Adjuvant Pembrolizumab (Keytruda®)
Posted: Monday, January 20, 2020
Immunotherapy that successfully overcomes tumor-mediated immune suppression has significantly shifted the landscape in the management of patients with advanced melanoma. The introduction of immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) monoclonal antibodies, has had a dramatic clinical impact on the treatment of patients with advanced melanoma, resulting in durable responses and longer survival with the possibility of a cure in some.1
Prior to 2015, interferon-α was the only type of immunotherapy approved by the U.S. Food and Drug Administration for adjuvant treatment of stage III melanoma. The results varied across trials,2 and a recent meta-analysis reported improvements in survival that are statistically significant but small.3 Interferon-α also is associated with substantial toxicity.4 In 2015, ipilimumab was the first immune checkpoint inhibitor to be approved for this indication. Ipilimumab significantly prolonged overall survival and distant metastasis–free survival compared with placebo in the phase III EORTC 18071 study.5 Despite these encouraging findings, approximately half (53%) of patients discontinued treatment due to adverse events, and there was a 1% drug-related mortality rate.5
The approvals of the anti–PD-1 monoclonal antibodies nivolumab and pembrolizumab followed for the adjuvant treatment of patients with melanoma with involvement of lymph node(s), after complete resection.6,7 In their respective trials, treatment with nivolumab or pembrolizumab resulted in a statistically significant improvement in recurrence-free survival when compared with ipilimumab or placebo, respectively.8,9 Additionally, nivolumab and pembrolizumab have similar toxicity profiles, and both are better tolerated than ipilimumab.8,9 The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (NCCN Guidelines) for Melanoma currently list pembrolizumab or nivolumab as preferred adjuvant systemic therapy options for resected stage III–IV cutaneous melanoma while reserving high-dose ipilimumab for certain circumstances.2
Noting that no head-to-head studies have directly compared the efficacy of pembrolizumab with nivolumab, Jennifer Wargo, MD, Professor in the Department of Genomic Medicine at The University of Texas MD Anderson Cancer Center, Houston, does not have a preference. “There is no significant advantage for one agent over the other. At MD Anderson, we have a large number of patients who travel from many hours away, so the every-4-week dosing of nivolumab can be appealing to them; however, every 3-week dosing with pembrolizumab is an option, too,” she acknowledged.
Weighing Risk Versus Benefit
Ryan Sullivan, MD, Associate Director of the Melanoma Program at Massachusetts General Hospital, Boston, and Dr. Wargo both told JNCCN 360 that adjuvant therapy is generally reserved for patients with stage IIIB–D disease. “The risk of recurrence is much lower in patients with stage IIIA disease, which means the risk/benefit ratio shifts,” explained Dr. Sullivan. “We know that most of those patients do really well and will not relapse anyway,” added Dr. Wargo. “It is very much a personalized conversation with the patient. Many of our treating oncologists would lean toward close surveillance with serial CT rather than treating them with adjuvant immune checkpoint blockade.”
Managing Common Side Effects of Pembrolizumab
Itch and Rash
Itching and/or rash is one of the first side effects to emerge after a patient starts pembrolizumab, and it can be bothersome if not proactively managed. “If a patient has profoundly dry skin prior to treatment, I work to improve the dryness before starting pembrolizumab,” said Krista Rubin, NP, of Massachusetts General Hospital, Boston. “I simply ask patients to start applying an over-the-counter, nonsteroid moisturizing agent every day to minimize itch.” She also advises clinicians to think about itch and rash separately, as they can present either independently or at the same time. “I’m much more aggressive with patients who experience itching, because being itchy is miserable; in contrast, you can have a rash and not be bothered by it at all.”
For relieving itch, Ms. Rubin suggests increasing the application of the moisturizer to twice a day and considering the addition of a topical steroid cream or ointment. Tepid water should be used for bathing, with the moisturizer applied within 3 minutes of bathing. “If those interventions don’t work, we will add a topical or oral antihistamine, such as cetirizine or fexofenadine, for daytime use and over-the-counter diphenhydramine or prescription hydroxyzine for nighttime relief.”
The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide additional recommendations for grade 2 and grade 3 pruritus.10
One interesting thing Ms. Rubin has noticed is the stark difference in skin habits between men and women. “I treat male and female patients very differently because men are often hesitant to moisturize. Some men completely refuse, so we have to use topical steroids more frequently.” Overall, itch and rash are “extraordinarily manageable,” according to Ms. Rubin. “Very rarely do we need to stop treatment for it.”
New or worsening fatigue that limits or interrupts an individual’s activities warrants prompt assessment.
Fatigue is another common complaint with pembrolizumab. “Mild fatigue is common within 12 to 24 hours after receiving an infusion,” explained Ms. Rubin. However, she stressed that fatigue with pembrolizumab should not limit day-to-day activities, unlike the type of fatigue associated with chemotherapy. “New or worsening fatigue that limits or interrupts an individual’s activities warrants prompt assessment. Something else may be going on, such as an evolving endocrinopathy—for example, thyroiditis.”
Joint aches and pains are also often experienced with pembrolizumab treatment and can range from mild to severe. Ms. Rubin pointed out that a thorough patient history may include important clues about what to watch for. “If patients have had an ‘old football injury,’ poor knees, or a previous musculoskeletal injury from sports or an accident, those inflammatory areas are much more likely to flare up during treatment,” she explained. Recent studies have revealed that when joint aches and pains associated with immune therapy are left untreated, they can lead to joint destruction.11 “Therefore, we really want to be proactive.”
In terms of management, Ms. Rubin starts with conservative measures such as over-the-counter nonsteroidal anti-inflammatory drugs at moderate doses. “Early intervention is key. For advanced practice providers, I recommend taking a comprehensive history to identify patients at risk and proactively referring to rheumatology.”
The NCCN Guidelines provide further recommendations for pain that limits activities of daily living.10
In the setting of treatment with checkpoint inhibitors, both Drs. Wargo and Sullivan stressed the importance of being aware of the potential for toxicity. “You must be cognizant of the toxicity you can see with these agents and how that would impact your management,” said Dr. Wargo. “We are seeing much more hypophysitis and adrenal crisis, which we never saw before treatment with checkpoint inhibitors. If these signs of toxicity are missed, patients may have delayed treatment, which could negatively affect outcomes.”
The most important thing about PD-1 inhibitor therapy is to be prepared for the toxicity.
“The most important thing about PD-1 inhibitor therapy is to be prepared for the toxicity,” emphasized Dr. Sullivan. “This means that staff are prepared to field phone calls about toxicity, but it also means doing appropriate baseline studies, so you are ready to perform diagnostic testing and appropriately treat as quickly as possible when a potential toxicity arises.” He identified myocarditis as a rare, but serious, side effect that can be quickly identified if a baseline troponin level has been drawn. “When myocarditis happens, it can be devastating. If the troponin level is dramatically higher than baseline, we can begin treatment promptly.”
Dr. Sullivan also recommends checking hepatitis B and tuberculosis status prior to therapy with checkpoint inhibitors. This is important because if toxicity develops during treatment that requires the use of infliximab, this immunosuppressive therapy may reactivate latent infections. “We know that 70% to 80% of patients will never need any of those baseline tests, but in the 20% to 30% who do need them, it is nice to have them rather than scrambling during a crisis.”
Ms. Rubin cautioned that although pembrolizumab is generally well tolerated, patients and providers must remain vigilant. “Immune effects can even occur after treatment is discontinued, because you have manipulated and ‘retrained’ the immune system.”
Next on the Horizon: Neoadjuvant Therapy?
“With the advent and use of targeted therapy and immunotherapy first in the setting of stage IV disease, and now in adjuvant therapy, we know these agents are highly effective,” said Dr. Wargo. Because adjuvant therapy clearly helps to prevent local and regional recurrence, research has shifted to the next question: Could neoadjuvant therapy offer patients a clinical advantage even earlier in treatment? Shrinking large tumors prior to surgery may increase the likelihood of complete surgical removal of disease and may decrease the need for postoperative radiation or other treatments. “There is a real clinical and scientific rationale for using these agents before surgery,” she explained. “For patients with stage IIIB–D melanoma and bulky nodal disease, the current standard of care is upfront surgery with or without adjuvant therapy. However, if these patients are treated with upfront surgery, a significant portion will relapse and potentially die of disease.”
Although the studies so far are randomized phase II trials and adjuvant and neoadjuvant therapies have not been directly compared, Dr. Wargo described several preclinical and clinical studies suggesting that not only is neoadjuvant therapy efficacious, it also stimulates a stronger immune response. A study published in Cancer Discovery revealed significantly greater therapeutic efficacy of neoadjuvant, compared with adjuvant, immunotherapy in mouse models of breast cancer to eradicate distant metastases after primary tumor resection.12 Additionally, elevated and sustained peripheral tumor-specific immune responses were observed in the neoadjuvant models.
The phase Ib OpACIN trial evaluated standard-dose ipilimumab (3 mg kg−1) plus nivolumab (1 mg kg−1) in both the adjuvant and neoadjuvant settings.13 In addition to a high pathologic complete response rate of 45% in the neoadjuvant arm after 6 weeks of treatment, “patients receiving neoadjuvant checkpoint blockade also had an expansion of tumor-reactive T cells in the peripheral blood,” said Dr. Wargo. However, 90% of patients in both arms experienced one or more grade 3 or 4 adverse events, warranting the exploration of alternatives with less toxicity. Subsequently, the OpACIN-neo trial confirmed the high pathologic response rate observed in the OpACIN trial with neoadjuvant ipilimumab plus nivolumab, but at lower doses with “tolerable” toxicity.14
Giving a single dose of pembrolizumab prior to resection was associated with a high degree of major pathologic response.
At the University of Pennsylvania, researchers found that giving a single dose of pembrolizumab prior to resection was associated with a high degree of major pathologic response.15 Additionally, they observed a rapid immune response in peripheral blood after PD-1 blockade, with T-cell re-invigoration peaking just 7 days after treatment. “These patients actually have a long-term, durable benefit,” said Dr. Wargo.
Several studies of neoadjuvant dabrafenib plus trametinib in patients with stage III/IV resectable BRAF V600–mutated melanoma have also produced positive results. A study published in The Lancet Oncology found that significantly more patients were alive without disease progression after 18.6 months of follow-up in the neoadjuvant-plus-adjuvant-treatment group compared with the standard-of-care (adjuvant-alone) group.16 In the NeoCombi trial, 12 weeks of neoadjuvant dabrafenib plus trametinib and an additional 40 weeks of adjuvant therapy yielded a complete pathologic response in 49% of patients after resection.17 “If patients with a BRAF mutation are treated with neoadjuvant plus adjuvant BRAF/MEK inhibitors, they do much better than patients who are treated with upfront surgery—that’s very clear,” Dr. Wargo told JNCCN 360. “Also, if patients have a pathologic complete response, they are likely to have long-term disease control compared with patients who failed to have pathologic complete response after 8 weeks of therapy.”
A pooled analysis presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting revealed that the achievement of a pathologic complete response with either neoadjuvant immune checkpoint blockade or targeted therapy appears to be correlated with improvement in relapse-free survival in patients with stage III melanoma.18 “What they found was quite striking,” Dr. Wargo told JNCCN 360. “Virtually all patients who were treated with checkpoint blockade in the neoadjuvant setting and achieved a pathologic complete response had long-term durable disease control.” However, this result was not observed in both cohorts: The recurrence rate for patients who achieved a pathologic complete response with targeted therapy was 41%.
That analysis was performed by the International Neoadjuvant Melanoma Consortium. “It is critical for us to collaborate on these efforts,” said Dr. Wargo, who is a member of the Consortium and coauthor of the organization’s white paper, published recently in The Lancet Oncology.19 “There are still a lot of unanswered questions that we must work together to answer.”
Dr. Sullivan agrees that although there are some “interesting” data, nothing generated in clinical trials so far has been practice-changing. “That’s mainly because there is no comparison between adjuvant and neoadjuvant therapies,” he explained. “I think we feel more comfortable using BRAF-targeted therapy to reduce the size of tumors based on some of the neoadjuvant data, but at this point, a patient who has bulky but resectable stage III melanoma should either have appropriate surgical management and be offered subsequent adjuvant therapy or be enrolled into a neoadjuvant clinical trial.”
Ryan Sullivan, MD, has received research funding from Amgen and Merck and has served on an advisory board or as a consultant for Novartis, Merck, Array Biopharma, Replimune, and Bristol-Myers Squibb.
Jennifer Wargo, MD, is an inventor on a U.S. patent application (PCT/US17/53.717) submitted by The University of Texas MD Anderson Cancer Center that covers methods to enhance immune checkpoint blockade responses by modulating the microbiome; reported compensation for speakers bureau and honoraria from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, PeerView, Physician Education Resource, MedImmune, Exelixis, and Bristol-Myers Squibb; served as a consultant/advisory board member for Roche/Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck, Biothera Pharmaceuticals, and Microbiome DX; and also received research support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis.
Krista Rubin, NP, has served on an advisory board or as a consultant for Merck, Bristol-Myers Squibb, and EMD Serono.
- Achkar T, Tarhini AA. The use of immunotherapy in the treatment of melanoma. J Hematol Oncol 2017;10:88.
- Coit DG, Thompson JA, Albertini MR, et al. NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. Version 2.2020—December 19, 2019. Accessed December 23, 2019. To view the most recent version of these guidelines, visit NCCN.org.
- Ives NJ, Suciu S, Eggermont AMM, et al. Adjuvant interferon-alpha for the treatment of high-risk melanoma: an individual patient data meta-analysis. Eur J Cancer 2017;82:171–183.
- Palumbo G, Di Lorenzo G, Ottaviano M, et al. The future of melanoma therapy: developing new drugs and improving the use of old ones. Future Oncol 2016;12:2531–2534.
- Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–1855.
- S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-nivolumab-adjuvant-treatment-melanoma. Accessed December 23, 2019.
- S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves pembrolizumab for adjuvant treatment of melanoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adjuvant-treatment-melanoma. Accessed December 23, 2019.
- 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;377:1824–1835.
- Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III Melanoma. N Engl J Med 2018;378:1789–1801.
- Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities. Version 1.2020—December 16, 2019. Accessed January 13, 2019. To view the most recent version of these guidelines, visit NCCN.org.
- Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017;76:43–50.
- Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 2016;6;1382–1399.
- Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:1655–1661.
- Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol 2019;20:948–960.
- Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med 2019;25:454–461.
- Amaria RN, Prieto PA, Tetzlaff MT, et al. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol 2018;19:181–193.
- Long GV, Saw RPM, Lo S, et al. Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAFV600 mutation-positive melanoma (NeoCombi): a single-arm, open-label, single-centre, phase 2 trial. Lancet Oncol 2019;20:961–971.
- Menzies AM, Rozeman EA, Amaria RN, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium. J Clin Oncol 37(15 suppl):9503.
- Amaria RN, Menzies AM, Burton EM, et al. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium. Lancet Oncol 2019;20:e378–e389.