January 2015, Vol. 2, No. 1

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Commercial Availability of Anti–PD-1 Antibodies in Melanoma: A Benchmark of Success

Brianna W. Hoffner, MS, RN, ANP-BC, AOCNP


On September 4, 2014, the FDA approved pembrolizumab for use in advanced or unresectable melanoma following progression on prior therapies. This approval was based on clinical data from the phase 1b KEYNOTE-001 trial and made pembrolizumab the first anti–PD-1 antibody to gain approval in the United States for any solid tumor. Subsequently, the FDA approved nivolumab for the same indication based on the phase 3 CheckMate-037 trial on December 22, 2014. The commercial availability of anti–PD-1 antibodies – therapies shown to be well tolerated with overall response rates higher than any other immunotherapy – has revolutionized the treatment of melanoma and mandated a discussion about therapeutic decisions.

Historically, the median overall survival for stage IV melanoma was less than 1 year, and the 5-year survival rate was approximately 10%.1 However, recent advances in immunotherapy, targeted therapy, and combination therapy have increased the anticipated survival rate to 20%.1 Previously, immunotherapy in melanoma focused entirely on high-dose interleukin-2 (HD IL-2), a T-cell–activating cytokine given in the inpatient setting with severe side effects, including hypotension, pulmonary edema, tachycardia, diarrhea, and chills. Overall response rates range from 6% to 16%, but selection of patients is limited to those with excellent cardiac and pulmonary function. Furthermore, patients with central nervous system (CNS) metastases are often excluded from HD IL-2 because of a concern for increased intracranial pressure from edema secondary to capillary leak syndrome.2 Given that brain metastases are clinically detected in nearly 50% of melanoma patients and are associated with significant mortality, this is an enormous treatment limitation.2

In 2011, the FDA approved ipilumumab for the treatment of unresectable or metastatic melanoma based on data from 2 randomized, controlled phase 3 trials (MDX010-20 and CA184-024). In MDX010-20, ipilimumab demonstrated improved overall survival (OS) versus the melanoma peptide vaccine gp100 (10.0 months vs 6.4 months, respectively). The hazard ratio for death was 0.66 for the ipilimumab group compared with the gp100 group. In CA184-024, patients were treated with ipilimumab plus dacarbazine versus dacarbazine plus placebo. The OS for these treatment groups was 11.2 months and 9.1 months, respectively. Additionally, a meta-analysis of pooled OS data from ipilimumab trials, which included 1861 patients with melanoma, demonstrated a 3-year OS rate of 22% and a plateau in the pooled Kaplan-Meier curve beginning at approximately 3 years after initiation of therapy and continuing through 10 years.1 In short, patients who respond to ipilimumab have the potential to be long-term responders and survivors in a fashion similar to IL-2. The ability to give ipilimumab to a greater proportion of patients in the outpatient setting revolutionized immunotherapy in melanoma. Finally, a 2010 study of ipilimumab in patients with CNS metastases (CA184-042) revealed similar levels of activity in brain and non-CNS lesions.3 Ipilimumab became the first nonchemotherapeutic agent known to cross the blood-brain barrier and provide a treatment option for patients with CNS metastases.

Ipilimumab is administered in the outpatient setting at a dose of 3 mg/kg every 3 weeks for a total of 4 doses. As physicians became more familiar with ipilimumab, concerns arose in relation to immune toxicities termed immune-related adverse events (irAEs). irAEs most commonly include colitis, hepatitis, dermatitis, and endocrinopathies. Colitis has been reported in up to 31% of patients, with 6% experiencing severe colitis.4 Treatment-related fatalities, although rare, have most commonly been associated with bowel perforation secondary to colitis. Hepatitis occurs less commonly, with an incidence ranging from 2% to 9%.4 However, hepatitis prevalence increases when ipilimumab is combined with other agents, including dacarbazine,5 vemurafenib,6 or anti–PD-L1 antibodies.7 Dermatitis is the most common ipilimumab-induced irAE, with approximately 40% of patients reporting dermatologic toxicity.4 Rashes are often associated with pruritus and are macular in nature. Endocrinopathies related to ipilimumab vary in nature and severity and include hypophysitis, hyperthyroidism, hypothyroidism, and adrenal insufficiency.

Ipilimumab has been the great teacher in the management of irAEs. As providers, we have gained an understanding of minor interventions including dietary modifications for colitis or topical agents for dermatitis, as well as more significant interventions such as high-dose systemic corticosteroids, anti–TNF-alpha agents, and antimetabolite immunosuppressants. irAEs are temporally different in occurrence from chemotherapeutic side effects, with some irAEs occurring months after initial administration. Armed with this new knowledge of targeted immunotherapies and the ability to safely manage them, the melanoma community welcomed the advent of anti–PD-1 antibodies.

KEYNOTE-001 investigated pembrolizumab in 411 patients with unresectable or metastatic melanoma at either 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Both ipilimumab-naive and -refractory patients were included in the trial, although patients with a history of severe immune-related toxicity to ipilimu­mab were excluded. Patient characteristics included a median age of 61 years, 60% male, 97% white, 73% with M1c disease, 8% with brain metastases, 35% with elevated lactate hydrogenase (LDH), 54% with prior exposure to ipilimumab, and 47% with ?2 prior systemic therapies for advanced or metastatic melanoma.

Of the patients refractory to ipilimumab, 89 received the 2-mg/kg dose and 84 received the 10-mg/kg dose. Thirteen percent tested positive for a BRAF mutation in the 2-mg/kg arm and 23% tested positive in the 10-mg/kg arm. Results presented at ASCO 2014 showed the overall response rate (ORR) for patients treated with the 2-mg/kg dose to be 26% by RECIST, with disease control in 51% of patients. The progression-free survival rate at 24 weeks was 44% with the 2-mg/kg dose and 37% with the 10-mg/kg dose. A subsequent updated analysis of the data submitted to the FDA noted an ORR in the 2-mg/kg arm of 24%, with 86% of patients still responding to therapy as of May 2014. Thus, the approved indication for pembrolizumab is for patients with unresectable or metastatic melanoma who have had prior ipilimumab therapy and, if BRAF positive, a prior BRAF inhibitor.

The safety profile for pembrolizumab was established based on the entire multicohort population of 411 patients. The drug was discontinued for adverse reactions in 9% of patients, with the most frequent serious adverse events (reported in ?2% of patients) being renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions of any grade include fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%). Of note, the incidence of irAEs is significantly less than that seen with ipilimumab, with colitis occurring in only 1% of patients, hepatitis in 0.5%, hypophysitis in 0.5%, hyperthyroidism in 1.2%, and hypothyroidism in 8.3%.

CheckMate-037 studied nivolumab versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma who were previously treated with ipilimumab. ICC was limited to either dacarbazine or the combination of carboplatin plus paclitaxel. Seventy-three percent of patients had received ?2 prior therapies for advanced or metastatic melanoma and 18% for brain metastasis. Data presented at ESMO 2014 included an ORR per RECIST of 32% in the nivolumab arm (n=120) versus 11% in the ICC reference arm (n=47). Similar to the pembrolizumab data, the majority of responses (95%) were ongoing in the nivolumab arm with the median duration of response not yet reached.

The safety profile for nivolumab was evaluated based on the 268 patients randomized to this treatment arm. Twenty-six percent of patients had a drug delay for an adverse reaction, and 9% of patients were discontinued for adverse reactions. Serious adverse reactions occurred in 41% of patients, with grade 3 or 4 reactions in 42% of patients. The most common grade 3 or 4 reactions occurring in 2% to 5% of patients included abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common reactions of any grade included rash (21%), pruritus (19%), cough (17%), upper respiratory tract infection (11%), and peripheral edema (10%).

KEYNOTE-001 and CheckMate-037 produced remarkably similar results and study characteristics. Pembrolizumab demonstrated an ORR of 24% in patients previously treated with ipilimumab and, when applicable, a BRAF inhibitor versus 32% in the same population for nivolumab. Responses were still ongoing in 86% of pembrolizumab patients at the time of evaluation versus 95% of nivolumab patients. Nine percent of patients in both studies discontinued treatment because of toxicity. The most common irAE in pembrolizumab patients was fatigue (47%) versus rash (21%) in nivolumab patients. Serious adverse reactions occurred in just 2% to 5% of patients in both studies.

One key difference in these anti–PD-1 antibodies is frequency of administration: pembrolizumab is dosed at 2 mg/kg every 3 weeks, and nivolumab is dosed at 3 mg/kg every 2 weeks. Nivolumab approval was based on a phase 3 trial that had duplicated the results of an earlier phase 1 study (Study-003). Pembrolizumab was based on a single phase 1b KEYNOTE-001 protocol, and subsequently second-line results were presented in KEYNOTE-002. Finally, CheckMate-037 included a slightly higher incidence of patients with CNS disease (18%) versus KEYNOTE-001 (8%), although a trial specifically investigating the efficacy of pembrolizumab in CNS disease is ongoing (NCT02085070), and therefore the significance of this discrepancy is unclear.

Today, those treating patients with melanoma are left in the unfamiliar but enviable position of being able to choose between multiple efficacious and well-tolerated therapies. The decision of whether to use pembrolizumab or nivolumab will likely be based on convenience, cost, and investigator familiarity. Because pembrolizumab is dosed every 3 weeks and nivolumab is dosed every 2 weeks, the difference in 17 infusions per year versus 26 infusions per year may be significant with regard to patient convenience and availability in oncology infusion rooms. As each drug is currently approved for indefinite dosing, pending intolerable toxicity or disease progression, issues with more frequent administration could be significant. Patient assistance programs, and the ease of consumer use and efficacy of such programs, will play a significant role. As physicians and providers begin dosing with these drugs, familiarity with ease of administration and lack of toxicity will provide a clear path for use of immunotherapy in other indications in the future.

Although the story of anti–PD-1 antibodies begins in the melanoma setting, ongoing trials are investigating these agents in nearly all cancer types, with particularly exciting results in non–small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, and lymphoma. Pembrolizumab recently gained breakthrough designation from the FDA for NSCLC based on a separate cohort of the same KEYNOTE-001 phase 1b study. The accelerated approval of these drugs speaks to successful trial design and implementation, allowing patients access to lifesaving therapies in an expedited fashion. Ongoing studies evaluate anti–PD-1 antibodies in the first-line setting (NCT01866319, NCT01844505) as well as in combination therapy (NCT02263508). Additionally, anti–PD-1 antibodies will soon be evaluated in the adjuvant melanoma setting, providing hope that fewer patients will reach stage IV disease. The cancer landscape has forever changed based on the first FDA approval of these 2 anti–PD-1 antibodies in metastatic melanoma. A benchmark has been set with a mandate for a brighter future for our patients.


  1. McDermott D, Lebbé C, Hodi FS, et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev. 2014;40:1056-1064.
  2. Guirguis LM, Yang JC, White DE, et al. Safety and efficacy of high-dose interleukin-2 therapy in patients with brain metastases. J Immunother. 2002;25:82-87.
  3. Lawrence DP, Hamid O, McDermott DF, et al. Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastases. J Clin Oncol. 2010;28(suppl). Abstract 8523.
  4. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
  5. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
  6. Ribas A, Hodi FS, Callahan M, et al. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365-1366.
  7. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
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FDA Grants Breakthrough Therapy Designation for Genentech’s Investigational Cancer Immunotherapy MPDL3280A (Anti–PD-L1) in Non–Small Cell Lung Cancer

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