-year OS rate, all patients versus treatment-naïve patients, 34% vs 41%; KEYNOTE-006 4-year OS rate, all patients vs treatment-naïve patients, 41.7% vs 44.3%).5,7
PD-1 therapy makes its debut in the preoperative and perioperative settings
Most cases of melanoma are diagnosed at earlier stages, where resection with curative intent is possible. However, patients with high-risk features (eg, nodal involvement) tend to have short recurrence-free survival if no follow-up therapy is provided.8 Adjuvant treatment with ipilimumab has been approved for adjuvant treatment following complete resection of high-risk melanoma, based on phase III study data showing improved recurrence-free survival (RFS) for ipilimumab versus placebo (median RFS, 26.1 months vs 17.1 months, HR 0.75, P = .0013).9
Unsurprisingly, anti-PD-1 antibodies have also made their way into adjuvant therapy for high-risk, resectable melanoma. Nivolumab was the first to be approved in this setting, with the CheckMate 238 study showing a significant RFS improvement for nivolumab compared with ipilimumab.10 A recent update to CheckMate 238 showed an ongoing RFS benefit for nivolumab vs ipilimumab (24-month RFS rate, 62.6% vs 50.2%, HR 0.66, P<.0001).11 The findings from CheckMate 238 led to the United States Food and Drug Administration (US FDA) approval of nivolumab for melanoma with lymph node involvement or metastatic disease following complete resection in December 2017, followed by a European Union approval in July 2018.
The randomized, phase III KEYNOTE-054 study assessed the role of anti-PD-1 therapy vs placebo in the adjuvant setting. However, this study enrolled only patients with stage IIIA, IIIB, or IIIC disease, whereas CheckMate 238 included stage IIIB, IIIC, and resectable stage IV melanoma.11,12 Patients in the pembrolizumab arm experienced significantly improved RFS (12-month RFS rate, pembrolizumab vs placebo, 75.4% vs 61.0%, HR 0.57, P<.001).12 This benefit persisted through 18 months, as well (18-month RFS rate, pembrolizumab vs placebo, 71.4% vs 53.2%).12 Based on these data, pembrolizumab was approved by the FDA in February 2019 for adjuvant treatment of melanoma with lymph node involvement following complete resection.
Researchers have also begun to investigate the potential role of immunotherapy in the neoadjuvant and perioperative settings. A pilot study randomized 20 patients to undergo either two courses of low-dose nivolumab (1 mg/kg), high-dose ipilimumab (3 mg/kg) prior to and immediately following surgery, or four courses of adjuvant nivolumab-ipilimumab.13 This study demonstrated the feasibility of neoadjuvant immunotherapy in this setting, with a pathological response achieved in 7 of 9 patients in the neoadjuvant treatment arm.13 However, almost all of the patients experienced ≥1 high-grade adverse event.13
The activity and tolerability of the pilot study led to the opening of the OpACIN-Neo study, which randomized patients with stage III melanoma to receive one of two dosing regimens of combination nivolumab-ipilimumab (high-dose nivolumab with low-dose ipilimumab or low-dose nivolumab with high-dose ipilimumab) or sequential high-dose ipilimumab then nivolumab.14 Both of the combination arms had radiological response rates of 60%, while the sequential therapy arm had a 42% response rate.14 These response rates were revised upward upon central review of pathologic response (80% for the high-dose ipilimumab, low-dose nivolumab arm, 77% for the high-dose nivolumab, low-dose ipilimumab arm, 65% for the sequential therapy arm).14 These findings indicate encouraging activity for each of these neoadjuvant approaches, particularly in the combination arms. However, the low-dose ipilimumab (1 mg/kg) plus higher-dose nivolumab (3 mg/kg) arm was found to be safest, with only 20% of patients experiencing a grade ≥3 adverse event in the first 12 weeks, compared with 40% and 50% for the high-dose ipilimumab and sequential arms, respectively.14
Immunotherapy impacts melanoma brain metastases
Melanoma has a strong potential to metastasize to the brain, with a prevalence as high as 75% at autopsy.15 Overall, outcomes remain poor in this setting, driving research toward developing new treatment options. CheckMate 204 was the first clinical study to assess the role of anti-PD-1-based immunotherapy in patients with advanced melanoma and brain metastasis.16 This phase II trial enrolled 101 patients with asymptomatic brain metastases to receive nivolumab-ipilimumab, with 94 having follow-up of at least 6 months at the time of data cutoff.16 Combination immunotherapy with nivolumab and ipilimumab yielded an intracranial objective response rate (ORR) of 56%, and an extracranial ORR of 50%.16 At the time of analysis, 90% of the intracranial responses were ongoing after a median follow-up of 14.0 months.16
These findings are consistent with the results of the Anti-PD-1 Brain Collaboration (ABC) study, which randomized asymptomatic patients (regardless of prior BRAF/MEK inhibitor treatment) to either nivolumab or nivolumab-ipilimumab.17 After median follow-up of 17 months, the intracranial ORRs were 46% and 20% for the nivolumab-ipilimumab and nivolumab cohorts, respectively.17 This apparent doubling of the intracranial ORR is remarkable, considering that patients in the nivolumab-ipilimumab arm were more likely to have four or more brain metastases (14/35 patients, 40%) than did patients in the nivolumab arm (5/25 patients, 20%).17 ABC also included a small cohort (n = 16) of patients with previously treated, symptomatic, or leptomeningeal disease with magnetic resonance (MRI) progression; these patients received nivolumab monotherapy, yielding an intracranial ORR of 6%.17
Taken together, the early data from these ongoing studies suggest that the combination of nivolumab-ipilimumab can yield durable control of asymptomatic brain metastases. Results from other ongoing studies like ABC-X (nivolumab-ipilimumab combined with radiotherapy) and a phase II study combining low-dose ipilimumab and pembrolizumab are anticipated in the future, in addition to longer follow-up of CheckMate 204 and ABC.18,19
Combinations are on the horizon in advanced melanoma
Although immunotherapy has dramatically improved the outcomes for a subset of patients, many fail to achieve long-term remission with anti-PD-1-based therapy. Combination therapy with other standard agents is one potential avenue for overcoming this challenge and improving response rates to immunotherapy-based treatment.
Because a large group (approximately 40%) of melanoma cases are associated with mutations in the BRAF gene, combining immune checkpoint inhibitors with BRAF/MEK targeted agents is an attractive research topic. Preliminary findings from several randomized studies were presented in 2018. For example, IMPemBra is comparing pembrolizumab alone to the combination of pembrolizumab and different courses of dabrafenib/trametinib in BRAFV600–mutant melanoma. Early data from the 2018 European Society for Medical Oncology (ESMO) Congress showed evidence of activity for combination pembrolizumab and intermittent dual-MAPK inhibition, with response rates at 18 weeks ranging from 50% to 83%.20 The phase II portion of KEYNOTE-022 randomized patients to dabrafenib-trametinib plus either placebo or pembrolizumab was also presented at the ESMO Congress.21 Although the pembrolizumab arm had a numerically higher median progression-free survival, this did not reach the threshold for statistical significance (pembrolizumab vs placebo, 16.0 months vs 10.3 months, HR 0.66, P = .04287).21 At the American Association for Cancer Research (AACR) Annual Meeting, findings from part 2 of the phase III COMBI-i study showed encouraging activity for the combination of the anti-PD-1 antibody spartalizumab and dabrafenib-trametinib in unresectable BRAFV600–mutant melanoma, with 0 of the 7 patients with at least 12-weeks follow-up experiencing disease progression.22
Other clinical studies are designed to also evaluate the efficacy and safety of combination versus sequential targeted and immunological therapy. DREAMseq is a phase III study comparing different sequences of dabrafenib-trametinib and nivolumab-ipilimumab.23 Patients with advanced, unresectable BRAFV600–mutant melanoma are randomized to either nivolumab-ipilimumab, followed by nivolumab maintenance or dabrafenib-trametinib. At the time of progression, patients are then switched to the alternative therapy. The primary endpoint of this study is 2-year OS rate.23 The phase II SECOMBIT study is assessing a similar pair of sequences, either beginning patients with encorafenib-binimetinib or nivolumab-ipilimumab until progressive disease.24 However, this study also includes a third arm in which patients receive 8 weeks of encorafenib-binimetinib and then are switched to immunotherapy until progression, at which time they are switched back to the targeted therapy combination.24
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- National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma, v2.2019. https://www.nccn.org/professionals/physician_gls/. Accessed April 17, 2019.
- Ascierto PA, Long G, Robert C, et al. Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: Three-year follow-up of a randomized phase 3 trial. JAMA Oncol. 2019;5(2):187–194.
- Topalian SL, Hodi FS, Brahmer JR, et al. Long-term survival in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. J Immunother Cancer. 2017;5(suppl 2): Abstract P216.
- Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19(11):1480–1492.
- Hamid O, Robert C, Daud A, et al. 5-year survival outcomes in patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. J Clin Oncol. 2018;36(suppl): Abstract 9516.
- Robert C, Ribas A, Hamid O, et al. Long-term outcomes in patients (pts) with advanced melanoma treated with pembrolizumab (Pembro): 4-year overall survival (OS) results from KEYNOTE-001. Presented at: 7th European Post-Chicago Melanoma/Skin Cancer Meeting; June 29-30, 2017: Munich, Germany. Abstract 8.
- Long G, Schachter J, Ribas A, et al. 4-year survival and outcomes after cessation of pembrolizumab after 2 years in patients with ipilimumab-naive advanced melanoma in KEYNOTE-006. J Clin Oncol. 2018;36(suppl): Abstract 9503.
- Romano E, Scordo M, Dusza SW, Coit DG, Chapman PB. Site and timing of first relapse in stage III melanoma patients: Implications for follow-up guidelines. J Clin Oncol. 2010;28(18):3042–3047.
- Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–530.
- Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835.
- Weber JS, Mandalà M, Vecchio M Del, et al. Adjuvant therapy with nivolumab versus ipilimumab after complete resection of stage III/IV melanoma: Updated results from a phase III trial (CheckMate 238). J Clin Oncol. 2018;36(suppl): Abstract 9502.
- Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–1801.
- Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med. 2018;24(11):1655–1661.
- Rozeman EA, Menzies A, van de Wiel B, et al. OpACIN-Neo: A multicenter phase 2 study to identify the optimal neoadjuvant combination scheme of ipilimumab (IPI) and nivolumab (NIVO). Ann Oncol. 2018;29(suppl 8): Abstract LBA42.
- Amer M, Al-Sarraf M, Baker L, Vaitkevicius V. Malignant melanoma and central nervous system metastases: Incidence, diagnosis, treatment and survival. Cancer. 1978;42(2):660–668.
- Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379(8):722–730.
- Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: A multicentre randomised phase 2 study. Lancet Oncol. 2018;19(5):672–681.
- National Institutes of Health. A phase II, open label, randomised, controlled trial of ipilimumab and nivolumab with concurrent intracranial stereotactic radiotherapy versus ipilimumab and nivolumab alone in patients with melanoma brain metastases. https://clinicaltrials.gov/ct2/show/NCT03340129. Accessed March 26, 2019.
- National Institutes of Health. A phase II study of open label low dose ipilimumab in combination with pembrolizumab in metastatic melanoma patients with brain metastases. https://clinicaltrials.gov/ct2/show/NCT03873818. Accessed March 26, 2019.
- Rozeman E, Sikorska K, Grijpink-Ongering L, et al. Phase 2 Study comparing pembrolizumab (PEM) with intermittent/short‐term dual MAPK pathway inhibition plus PEM in patients harboring the BRAF V600 mutation. Ann Oncol. 2018;29(suppl_8): Abstract LBA46.
- Ascierto PA, Ferrucci PF, Stephens R, et al. KEYNOTE-022 Part 3: Phase II randomized study of 1L dabrafenib (D) and trametinib (T) plus pembrolizumab (Pembro) or placebo (PBO) for BRAF-mutant advanced melanoma. Ann Oncol. 2018;29(suppl_8): Abstract 1244O.
- Dummer R, Schadendorf D, Nathan P, et al. The anti-PD-1 antibody spartalizumab (PDR001) in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600-mutant melanoma: First efficacy, safety, and biomarker findings from the part 2 biomarker cohort of COMBi-i. Cancer Res. 2018;78(14_suppl): Abstract CT182.
- National Institutes of Health. DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing) a phase III trial. https://clinicaltrials.gov/ct2/show/NCT02224781. Accessed March 27, 2019.
- National Institutes of Health. A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (LGX818/MEK162) in patients with metastatic melanoma and BRAF mutation. https://clinicaltrials.gov/ct2/show/results/NCT02631447. Accessed March 27, 2019.
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Recent Reflections on Immuno-Oncology: Melanoma
This educational activity is designed to meet the needs of medical oncologists and other healthcare professionals involved in the treatment of patients with lung cancer, bladder cancer, and melanoma.
After successful completion of this educational activity, participants should be able to:
- Evaluate clinical trial data assessing the efficacy and safety of immune checkpoint inhibitors for the management of patients with solid tumors
- Develop optimal treatment plans utilizing immune checkpoint inhibitors for the treatment of solid tumors
- Assess the rationale for using immune checkpoint inhibitors, alone, and in combination with chemotherapy or other novel agents, for the treatment of solid tumors
- Formulate treatment plans to manage immune-related adverse events associated with the treatment with immune checkpoint inhibitors
This educational activity is supported by a grant from Merck Sharp and Dohme Corp.
In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and prIME Oncology. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Lung newsletter: 0.5
Bladder newsletter: 0.75
Melanoma newsletter: 0.5
This activity is jointly provided by Postgraduate Institute for Medicine and prIME Oncology.
Method of Participation
Estimated time to complete activity: 1.75 hours
To contact Postgraduate Institute for Medicine please visit www.pimed.com.
Disclosure of Relevant Financial Relationships
Postgraduate Institute for Medicine (PIM) and prIME Oncology require instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.
Postgraduate Institute for Medicine Planners and Managers have disclosed no relevant financial relationships.
The employees of prIME Oncology have disclosed:
- Briana Betz, PhD (scientific content reviewer/planner) –(scientific content reviewer/planner) – worked on non–CME certified projects in the last 12 months supported by Helsinn Healthcare, ImmunoGen, Karyopharm Therapeutics, Novartis, Pfizer, and TG Therapeutics
- Zach Hartman, PhD (author) – no relevant financial relationships
- Heather Tomlinson, ELS (editorial content reviewer) – worked on non–CME certified projects in the last 12 months supported by AstraZeneca, Clovis Oncology; F. Hoffmann-La Roche Ltd; ImmunoGen; Merck KGaA, Darmstadt, Germany; Pfizer; Novartis Oncology; Puma Biotechnology; and Tesaro
Disclosure Regarding Unlabeled Use
This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration or European Medicines Agency. Please refer to the official prescribing information for each product discussed for discussions of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.