Lugano/Madrid, 27 September 2014 -- One of the most exciting features of immune checkpoint inhibitors (ICIs) is that they provide impressive tumour responses in metastatic cancers of different histologies, according to Dr Lillian L. Siu, professor of medicine and medical oncologist at the Princess Margaret Cancer Centre in Toronto, Canada. “The antitumour activity of ICIs appears to cross the traditional boundary of ‘immune-driven’ malignancies, namely melanoma and renal cell cancer,” she said.
Siu commented on checkpoint inhibition across malignant diseases as the latest research in the field was presented at the ESMO 2014 Congress in Madrid, Spain.
She said: “The remarkable antitumour activity encountered thus far across broad tumour types has generated an unprecedented wave of interest for ICIs in the field of oncology. The potential of these compounds given alone or in combination with existing therapeutics is enormous.”
Siu continued: “The strategy to harness the host’s immune system to fight cancer has been a cornerstone of immunotherapy in oncology and has gained substantial momentum with the emergence of ICIs. These agents block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death-1 (PD-1) and its ligand PD-L1, and thus liberate tumour-specific T cells to exert their effector function against tumour cells.”
Providing an overview of the ICIs approved or in development, Siu said: “Ipilimumab and pembrolizumab are the only two FDA-approved ICIs for the treatment of metastatic malignant melanoma. It is expected that other anti-PD-1/PD-L1 antibodies will achieve regulatory approval in the near future, likely first in melanoma. For anti-CTLA4 blockade, ipilimumab is the only antibody approved for clinical use and tremelimumab is presently undergoing phase II to III development. There are at least eight anti-PD-1/PD-L1 antibodies in clinical development, spanning phases I to III. These include nivolumab, pembrolizumab/MK-3475, pidilizumab and AMP-224 targeting PD-1; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting PD-L1. In addition, the preclinical and early clinical development of inhibitors against other immune checkpoints, such as TIM3, LAG3 and VISTA, and against costimulatory molecules, such as OX40 and CD137, are underway.”
“The clinical development of ICIs is most advanced in malignant melanoma,” continued Siu. “Besides the approval of ipilimumab, in September 2014, the FDA has granted pembrolizumab Accelerated Approval status for patients with advanced melanoma previously treated with ipilimumab.”
When tested as a single agent in 411 patients with advanced melanoma, pembrolizumab demonstrated an overall response rate of 34% by RECIST v1.1 in all patients, and a 28% response rate among those refractory to ipilimumab. The phase III CheckMate-066 trial comparing nivolumab versus dacarbazine in 418 patients with previously untreated BRAF wild-type advanced melanoma was stopped early because of an improvement in overall survival favouring the nivolumab arm. An expanded phase I study of the ICI doublet ipilimumab and nivolumab in 53 patients gave overall response rates of 42% and an impressive two-year overall survival rate of 79% across concurrent schedules tested.
“The efficacy results of ICIs in renal cell carcinomas are highly promising,” said Siu. The phase II CheckMate-010 study of nivolumab as monotherapy in 168 patients with advanced renal cell carcinoma previously treated with anti-angiogenic therapy reported an overall response rate of 20% to 22%. CheckMate-016, a multi-arm phase Ib study evaluating nivolumab in combination with targeted agents and with ipilimumab found overall response rates of 43% to 48% in the ICI doublet arms (n = 44) and progression-free survival rates at 24 weeks of about 65%. A phase I/II study to assess the safety and efficacy of pembrolizumab and pazopanib in patients with advanced renal cell carcinoma is ongoing (NCT02014636).
Siu discussed the clinical development of ICIs in tumour types beyond melanoma and renal cell carcinoma. These include non-small cell lung cancer, head and neck cancer and bladder cancer. She said: “In non-small cell lung cancer, ICIs --especially anti-PD-1/PD-L1 antibodies-- have garnered extensive interest. Overall response rates of these agents given as monotherapy have ranged from 10% to 24%. Many clinical trials are going to evaluate ICIs as first-line or in the relapsed setting of non-small cell lung cancer.”
In recurrent or metastatic squamous cell cancer of the head and neck, pembrolizumab produced an overall response rate of 20%, with subgroup analysis showing a higher response rate (45.5%) in those with tumours expressing PD-L1 above a cut point (1% of staining in tumour cells or stroma) versus 11.4% in those below the cut point. Similarly, preliminary data from MEDI4736 across different tumour types revealed an overall response rate of 14% in 22 patients with recurrent or metastatic squamous cell cancer of the head and neck, with a response rate of 50% in those whose tumours are PD-L1 positive versus 6% in those whose tumours are PD-L1 negative.
Siu said: “These data must be interpreted with caution as they are derived from single arm studies with limited numbers of patients. Regardless, these results have sparked the development of several planned or ongoing phase II and III trials in recurrent or metastatic squamous cell cancer of the head and neck, a disease where the only non-cytotoxic agent with FDA approval is the anti-epidermal growth factor receptor inhibitor, cetuximab.”
Results from an expanded phase I study of the anti-PD-L1 antibody MPDL3280A in 175 patients with melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial bladder cancer and other tumour types showed an overall response rate of 21%. In the cohort of 30 patients with PD-L1 positive (2+ or 3+ by immunohistochemistry) urothelial bladder cancer, an overall response rate of 42% was achieved. Among the 35 patients with PD-L1 negative tumours (0 or 1+ by immunohistochemistry), an overall response rate of 11% was reported.
On the topic of which patients will benefit from ICIs, Siu said: “At the present time, there are no validated markers to enable patient selection for ICIs, although different pharmaceutical companies have focused their efforts on companion diagnostic tests such as PD-L1 testing (for anti-PD-1/PD-L1 antibiotics). It appears that a proportion of PD-L1 negative patients may benefit from such agents, thus further complicating the selection strategy and trial designs.”
As ICIs continue to penetrate the field of oncology, Siu warned of the potential for adverse events. She said: “These compounds can give rise to immune-related adverse events that can be subtle and difficult to recognise, and unless managed with care and caution, they can lead to significant and life-threatening consequences.”
Siu’s group performed a systematic review of prospectively conducted clinical trials of ICIs, and evaluated their reporting of adverse events using a quality score adapted from the CONSORT harms extension statement. She said: “We recommend a standardised reporting method that accounts for tolerability, management and reversibility of immune-related adverse events to ensure completeness and transparency of published trial data. In addition, we are actively developing a standardised patient-reported tool to evaluate the impact of immune-related adverse events from ICIs on health related quality of life.”
Commenting on the data revealed at the ESMO 2014 Congress, Siu said: “Exciting results of phase I to III clinical trials of ICIs are being presented. As expected, the most mature data emerge from the development of such agents in melanoma. The late breaking results of two large randomised studies of ICIs (nivolumab; pembrolizumab) versus chemotherapy in patients with ipilimumab-refractory advanced melanoma are being presented. In the adjuvant setting, the phase III EORTC 18071 study of ipilimumab versus placebo after complete resection of stage III cutaneous melanoma demonstrated clinically and statistically significant improvement in recurrence-free survival. However, the ipilimumab arm had a higher incidence of immune-related adverse events and nearly half of the patients discontinued treatment due to toxicity (Eggermont et al. 1087O).”
She continued: “Phase IB and phase II trials report on the efficacy of ICIs administered as monotherapy or in combination in various solid tumours, including head and neck cancer (Chow LBA31; Fury et al. 988 PD), urothelial tract cancer (Plimack LBA23; Bellmunt et al 808O), renal cell cancer (McDermott et al 809O; Motzer et al. 810O; Hammers 1050O), and mixed histologies (Segal et al 1058PD).”
Siu concluded: “Finally, combination studies of ICIs with cytotoxic chemotherapy, or with molecularly targeted agents such as inhibitors of the epidermal growth factor receptor or angiogenesis, are actively being conducted with acceptable safety profiles in most cases (Gettinger et al. 1054PD; Lieu et al. 1049O).”
Notes to Editors
1Antoni Ribas FSH, Richard Kefford, Omid Hamid, Adil Daud, Jedd D. Wolchok, Wen-Jen Hwu, Tara C. Gangadhar, Amita Patnaik, Anthony M. Joshua, Peter Hersey, Jeffrey S. Weber, Roxana Stefania Dronca, Hassane M. Zarour, Kevin Gergich, Xiaoyun (Nicole) Li, Robert Iannone, Soonmo Peter Kang, Scot Ebbinghaus, Caroline Robert; David Geffen. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s 2014; (suppl; abstr LBA9000^).
2Phase 3 First-Line Melanoma Study of Nivolumab, an Investigational PD-1 Checkpoint Inhibitor, Demonstrates Superior Overall Survival Compared to Dacarbazine; Study Stopped Early
3Mario Sznol HMK, Margaret K. Callahan, Michael Andrew Postow, Ruth Ann Gordon, Neil Howard Segal, Naiyer A. Rizvi, Alexander M. Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda L. Ralabate, Angel L. Rivera, Stephanie Anne Kronenberg, Blessing Agunwamba, William Feely, Quan Hong, Suba Krishnan, Ashok Kumar Gupta, Jedd D. Wolchok. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol 32:5s 2014; (suppl; abstr LBA9003^).
4Robert J. Motzer BIR, David F. McDermott, Bruce G. Redman, Timothy Kuzel, Michael Roger Harrison, Ulka N. Vaishampayan, Harry A. Drabkin, Saby George, Theodore F. Logan, Kim Allyson Margolin, Elizabeth R. Plimack, Ian Waxman, Alexandre Lambert, Hans J. Hammers. Nivolumab for metastatic renal cell carcinoma (mRCC): Results of a randomized, dose-ranging phase II trial. J Clin Oncol 32:5s 2014; (suppl; abstr 5009).
5Hans J. Hammers ERP, Jeffrey R. Infante, Marc S. Ernstoff, Brian I. Rini, David F. McDermott, Albiruni R. A. Razak, Sumanta Kumar Pal, Martin Henner Voss, Padmanee Sharma, Christian K. Kollmannsberger, Daniel Yick Chin Heng, Jennifer L. Spratlin, Yun Shen, John F. Kurland, Paul Gagnier, Asim Amin. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 32:5s 2014; (suppl; abstr 4504).
6David F. McDermott JRI, Martin Henner Voss, Robert J. Motzer, John B. A. G. Haanen, Simon Chowdhury, Rodolfo F. Perini, Robert Iannone, Rachel Hodge, David Figueroa, Benjamin B. Suttle, Alicia Allred, Stephen D. Rubin, Brian I. Rini. A phase I/II study to assess the safety and efficacy of pazopanib and MK-3475 in subjects with advanced renal cell carcinoma. J Clin Oncol 32:5s 2014; (suppl; abstr TPS4604^).
7Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control 2014; 21: 80-89.
8Tanguy Y. Seiwert BB, Jared Weiss, Iris Gluck, Joseph Paul Eder, Sara I Pai, Marisa Dolled-Filhart, Kenneth Emancipator, Kumudu Pathiraja, Christine Gause, Robert Iannone, Holly Brown, Jennifer Houp, Jonathan D. Cheng, Laura Quan Man Chow. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. J Clin Oncol 32:5s 2014; (suppl; abstr 6011).
9Neil Howard Segal, Scott Joseph Antonia, Julie R. Brahmer, Michele Maio, Andy Blake-Haskins, Xia Li, Jim Vasselli, Ramy A. Ibrahim, Jose Lutzky, Samir Khleif. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol 32:5s, 2014 (suppl; abstr 3002^).
10Neil Howard Segal SJA, Julie R. Brahmer, Michele Maio, Andy Blake-Haskins, Xia Li, Jim Vasselli, Ramy A. Ibrahim, Jose Lutzky, Samir Khleif. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol 32:5s 2014; (suppl; abstr 3002^).
11Wei-Wu Chen ARAR, Philippe L. Bedard, Lillian L. Siu, Aaron Richard Hansen. A systematic review of immune-related adverse event (irAE) reporting in clinical trials of immune checkpoint inhibitors (ICIs). J Clin Oncol 32:5s 2014; (suppl; abstr 3057).
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