Immune Checkpoint Inhibitor Combination Therapy

Immune checkpoints refer to events related to the recognition of tumor antigens by immune system cells, and the subsequent interactions between the immune system and tumors. The most therapeutically relevant checkpoint events involve cytotoxic T lymphocyte antigen 4 (CTLA4) or the programmed cell death 1 (PD-1) receptor.

Immune checkpoint inhibitor (ICI) monoclonal antibody drugs thus interfere, through either stimulatory or inhibitory mechanisms, with the immune response to cancer involving CTLA4 or PD-1. ICIs prevent tumors from switching off the normal, cancer-fighting immune response by blocking interactions between PD-1/CTLA4 ligands on the tumor and the receptors to those ligands on T cells.

ICI therapy works best on tumors for which the body’s cancer-fighting mechanisms are unable to correct DNA copy errors, which includes some (but not all) cancers of the major solid organs and several blood malignancies. The U.S. Food and Drug Administration has approved 14 immunomodulation agents, including seven CPI drugs:

• Atezolizumab (Tecentriq^®), which targets the PD-1/PD-L1 pathway, approved for some tumors of the bladder, breast, liver, lung, and skin
• Avelumab (Bavencio^®), which targets PD-1/PD-L1, approved for bladder, kidney, and Merkel cell (skin) carcinoma
• Cemiplimab (Libtayo^®), which targets PD-1/PD-L1 and is approved for certain cancers of the skin and lung
• Dostarlimab (Jemperli), targeting the PD-1 pathway, for endometrial cancer
• Durvalumab (Imfinzi™), targeting PD-1/PD-L1 pathway and approved for some tumors of the bladder and lung
• Ipilimumab (Yervoy^®), the first approved CPI (in 2011), targeting CTLA4 and approved for subsets of patients with melanoma, mesothelioma, and cancers of the liver and lung
• Nivolumab (Opdivo^®), which acts on the PD-1/PD-L1 pathway, is licensed for some cancers of the bladder, colon, esophagus, digestive system, head and neck, kidney, liver, lung, and skin
• Pembrolizumab (Keytruda^®), interferes with the PD-1/PD-L1 pathway, and is used for subsets of patients with tumors of the bladder, breast, cervix, colon, esophagus, skin, head and neck, kidney, liver, lung, plus lymphoma. Pembrolizumab is also used to treat other cancers with specific genetic mutations (MSI-H, dMMR, or TMB-H).

Caveats

The early successes of ipilimumab and subsequent CPI approvals has fueled a new cancer treatment industry around immunomodulators. Today, more than 1,000 development-stage immunomodulatory treatments are under study, of which around 70 are in clinical testing. With current markets in excess of $16 billion per year, cancer immunotherapy has its own stock exchange traded fund.

Yet ICIs are not magic bullets. According to the Johns Hopkins School of Medicine, “Immunotherapy drugs work better in some cancers than others and while they can be a miracle for some, they fail to work with all patients. Overall response rates are about 15% to 20%.”

ICIs are associated with myriad side effects, mostly related to the immune system attacking healthy cells and tissues through various (and often unpredictable) inflammatory processes. Adverse events may involve the skin, gastrointestinal tract, muscles/skeleton, kidneys, nerves, blood, lungs, the endocrine system, heart, blood, etc. Approximately one percent of patients treated with ICIs experience fatal, treatment-associated toxicities.

Finally, ICI regimens are expensive, adding at least $100,000 (and in some cases, $1 million) to the cost of cancer care.

Treatments that combine ICIs with traditional chemotherapy and/or radiation have the potential to address these three major concerns by 1) improving efficacy through synergistic or orthogonal mechanisms of action, 2) allowing the rational management of side effects, 3) improving quality of life, and 4) despite the higher up-front cost, possibly delaying or avoiding treatment resistance, relapse, and providing greater long-term value.

Combination therapy

Therapies combining two or more drugs, with the general benefits listed above, have a long history of effective use in oncology. Combination protocols, which have greatly expanded the scope of applicability for a wide range of oncology drugs, work by attacking cancer from multiple angles, through two or more mechanisms of action. One very early study, showing that Ipilimumab plus the glycoprotein GP100 improves overall survival in patients with metastatic melanoma from 6.4 months to 10 months compared with administration of GP100 alone, has led to dozens of ongoing clinical trials that seek to exploit synergies between older oncology drugs and emerging ICIs.

The GP100 study opened the floodgates to novel combinations of ICIs and chemotherapy agents. One combinatorial option class, cytotoxic agents, includes such familiar categories as anthracyclines, cyclophosphamide, platinum-based agents, gemcitabine, temozolomide, and paclitaxel. These agents enhance tumor immunity at lesser doses, and at normal dosages result in the release of targets for tumor-targeting immune responses.

Many targeted therapies are also under investigation as potential ICI co-therapies. These include cyclin-dependent kinase inhibitors, anti-angiogenesis drugs, DNA repair agents, plus tyrosine kinase inhibitors, oncolytic viruses, and estrogen down-regulators.

Combination approaches to therapy are not limited to ICI + “conventional” treatments. Numerous agents not typically used in oncology have shown promise, including rosiglitazone (originally indicated for diabetes), phosphodiesterase inhibitors (e.g., sildenafil), vitamin D (and paricalcitol, a synthetic derivative), amiloride (a diuretic), and cimetidine (proton pump inhibitor).

FDA recently approved the combination of two ICIs, atezolizumab and durvalumab, with platinum-based chemotherapy for first-line treatment of patients with metastasized small cell lung cancer. The approvals, occurring in 2019 and 2020, respectively, were based on data from two randomized, placebo-controlled studies: IMpower133 (atezolizumab) and CASPIAN (durvalumab). Both studies showed modest but significant improvements in overall survival compared with chemotherapy alone (12.3 months vs. 10.3 months in the IMpower133 trial, 13.0 months vs. 10.3 months in CASPIAN).

Conclusion

Since cancer is a multi-dimensional disease, multi-pronged approaches to therapy based on combining emerging and conventional treatments are an attractive option to monotherapy. Clinical experience has shown these strategies to provide modest but significant improvements in survival and quality of life. These benefits derive to varying degrees from orthogonal mechanistic synergy, the potential to manage side effects, overcoming or delaying drug resistance, and improved patient quality of life.