Combination Therapies

What Are Combination Therapies?

Combination therapies involve using two or more therapeutical approaches as a single treatment – typically different drugs that complement each other.

For example, doctors might combine traditional chemotherapy with a drug that specifically targets cancer cells, or use two targeted drugs at the same time, or combine two immunotherapy drugs to help the immune system attack the cancer more effectively^1,2.

This is the current understanding of combination therapies. The combined use of different methods, such as chemotherapy and surgery, is not combination therapies. Now, this strategy has become common in modern oncology as more drugs become available.

Why Use Combination Therapies?

Cancer cells can sometimes develop resistance (stop responding) to a single treatment by finding new ways to survive and grow.

For example, they may switch on different pathways in the body to avoid being affected by the drug. Hitting multiple targets at once can forestall or overcome resistance. 

Clinical trials have shown that well-chosen combinations can dramatically improve outcomes.

For example, in melanoma (a type of skin cancer), combining two immunotherapy drugs – nivolumab and ipilimumab – significantly improved 5-year survival rates compared to using just one drug alone³. Similarly, in a type of lung cancer called nonsquamous non-small-cell lung cancer, adding an immunotherapy drug (pembrolizumab) to chemotherapy (pemetrexed and platinum) improved the 5-year survival rate from about 11% to 20%⁴. And in kidney cancer, a combination of pembrolizumab with a targeted drug called axitinib helped patients live longer than those who received only one type of treatment⁵.

Combination therapies can also allow dose reduction and toxicity sparing.

When two drugs act synergistically, each can often be used at a lower dose to achieve the same effect^6,7. In contrast, other combinations do add toxicity: in a colorectal cancer trial, nivolumab+ipilimumab caused more severe side effects than nivolumab alone⁸. Thus, carefully selecting agents with non-overlapping toxicities can improve efficacy without a proportional rise in side effects.

Combination therapies also support precision medicine

Precision medicine means care that is tailored to each person’s specific cancer. Modern genomic testing often reveals several important mutations in a tumor. Research shows that using treatments that target as many of them as possible can help control cancer better and help patients live longer⁹.

What Do Patients Need to Know?

Molecular Testing and Clinical Trials

Many new combination treatments are chosen based on the tumor’s specific genetic changes. For patients with advanced cancer or those whose cancer no longer responds to standard treatment, genetic testing can help identify targeted therapies or clinical trials they may qualify for.

Drug Access

Not all combinations are EMA-approved for every cancer type. Some are only available through clinical trials or in non-commercial formats. Insurance coverage and national health system policies vary. Patients may need to enroll in a precision-medicine trial or obtain special approval for experimental combinations.

Balancing Benefits and Risks

Combination therapy often increases the chance of response, but may also raise side effect risk. Discuss with your doctor the expected trade-offs. In some cases, more drugs does not mean more toxicity, in other cases it does.

Personalised Approach

Remember that combination therapy is most useful when tailored to the individual. If your tumor has known targets (EGFR mutations, HER2 amplification, BRCA mutation, MSI/dMMR status, etc.), ask whether there are approved combinations or trials for your profile. Sometimes adding a second agent can overcome resistance. For example, if a tumor became resistant to one targeted drug, combining it with another pathway inhibitor might work.

Support and Monitoring

With more drugs in play, careful monitoring is important. You may need extra blood tests, scans, or specialty consultations (e.g. cardiologist for HER2 drugs, endocrinologist for immunotherapy side effects). Report any new symptoms early; combination regimens often have protocols for managing overlapping toxicities.

1. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012 Mar 22;12(4):237-51. doi: 10.1038/nrc3237.
2. Birnboim-Perach R, Benhar I. Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment. Int J Biol Sci. 2024 Jul 15;20(10):3911-3922. doi: 10.7150/ijbs.93697.
3. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined Opdivo and Yervoy in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi: 10.1056/NEJMoa1910836.
4. Marina C. Garassino et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol. 2023 Jun 10;41(17):1992-1998. doi: 10.1200/JCO.22.01989.
5. Plimack ER, Powles T, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 KEYNOTE-426 study. Eur Urol. 2023 Nov;84(5):449-454. doi: 10.1016/j.eururo.2023.06.006.
6. Albain KS, Nag SM, et al. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. doi: 10.1200/JCO.2007.11.9362.
7. Mokhtari RB, Kumar S, et al. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. BMC Cancer. 2013 Aug 8;13:378. doi: 10.1186/1471-2407-13-378.
8. Immunotherapy Combo Approved for dMMR Colorectal Cancer – NCI
9. Sicklick JK, Kato S, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019 May;25(5):744-750. doi: 10.1038/s41591-019-0407-5.