Checkpoint inhibitors have been effective in several cancer types, but many do not provide durable disease control. Monotherapy with checkpoint inhibitors has proved ineffective in many tumor types as well. Researchers have begun to evaluate whether combination therapy or targeting use based on biomarkers may improve durable response.

A review article in The Lancet, investigatorslooked at the current research on immunotherapy response biomarkers, combination therapies with checkpoint inhibitors, and clinical considerations when choosing therapy with these treatments.

Targeted Therapy Combinations

Ongoing trials are exploring combinations with targeted therapies and chemotherapy. Initial trial data combining targeted therapies with checkpoint inhibitors in melanoma have shown promise. The US Food and Drug Administration has approved some treatment combinations with targeted therapies and checkpoint inhibitors.

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Limited understanding exists of biomarkers of sensitivity and resistance to immunotherapy. Programmed cell death ligand 1 (PD-L1) status is used in some cancers to determine whether to treat patients with immunotherapy, but it is not yet used to guide combination therapies. Some studies have looked into using tumor mutation burden to predict response for checkpoint inhibitors.

Checkpoint inhibitors with anti-PD-1 or anti-PD-L1 therapies have received the most attention in studies. Some success has been seen with this combination in renal cell carcinoma.

Radiation Therapy

Immunotherapy combined with radiation therapy is being studied in more than 100 trials. It is thought that radiation therapy may enhance response to checkpoint inhibitors. A trial in nonsmall cell lung cancer has been promising, but no optimal combination strategy has been determined.

CAR-T Cells and Checkpoint Inhibitors

CAR-T cells are an exciting area of cancer immunotherapy. CAR-T cells have led to positive responses in acute lymphoblastic leukemia and B-cell lymphomas, with future trials examining their use in multiple myeloma and acute myeloid leukemia.  CAR-T cells with immune checkpoint inhibitors have been promising in trials of patients with B-cell non-Hodgkin lymphoma.

Other Combinations

Several studies are evaluating the combination of checkpoint inhibitors with other immune inhibitors, systemic therapies, bispecific antibodies, microbiome modulation to increase diversity, and vaccines.

Future Directions

One concern of combination therapy is the increased toxicity compared with monotherapy. This leads to questions about the point at which treatment course checkpoint inhibitors should be introduced. Many trials attempt combinations after monotherapy has failed. The authors suggested that introducing combination therapy early may prevent some issues that could reduce the effectiveness of immunotherapy combinations; however, this has to be balanced with the possibility of unnecessary toxicity for patients who would have responded to monotherapy.

Despite extensive testing, only a few immunotherapy combinations have been successful in clinical trials. Although some combination therapies may produce a response, they are only considered beneficial if the results are statistically better than monotherapy.

Many questions exist for areas of future research and how to find the right combinations for the right patients. Future research needs to include comprehensive molecular and immune profiling and make that data publicly available. The research should also answer how to integrate biomarkers of response. Better understanding of the immune state of the tumor can help personalize combination therapies.

Disclosure: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Meric-Bernstam F, Larkin J, Tabernero J, Bonini C. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet. Published online December 4, 2020. Lancet. doi:10.1016/S0140-6736(20)32598-8