JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
INHIBITION OF PD-1
glycoprotein-100 peptide vaccine (10.1 vs 6.4 months). 15 The impressive findings from this study were the one and two year OS rates for the ipilimumab arm: 45.6% and 23.5% respectively. Similar rates were seen in the combination arm. The 1-year OS rate was higher than any other experimental regimen for patients with metastatic melanoma. In the second phase III trial, previously untreated patients with metastatic melanoma were treated with ipilimumab plus dacarbazine versus dacarbazine alone. 14 The combination group median OS was superior to the dacarbazine alone group (11.2 vs 9.2 months). In both phase III trials, the response rate was only 10-15% and the disease control rate (complete response, partial response, and stable disease) was 30%. Pooled analysis of 10 prospective and two retrospective studies of ipilimumab as monotherapy in patients with advanced melanoma showed a three year OS of 22%. 16 A substantial number of patients in both trials continued to have long disease control more than five years after completion of therapy.
Programmed cell death ligand 1 (PD-L1) is expressed by many cells to induce immune tolerance. 17 The interaction between PD- L1 with the programmed cell death protein 1 (PD-1) receptor on CTLs leads to immune tolerance by causing apoptosis of the T cell. 18 So, for example, melanoma cells expressing PD-L1 on the tumor surface can evade host immune response through this down regulation. Antibodies directed against PD-1 or PD- L1 would be expected to block the down regulatory signal of the tumor and restore antitumor immunity within the tumor microenvironment (Figure 5). Clinical activity of the anti-PD-1monoclonal antibody nivolumab has been shown to result in OS rates of 62% at 1 year, 43% at two years, and 41 percent at three years. 19 Data presented at the 2016 American Association for Cancer Research (AACR) Annual Meeting showed a robust five year OS of 34% for patients with advanced melanoma treated with nivolumab. 20 The study population had never been treated with ipilimumab and had received between one and five prior therapies for their disease. Nivolumab has been studied as a second line setting. The Checkmate-037 trial randomized nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma whose disease had progressed after ipilimumab and a BRAF inhibitor administration if the tumor contained a BRAF V600 mutation. The study showed a superior overall response rate (ORR) in the nivolumab group of 31.7%, compared to an ORR of 10.6% in the chemotherapy arm. 21 Nivolumab has also been studied head-to-headwith ipilimumab in patients with metastatic melanoma, in the first-line setting. Checkmate-067 was a randomized phase III trial comparing ipilimumab to nivolumab in patients with advanced melanoma who were naïve to immunotherapy. 22 The ORR was 43.7% with nivolumab compared to 19.0% with ipilimumab. Nivolumab also had a longer PFS (HR, 0.57, P<0.001). A second PD-1 inhibitor, pembrolizumab has shown substantial activity in metastatic melanoma. 23 Pembrolizumab’s strong clinical activity was first seen in the phase-1 KEYNOTE-001 trial where pembrolizumab was shown to produce durable responses in both ipilimumab-naïve and previously treated patients with melanoma with an ORR of 33%. 24 KEYNOTE-002 was a phase II trial comparing pembrolizumab to physician’s choice of chemotherapy in patients with advanced melanoma. 25 Superior clinical activity was seen in the pembrolizumab group with an ORR of 25% vs 4% in the chemotherapy arm. Median PFS was 5.6 months vs. 3.6 months in the pembrolizumab and chemotherapy arms, respectively. OS was similar, however, crossover from the chemotherapy to pembrolizumab arms was permitted, making OS assessments difficult. Like nivolumab, pembrolizumab has also been studied head- to-head with ipilimumab. The Phase III study KEYNOTE-006 compared pembrolizumab versus ipilimumab in patients with melanoma whowere naïve to immunotherapy. 26 ORRwas higher
Figure 4. CTLA-4 functions as a negative co-stimulatory molecule on T-Cells. Blocking CTLA-4 maintains T-cell activation and proliferation, which promotes anti-tumor activity. TCR- T cell receptor, APC- Antigen Presenting Cell, MHC- Major Histocompatability Complex
80 J La State Med Soc VOL 169 MAY/JUNE 2017
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