2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond (2015)

The history of clinical oncology has witnessed several revolutionary therapeutic advances that have significantly improved cancer care. These have included the introduction of cisplatin in the 1970s for testicular and ovarian cancers, the taxanes in the 1990s for breast and other solid tumors, targeted therapy with anti-HER2 for breast cancer and c-Kit inhibitors for chronic myeloid leukemia and other cancers at the start of this millennium. Each of these treatments has revolutionized outcomes for patients with various types of cancer. Today, we are at the start of a new era in cancer care — that of immunotherapy. The approval of sipuleucel-T for the treatment of prostate cancer in 2010 and ipilimumab (anti-CTLA-4) for advanced melanoma in 2011 was the first notable success in the immunotherapy of cancer. After almost three years from the approval of the first checkpoint inhibitor (ipilimumab), the good news is not over. Quite the contrary, we are only at the beginning and, notably, these advances do not relate just to the treatment of melanoma. Immunotherapy has become the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy (including targeted therapy). This can be attributed primarily to the impact that another group of checkpoint inhibitors, the anti-PD-1/PD-L1 agents, is having on the treatment of various malignancies.As with anti-CTLA-4, the anti-PD-1/PD-L1 story starts with melanoma. Data from a large phase I study with pembrolizumab (Robert et al., 2014aRobert C. Ribas A. Wolchok J.D. Hodi F.S. Hamid O. Kefford R. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384 (Sep 20): 1109-1117Summary Full Text Full Text PDF PubMed Scopus (1412) Google Scholar, Robert et al., 2014bRobert C. Long G.V. Brady B. Dutriaux C. Maio M. Mortier L. Hassel J.C. Rutkowski P. McNeil C. Kalinka-Warzocha E. Savage K.J. Hernberg M.M. Lebbé C. Charles J. Mihalcioiu C. Chiarion-Sileni V. Mauch C. Cognetti F. Arance A. Schmidt H. Schadendorf D. Gogas H. Lundgren-Eriksson L. Horak C. Sharkey B. Waxman I.M. Atkinson V. Ascierto P.A. Nivolumab in previously untreated melanoma without BRAF mutation.N. Engl. J. Med. 2014; (Nov 16)https://doi.org/10.1056/NEJMoa1412082Crossref Scopus (3933) Google Scholar) led to its approval by the US Food and Drug Administration (FDA) in September 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This study of 411 patients showed that pembrolizumab resulted in an overall response rate (ORR) of 34%, a median progression-free survival (PFS) of 5.5 months, and overall survival (OS) rates of 69% at one year and 62% at 18 months. Moreover, a randomized phase II trial with pembrolizumab at two different dosages (2 mg/kg or 10 mg/kg every three weeks) in advanced melanoma refractory to previous ipilimumab therapy showed that both doses improved PFS compared with investigator choice chemotherapy (Ribas et al., 2014Ribas A. Wolchok J.D. Robert C. et al.Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (pembro, MK-3475) in 411 patients (pts) with melanoma (MEL).Pigment Cell Melanoma Res. 2014; 27: 1222Google Scholar). In fact, the 6-month PFS was 34% with pembrolizumab 2 mg/kg, 38% with pembrolizumab 10 mg/kg and 16% with chemotherapy, while the 9-month PFS was 24%, 29% and 8% respectively. The ORR in the three groups was 21%, 25% and 4%, respectively.More recently, in December 2014, another anti-PD-1, nivolumab, was approved by the FDA for patients with advanced melanoma with the same indication as pembrolizumab. Data from a large phase I trial with nivolumab showed an ORR of 32% and 1, 2, 3, and 4-year OS rates of 63%, 48%, 42%, and 32%, respectively. In addition, data from a phase III study in patients with metastatic melanoma previously treated with ipilimumab reported that nivolumab had an ORR of 32% compared with 11% with the chemotherapy control arm (D'Angelo et al., 2014D'Angelo S.P. Larkin J. Weber J. et al.Efficacy and Safety of Nivolumab vs Investigator's Choice Chemotherapy (ICC) in Subgroups of Patients with Advanced Melanoma after Prior Anti-CTLA-4 Therapy. SMR, 2014Google Scholar). Nivolumab was also compared to chemotherapy in another randomized phase III trial in which untreated patients with advanced BRAF wild-type melanoma received either nivolumab or dacarbazine. The ORR was 40.0% in the nivolumab group versus 13.9% in the dacarbazine group. At 1 year, the OS was 73.0% in the nivolumab group compared with 42.1% in the dacarbazine group. Median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (Robert et al., 2014aRobert C. Ribas A. Wolchok J.D. Hodi F.S. Hamid O. Kefford R. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384 (Sep 20): 1109-1117Summary Full Text Full Text PDF PubMed Scopus (1412) Google Scholar, Robert et al., 2014bRobert C. Long G.V. Brady B. Dutriaux C. Maio M. Mortier L. Hassel J.C. Rutkowski P. McNeil C. Kalinka-Warzocha E. Savage K.J. Hernberg M.M. Lebbé C. Charles J. Mihalcioiu C. Chiarion-Sileni V. Mauch C. Cognetti F. Arance A. Schmidt H. Schadendorf D. Gogas H. Lundgren-Eriksson L. Horak C. Sharkey B. Waxman I.M. Atkinson V. Ascierto P.A. Nivolumab in previously untreated melanoma without BRAF mutation.N. Engl. J. Med. 2014; (Nov 16)https://doi.org/10.1056/NEJMoa1412082Crossref Scopus (3933) Google Scholar).Considering historical data with a typical median OS of 6.2 months and 1-year OS rate of 25.5% and 1 and 2-year OS rates of 45% and 24% obtained with ipilimumab therapy in the treatment of advanced melanoma, the results achieved with anti-PD-1 therapy represent a terrific improvement in clinical benefit for these patients. Moreover, these data obtained in melanoma patients are just the start.OS data from a phase I study of nivolumab in solid tumors were particularly encouraging, even in patients with non-small-cell lung cancer (NSCLC), with a median OS of 9.6 months, 1-year OS of 42% and 2-year OS of 24%. Moreover, in a phase II study in patients with advanced, refractory NSCLC, nivolumab was associated with an ORR of 15% and a median OS of 8.2 months (Ramalingam et al., 2014Ramalingam S.S. Mazieres J. Planchard D. et al.Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer.in: Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1; Chicago, IL. 2014Summary Full Text Full Text PDF Google Scholar). Historically, these patients have ORRs of between 2 and 8% and a median OS of about 5 months. The estimated 1-year survival rate was 41%, which also compares favorably with historical data for patients with third-line squamous cell NSCLC of 1-year OS rates of 5.5–18%. Pembrolizumab has also shown interesting results in NSCLC. In the NSCLC expansion cohort of a phase I trial, pembrolizumab treatment resulted in an ORR of 21%. The median PFS in treatment-naïve patients was 27 weeks and 6-months OS was 86%, while in pretreated patients median PFS was 10 weeks and 6-months OS was 59% (Garon et al., 2014Garon E.B. Gandhi L. Rizvi N. et al.Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC). ESMO, 2014Google Scholar).Interesting preliminary results have also been reported for urothelial bladder cancer (UBC) and triple negative breast cancer (TNBC). In patients with platinum-pretreated, metastatic UBC, the ORR obtained with an anti-PD-L1 antibody (MPDLA3280) was between 11% and 43%, depending on the level of PD-L1 (Powles et al., 2014Powles T. Eder J.P. Fine G.D. Braiteh F.S. Loriot Y. Cruz C. Bellmunt J. Burris H.A. Petrylak D.P. Teng S.L. Shen X. Boyd Z. Hegde P.S. Chen D.S. Vogelzang N.J. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature. 2014; 515: 558-562Crossref PubMed Scopus (1805) Google Scholar). In patients with heavily pretreated advanced TNBC, pembrolizumab achieved an ORR of 18.5% with a durable response (median response duration was not reached) (Nanda et al., 2014Nanda R. Chow L.Q. Dees E.C. Berger R. Gupta S. Geva R. et al.KEYNOTE 012: triple negative breast cancer.in: S. Antonio Breast Cancer Symposium, December 9–13, 2014. 2014Google Scholar).Anti-PD-1 therapy has also achieved interesting results in patients with hematological malignancies. In a small phase I study that enrolled 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated, nivolumab resulted in a clinical benefit in all patients; the ORR was 87% (20/23), with 17% having a complete response and 70% a partial response. The remaining three patients (13%) all had stable disease (Ansell et al., 2014Ansell S.M. Lesokhin A.M. Borrello I. Halwani A. Scott E.C. Gutierrez M. Schuster S.J. Millenson M.M. Cattry D. Freeman G.J. Rodig S.J. Chapuy B. Ligon A.H. Zhu L. Grosso J.F. Kim S.Y. Timmerman J.M. Shipp M.A. Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.N. Engl. J. Med. 2014; (Dec 6)https://doi.org/10.1056/NEJMoa1411087Crossref Scopus (2570) Google Scholar). PFS at 6 months was 86%. In another phase Ib study, pembrolizumab also demonstrated promising antitumor activity in patients with heavily pretreated Hodgkin's lymphoma, with a 21% complete remission rate and an ORR of 65% (Craig et al., 2014Craig H.M. Robrag V. Michot J.M. et al.PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). ASH, 2014Google Scholar).What can we expect during 2015? New data in other types of cancer are surely expected. Studies with anti-PD-1/PD-L1 are ongoing in gastric cancer, small-cell lung cancer, glioblastoma, colorectal cancer, Merkel cell carcinoma and others. There are also likely to be more data concerning the role of PD-L1 as a predictive marker, even though data from phase III studies in melanoma seem to refute such a role. We will also see more important news on the potential of anti-PD-1/PD-L1s in combination with other approaches, including other immunotherapies (e.g. checkpoint inhibitors), radiotherapy, chemotherapy and targeted agents. We are observing the beginning of another new era in the fight against cancer: that of anti-PD-1/PD-L1 therapy.Conflicts of InterestPaolo A. Ascierto has/had an advisory/consultant role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Glaxo SmithKline, Ventana, Amgen, and Novartis. He also received research funds from Bristol Myers Squibb , Roche-Genentech , and Ventana . Francesco Marincola has no conflicts of interest to declare. The history of clinical oncology has witnessed several revolutionary therapeutic advances that have significantly improved cancer care. These have included the introduction of cisplatin in the 1970s for testicular and ovarian cancers, the taxanes in the 1990s for breast and other solid tumors, targeted therapy with anti-HER2 for breast cancer and c-Kit inhibitors for chronic myeloid leukemia and other cancers at the start of this millennium. Each of these treatments has revolutionized outcomes for patients with various types of cancer. Today, we are at the start of a new era in cancer care — that of immunotherapy. The approval of sipuleucel-T for the treatment of prostate cancer in 2010 and ipilimumab (anti-CTLA-4) for advanced melanoma in 2011 was the first notable success in the immunotherapy of cancer. After almost three years from the approval of the first checkpoint inhibitor (ipilimumab), the good news is not over. Quite the contrary, we are only at the beginning and, notably, these advances do not relate just to the treatment of melanoma. Immunotherapy has become the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy (including targeted therapy). This can be attributed primarily to the impact that another group of checkpoint inhibitors, the anti-PD-1/PD-L1 agents, is having on the treatment of various malignancies. As with anti-CTLA-4, the anti-PD-1/PD-L1 story starts with melanoma. Data from a large phase I study with pembrolizumab (Robert et al., 2014aRobert C. Ribas A. Wolchok J.D. Hodi F.S. Hamid O. Kefford R. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384 (Sep 20): 1109-1117Summary Full Text Full Text PDF PubMed Scopus (1412) Google Scholar, Robert et al., 2014bRobert C. Long G.V. Brady B. Dutriaux C. Maio M. Mortier L. Hassel J.C. Rutkowski P. McNeil C. Kalinka-Warzocha E. Savage K.J. Hernberg M.M. Lebbé C. Charles J. Mihalcioiu C. Chiarion-Sileni V. Mauch C. Cognetti F. Arance A. Schmidt H. Schadendorf D. Gogas H. Lundgren-Eriksson L. Horak C. Sharkey B. Waxman I.M. Atkinson V. Ascierto P.A. Nivolumab in previously untreated melanoma without BRAF mutation.N. Engl. J. Med. 2014; (Nov 16)https://doi.org/10.1056/NEJMoa1412082Crossref Scopus (3933) Google Scholar) led to its approval by the US Food and Drug Administration (FDA) in September 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This study of 411 patients showed that pembrolizumab resulted in an overall response rate (ORR) of 34%, a median progression-free survival (PFS) of 5.5 months, and overall survival (OS) rates of 69% at one year and 62% at 18 months. Moreover, a randomized phase II trial with pembrolizumab at two different dosages (2 mg/kg or 10 mg/kg every three weeks) in advanced melanoma refractory to previous ipilimumab therapy showed that both doses improved PFS compared with investigator choice chemotherapy (Ribas et al., 2014Ribas A. Wolchok J.D. Robert C. et al.Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (pembro, MK-3475) in 411 patients (pts) with melanoma (MEL).Pigment Cell Melanoma Res. 2014; 27: 1222Google Scholar). In fact, the 6-month PFS was 34% with pembrolizumab 2 mg/kg, 38% with pembrolizumab 10 mg/kg and 16% with chemotherapy, while the 9-month PFS was 24%, 29% and 8% respectively. The ORR in the three groups was 21%, 25% and 4%, respectively. More recently, in December 2014, another anti-PD-1, nivolumab, was approved by the FDA for patients with advanced melanoma with the same indication as pembrolizumab. Data from a large phase I trial with nivolumab showed an ORR of 32% and 1, 2, 3, and 4-year OS rates of 63%, 48%, 42%, and 32%, respectively. In addition, data from a phase III study in patients with metastatic melanoma previously treated with ipilimumab reported that nivolumab had an ORR of 32% compared with 11% with the chemotherapy control arm (D'Angelo et al., 2014D'Angelo S.P. Larkin J. Weber J. et al.Efficacy and Safety of Nivolumab vs Investigator's Choice Chemotherapy (ICC) in Subgroups of Patients with Advanced Melanoma after Prior Anti-CTLA-4 Therapy. SMR, 2014Google Scholar). Nivolumab was also compared to chemotherapy in another randomized phase III trial in which untreated patients with advanced BRAF wild-type melanoma received either nivolumab or dacarbazine. The ORR was 40.0% in the nivolumab group versus 13.9% in the dacarbazine group. At 1 year, the OS was 73.0% in the nivolumab group compared with 42.1% in the dacarbazine group. Median PFS was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (Robert et al., 2014aRobert C. Ribas A. Wolchok J.D. Hodi F.S. Hamid O. Kefford R. et al.Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384 (Sep 20): 1109-1117Summary Full Text Full Text PDF PubMed Scopus (1412) Google Scholar, Robert et al., 2014bRobert C. Long G.V. Brady B. Dutriaux C. Maio M. Mortier L. Hassel J.C. Rutkowski P. McNeil C. Kalinka-Warzocha E. Savage K.J. Hernberg M.M. Lebbé C. Charles J. Mihalcioiu C. Chiarion-Sileni V. Mauch C. Cognetti F. Arance A. Schmidt H. Schadendorf D. Gogas H. Lundgren-Eriksson L. Horak C. Sharkey B. Waxman I.M. Atkinson V. Ascierto P.A. Nivolumab in previously untreated melanoma without BRAF mutation.N. Engl. J. Med. 2014; (Nov 16)https://doi.org/10.1056/NEJMoa1412082Crossref Scopus (3933) Google Scholar). Considering historical data with a typical median OS of 6.2 months and 1-year OS rate of 25.5% and 1 and 2-year OS rates of 45% and 24% obtained with ipilimumab therapy in the treatment of advanced melanoma, the results achieved with anti-PD-1 therapy represent a terrific improvement in clinical benefit for these patients. Moreover, these data obtained in melanoma patients are just the start. OS data from a phase I study of nivolumab in solid tumors were particularly encouraging, even in patients with non-small-cell lung cancer (NSCLC), with a median OS of 9.6 months, 1-year OS of 42% and 2-year OS of 24%. Moreover, in a phase II study in patients with advanced, refractory NSCLC, nivolumab was associated with an ORR of 15% and a median OS of 8.2 months (Ramalingam et al., 2014Ramalingam S.S. Mazieres J. Planchard D. et al.Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer.in: Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1; Chicago, IL. 2014Summary Full Text Full Text PDF Google Scholar). Historically, these patients have ORRs of between 2 and 8% and a median OS of about 5 months. The estimated 1-year survival rate was 41%, which also compares favorably with historical data for patients with third-line squamous cell NSCLC of 1-year OS rates of 5.5–18%. Pembrolizumab has also shown interesting results in NSCLC. In the NSCLC expansion cohort of a phase I trial, pembrolizumab treatment resulted in an ORR of 21%. The median PFS in treatment-naïve patients was 27 weeks and 6-months OS was 86%, while in pretreated patients median PFS was 10 weeks and 6-months OS was 59% (Garon et al., 2014Garon E.B. Gandhi L. Rizvi N. et al.Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC). ESMO, 2014Google Scholar). Interesting preliminary results have also been reported for urothelial bladder cancer (UBC) and triple negative breast cancer (TNBC). In patients with platinum-pretreated, metastatic UBC, the ORR obtained with an anti-PD-L1 antibody (MPDLA3280) was between 11% and 43%, depending on the level of PD-L1 (Powles et al., 2014Powles T. Eder J.P. Fine G.D. Braiteh F.S. Loriot Y. Cruz C. Bellmunt J. Burris H.A. Petrylak D.P. Teng S.L. Shen X. Boyd Z. Hegde P.S. Chen D.S. Vogelzang N.J. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature. 2014; 515: 558-562Crossref PubMed Scopus (1805) Google Scholar). In patients with heavily pretreated advanced TNBC, pembrolizumab achieved an ORR of 18.5% with a durable response (median response duration was not reached) (Nanda et al., 2014Nanda R. Chow L.Q. Dees E.C. Berger R. Gupta S. Geva R. et al.KEYNOTE 012: triple negative breast cancer.in: S. Antonio Breast Cancer Symposium, December 9–13, 2014. 2014Google Scholar). Anti-PD-1 therapy has also achieved interesting results in patients with hematological malignancies. In a small phase I study that enrolled 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated, nivolumab resulted in a clinical benefit in all patients; the ORR was 87% (20/23), with 17% having a complete response and 70% a partial response. The remaining three patients (13%) all had stable disease (Ansell et al., 2014Ansell S.M. Lesokhin A.M. Borrello I. Halwani A. Scott E.C. Gutierrez M. Schuster S.J. Millenson M.M. Cattry D. Freeman G.J. Rodig S.J. Chapuy B. Ligon A.H. Zhu L. Grosso J.F. Kim S.Y. Timmerman J.M. Shipp M.A. Armand P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.N. Engl. J. Med. 2014; (Dec 6)https://doi.org/10.1056/NEJMoa1411087Crossref Scopus (2570) Google Scholar). PFS at 6 months was 86%. In another phase Ib study, pembrolizumab also demonstrated promising antitumor activity in patients with heavily pretreated Hodgkin's lymphoma, with a 21% complete remission rate and an ORR of 65% (Craig et al., 2014Craig H.M. Robrag V. Michot J.M. et al.PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results from a phase 1b study (KEYNOTE-013). ASH, 2014Google Scholar). What can we expect during 2015? New data in other types of cancer are surely expected. Studies with anti-PD-1/PD-L1 are ongoing in gastric cancer, small-cell lung cancer, glioblastoma, colorectal cancer, Merkel cell carcinoma and others. There are also likely to be more data concerning the role of PD-L1 as a predictive marker, even though data from phase III studies in melanoma seem to refute such a role. We will also see more important news on the potential of anti-PD-1/PD-L1s in combination with other approaches, including other immunotherapies (e.g. checkpoint inhibitors), radiotherapy, chemotherapy and targeted agents. We are observing the beginning of another new era in the fight against cancer: that of anti-PD-1/PD-L1 therapy. Conflicts of InterestPaolo A. Ascierto has/had an advisory/consultant role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Glaxo SmithKline, Ventana, Amgen, and Novartis. He also received research funds from Bristol Myers Squibb , Roche-Genentech , and Ventana . Francesco Marincola has no conflicts of interest to declare. Paolo A. Ascierto has/had an advisory/consultant role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Glaxo SmithKline, Ventana, Amgen, and Novartis. He also received research funds from Bristol Myers Squibb , Roche-Genentech , and Ventana . Francesco Marincola has no conflicts of interest to declare.