JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
in the pembrolizumab arm, 33.7% vs. 11.9%. The 6-month PFS rates were 47.3% in the pembrolizumab arm vs 26.5% in the ipilimumab arm. The data from KEYNOTE-006 and Checkmate-067 confirm the clinical superiority of anti-PD-1 therapy versus anti-CTLA-4 therapy in patients with metastatic melanoma.
patients with BRAF-wildtype tumors, the ORR was 61% in the combination group compared to 11% in the ipilimumab alone group. Median PFS was not reached in the combination group vs 4.4 months in the ipilimumab alone group. Checkmate-067 was a three arm, double blind, phase III trial that randomized patients to nivolumab alone, nivolumab plus ipilimumab followed by nivolumab maintenance, or ipilimumab alone. 22 The median PFS in the combination group was 11.5 months compared to 2.9 months in the ipilimumab group and 6.9 months in the nivolumab alone group. The results from Checkmate-069 and Checkmate-067 studies show that the combination of ipilimumab and nivolumab produces impressive antitumor activity.
IMMUNOTHERAPY TOXICITIES
Despite immunotherapy’s benefits, treatment with checkpoint inhibitors is associated with a unique spectrum of side effects termed immune-related adverse events (IrAEs). The most common IrAEs reported have been arthralgia, nausea, diarrhea, fatigue, pruritis, rash, and hypothyroidism. Severe cases of colitis, dermatitis, pneumonitis, and hepatitis have been reported in 1% or less of patients. IrAEs of any grade with ipilimumab occur in the majority of patients, as seen in 64.2% of patients in a pooled analysis of 14 phase I–III studies of ipilimumab. 30 Most toxicities are mild to moderate (grade 1–2), involve mainly skin and GI events. Furthermore, the incidence and severity of ipilimumab toxicities appear to be dose related. The rates of severe events (grade 3-5) in anti-PD-1 therapy have been lower than those seen with ipilimumab, occurring in 14% of patients treated with either pembrolizumab or nivolumab. 23,28 Optimal management of IrAEs includes the early recognition and the appropriately timed use of immunosuppressive agents, such as steroids or anti-TNF-α drugs, based on the severity of the event.
Figure 5. The interaction between PD-1 and PD-L1 can lead to immune tolerance and T-cell apoptosis. By blocking this interaction, antibodies against PD-1/PD-L1 can restore antitumor activity within the tumor microenvironment and activate the immune system to attack tumor cells. TCR- T cell receptor, MHC- Major Histocompatability Complex
DISCUSSION
COMBINATION IMMUNOTHERAPY
The development of checkpoint inhibitor immunotherapy has significantly changed the treatment landscape of advanced melanoma treatment. Anti-CTLA-4 and anti-PD-1 based therapies can produce response rates of above 50% and have been proven to be safer and more effective than traditional therapies such as systemic IL-2. Historically metastatic melanoma has been associated with a poor prognosis, with a median OS of 8-10 months, and a five-year survival of 10%. Immunotherapy has shown to significantly prolong the PFS as well as show a durable response with a 34% five-year response rate for nivolumab monotherapy. Harnessing the body’s immune system to target tumor cells is an effective and relatively safe approach to treating such an aggressive disease. As other promising immunotherapies for melanoma proceed through clinical trials, the more we will begin to understand the natural course of melanoma and the interaction between the body’s immune system and tumor cells. This understanding will ultimately lead to more treatment options for our patients, and ultimately longer survivals for those affected by advanced melanoma.
Preclinical models have suggested that combining PD-1 and CTLA-4 blockade could alter antitumor activity greater than either strategy alone. 27 Combination therapy increased the degree of tumor response and was associated with larger numbers of effector T cells in the TME in murine models. CTLA-4 mediated inhibition of T-cell activation and proliferation occurs at the site of antigenpresentation in the lymphoid compartment, while inhibition mediated by the PD-1 pathway occurs at the tumor site. This synergistic concept was studied in several trials, with promising results. A phase 1 trial of nivolumab and ipilimumab in patients with advanced melanoma demonstrated an ORR of 43% and a two year OS of 79%. 28 Subsequently, two randomized trials (Checkmate- 067 and Checkmate- 069) were conducted to further examine combination immunotherapy. Checkmate-069 was a double-blinded phase II trial, randomizing patients to ipilimumab plus nivolumab vs. ipilimumab alone, followed by nivolumab maintenance until disease progression. 29 In
J La State Med Soc VOL 169 MAY/JUNE 2017 81
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