Immune checkpoint blockade
Targeting the immune system instead of the cancer cells, these new drugs are revolutionizing the treatment of cancer.
More specifically, proteins of the immune-checkpoint pathways on the surface of T cells play important roles in the development of immune tolerance. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling for instance, inhibits T-cell activation. Thus CTLA-4 blockade using anti-CTLA-4 monoclonal antibody therapy has great potential because suppression of inhibitory signals results in the generation of an antitumor T-cell response. Other important immune-checkpoint proteins are Programmed cell Death protein 1 (PD-1), and Programmed Death-Ligand 1 (PD-L1), its ligand.
MAbs against CTLA-4 and PD-1 are furthest along in clinical development, with 3 approved drugs among them. Another important target with a number of drugs in late stage development is PD-L1. New drugs are being developed against other IO targets. Pfizer, for instance, with six IO agents in development against PD-L1, PD-1, 4-1BB, OX40, CCR2 and VIBR leads the way in terms of the breadth of its IO drugs portfolio.
These mAbs are being extensively studied as monotherapy, in combination with each others, or with other more established therapeutic regimen, offering potential for synergies.
Bristol Myers Squibb’s ipilimumab Yervoy, was the first immune checkpoint inhibitor to gain FDA approval in 2011 in unresectable or metastatic melanoma. Labeling was expanded in 2015 to include a new use as adjuvant therapy for patients with stage III melanoma. It is in numerous clinical trials, but failed in Phase 2 in advanced synovial sarcoma however.
AstraZeneca’s tremelimumab is being studied alone or in combination with PD-L1 mAb such as durvalumab. It failed as monotherapy in melanoma in 2008 and more recently, in 2016, in mesothelioma.
It is actively studied alone or in combination with durvalumab or other treatment regimens, is tested in a variety of cancers: NSCLC, squamous cell carcinoma of the head and neck, bladder, gastric and pancreatic cancers.
Bristol Myers Squibb’s nivolumab Opdivo was first approved by the FDA in December 2014 for the treatment of patients with unresectable or metastatic melanoma who no longer respond to other drugs. In gained additional approval in March 2015 in squamous non-small cell lung cancer, and in November 2015 in advanced renal cell carcinoma (RCC). It is being tested in a wide spectrum of tumors.
Merck penbolizumab, Keytruda was first approved by the FDA in October 2015 in metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1. It is being investigated for use in more than 30 types of cancers, as monotherapy and in combination.
There are 9 other mAbs against PD-1 in the pipeline:
Pfizer PF-06801591 is in Phase 1 dose escalation studies in patients with locally advanced or metastatic melanoma, squamous cell head and neck cancer, ovarian cancer, sarcoma and relapsed or refractory classic hodgkin lymphoma.
Sanofi, in an alliance with Regeneron, is developing REGN2810. It is in Phase 1 in lymphoma and in an open-label, multicenter, ascending-dose escalation study alone and in combination with other anti-cancer therapies in patients with advanced malignancies.
AstraZeneca’s MEDI0680 is Phase 1 alone and in combination with durvalumab in advanced malignancies.
Novartis is developing PDR001 in melanoma, NSCLC, triple negative breast cancer and other solid tumors. It is also recruiting for a Phase 1 in nasopharyngeal carcinoma. It is being investigated alone or in combination with MBG453 (mAb against TIM-3) or LAG525 (mAb against LAG-3).
Other PD-1 mAbs in Phase 1 clinical trials are Curetech’s CT 011, Amplimmune‘s AMP 224, Medivation’s pidilizumab, Beigene (in collaboration with Boehringer Ingelheim)’s BGB-A317 and Incyte (licensed from Jiangsu Hengrui Medicine’s in September 2015) SHR-1210.
AstraZeneca’s durvalumab MEDI 4736 is in Phase 3 in NSCLC. It received breakthrough designation in bladder cancer in Feb 2016. It is in about 40 trials alone or in combination with other agents: with AstraZeneca’s tremelimumab, Advaxis’s ADXS-HPV HPV Therapeutic vaccine in head and neck cancer; with Isis’s STAT-3-2 5Rx STAT3 inhibitor antisense in Hepatocellular carcinoma and diffuse large B-cell lymphoma and with Juno’s anti CD19- CAR-T Therapy in non-Hodgkin lymphoma.
Roche/Genentech atezolizumab MPDL 3280 is in 6 Phase 3 and 2 Phase 2 studies in various kind of lung cancer alone or in combination with Tarceva. In February 2015, it received Breakthrough Therapy Designation from the FDA for the treatment of people whose NSCLC expresses PD-L1 and who progressed during or after standard treatments (e.g., platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease). It is also being investigated in bladder and triple negative breast cancer (alone), in renal cancer(in combination with Avastin), in melanoma (with Zelboraf) and in other tumors.
Pfizer is developing avelumab in collaboration with Merck KgA , across more than 15 tumor types, including breast cancer, gastric/gastro-esophageal junction cancers, head and neck cancer, melanoma, Merkel cell carcinoma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and urothelial (e.g. bladder) cancer. The alliance has initiated six pivotal trials, reaching its goal for 2015, with additional trials expected to initiate in 2016. In November 2015, the FDA granted a Breakthrough Therapy designation to avelumab as a potential treatment for patients with metastatic Merkel cell carcinoma (MCC) following progression on at least one prior chemotherapy regimen. Avelumab is the first PD-L1 inhibitor being investigated in a Phase 3 clinical trial setting in patients with platinum-resistant/refractory ovarian cancer. It is designed to evaluate the superiority of avelumab as a monotherapy or in combination with pegylated liposomal doxorubicin (PLD), compared with PLD alone. It is also in phase 3, versus Platinum-based Doublet as a First-line Treatment of Recurrent or Stage IV PD-L1+ Non-small Cell Lung Cancer. Moreover, it is also investigated as a maintenance treatment, in the first-line setting, in patients with locally advanced or metastatic urothelial cancer.
Bristol Myers Squibb has a few PD-L1 mAbs in Phase 1 clinical trials.