Combination therapy clinical trials: medicine plus immunotherapy

What is combination therapy in cancer care?

Combination therapy means using more than one cancer medicine together, instead of giving a single drug on its own^[1]. In modern oncology this usually means an immunotherapy backbone, such as a PD-1 or PD-L1 inhibitor, given alongside chemotherapy, radiotherapy, a targeted drug or novel checkpoint stimulators^[2]. The EMA has authorised pembrolizumab (Keytruda) to be used either alone or in combination with other cancer medicines such as lenvatinib, axitinib or enfortumab vedotin, with chemotherapy alone, with chemotherapy combined with trastuzumab or bevacizumab, or with chemotherapy combined with radiotherapy^[3].

You will also see combination treatment described as immunochemotherapy, because one part of the treatment is an immunotherapy and the other is a cytotoxic medicine^[4]. The reason for combining is that a single immune checkpoint inhibitor rarely produces a strong and long-lasting response in every patient – the strongest and most durable immune responses do not last long, and more durable responses occur only in a small subset of patients^[2]. Researchers describe three problems that combination strategies are meant to address: resistance to treatment, immune-related adverse events, and suboptimal response rates. By targeting more than one pathway at the same time, a combination is intended to increase efficacy, reduce toxicity, and make it harder for resistance to develop^[1].

How does the immunotherapy part work?

The active substances in this group are monoclonal antibodies, which are proteins designed to recognise and block a specific receptor or ligand. Pembrolizumab, the substance in Keytruda, blocks a receptor called PD-1^[3]. Atezolizumab, the substance in Tecentriq, attaches to a protein called PD-L1, which is present on many cancer cells^[5].

Some cancers produce PD-L1, which combines with PD-1 and switches off certain cells of the immune system, preventing them from attacking the cancer. By blocking PD-1, pembrolizumab stops the cancer from switching off these immune cells and increases the immune system's ability to kill cancer cells^[3]. Atezolizumab works in the same direction: by attaching to PD-L1 it reduces its effects, so the immune system can attack cancer cells and progression of the disease slows down^[5].

These drugs are called checkpoint inhibitors because they block checkpoint proteins that stop the immune system from attacking cancer cells. The proteins that are blocked include PD-1, CTLA-4, PD-L1 and LAG-3. Checkpoint inhibitors can also be described as a type of monoclonal antibody or as a targeted treatment. Combinations of two checkpoint inhibitors exist as well – for example ipilimumab, which blocks CTLA-4, can be given with a PD-1 inhibitor such as nivolumab to some people with melanoma, advanced kidney cancer, mesothelioma, bowel cancer or non-small cell lung cancer^[6].

What other kinds of immunotherapy can be combined?

Immunotherapy is not one treatment but a family of treatments, and a trial may combine the drug you already know with a different member of that family. The main groups are described below^[7].

• Checkpoint inhibitors – monoclonal antibodies that block the signals which switch off lymphocytes, a type of white blood cell that can attack a cancer cell^[7].
• Immune system modulators – drugs given as tablets that help the immune system attack and destroy cancer cells; examples include lenalidomide, pomalidomide and thalidomide, alongside artificial versions of interferon and interleukin given by injection^[7].
• Cancer vaccines – vaccines that train the immune system to find and attack certain abnormal cells; new cancer vaccines are usually only available as part of a clinical trial^[7].
• Adoptive cell transfer and CAR-T therapy – treatments that use a person's own white blood cells to find and destroy cancer cells^[7].
• Cytokine therapy – artificial cytokines that mimic proteins found in the body, such as interferons and interleukins, to boost the body's ability to fight cancer^[8].
• Antibody-drug conjugates and bispecific antibodies – proteins that carry a cytotoxic payload or bind two targets at once^[8].

Why is a second medicine added to immunotherapy?

Immunotherapy on its own has an important limit: the strongest and most durable immune responses do not last long, and they occur in only a small subset of patients. Adding a second treatment is one of the solutions proposed to overcome this. The backbone is usually a PD-1 or PD-L1 antagonist, given with cytotoxic chemotherapies, radiation, targeted drugs or novel checkpoint stimulators. This is described as the most promising approach and the one expected to be on stage in forthcoming years^[2].

A second mechanism under study is chemotherapy-induced immunogenic cell death, which is being examined in combination with immune checkpoint inhibitors. A further line of research looks at DNA-damaging agents combined with DNA damage response inhibitors. Some combinations work through an additive effect rather than a shared pathway: the antitumour efficacy of doxorubicin in soft-tissue sarcoma was potentiated by activation of the STING pathway in one study reported under this research topic. Combinations of PD-1/PD-L1 inhibitors with tyrosine kinase inhibitors as first-line treatment for hepatocellular carcinoma have been assessed in a meta-analysis and trial sequential analysis of randomised controlled trials. Antibody-drug conjugate combinations are another area with clinical efficacy and ongoing clinical study perspectives^[4].

What does a combination trial measure, and what were the results?

Regulators assess a combination by the same outcomes used for any cancer medicine: whether tumours shrink or disappear, how long patients live, and how long they live without their disease getting worse. In urothelial cancer, a study of 429 patients found the cancer shrank or was eliminated after atezolizumab in 23% of patients who were not eligible for platinum chemotherapy and in 16% of patients who had previously had platinum chemotherapy. In another study of 931 patients with urothelial cancer, those given atezolizumab lived 8.6 months on average compared with 8 months for patients given chemotherapy, although the difference could be due to chance^[5].

In advanced non-small cell lung cancer, one main study of 850 patients showed that patients given atezolizumab lived 14 months on average, while those given docetaxel lived 10 months; in a second study of 287 patients the figures were 13 months compared with 10 months. In a study of 1,202 patients with advanced non-small cell lung cancer who had not received chemotherapy before, patients given atezolizumab together with paclitaxel, carboplatin and bevacizumab lived on average 8.4 months without their disease getting worse, compared with 6.8 months for those given the same three medicines without atezolizumab. Overall, patients in that combination group lived 19.8 months on average compared with 14.9 months without atezolizumab^[5].

Knowing which design a study used helps you read its results, because a randomised controlled trial and a single-arm study answer different questions. A timeline of FDA approvals of immune checkpoint inhibitor combinations has been published in a review of combination strategies^[1].

How does the trial decide who receives which treatment?

In a randomised trial, participants are allocated to a treatment group by chance rather than by the doctor's choice. Regulators use the comparison between those groups to judge whether the combination adds benefit over the standard treatment; in the lung cancer study described above, the comparison was between a group receiving four medicines and a group receiving the same three without atezolizumab. The number of participants matters too – the studies cited above enrolled 429, 931, 850, 287, 1,202 and 679 patients respectively, and the results you read are averages for a whole group, not a prediction for one person^[5].

Some comparisons are made with a placebo or with an older medicine rather than with no treatment at all, which is why a study may describe a "control" group. When a combination contains four different medicines, the combination is only one of the variables under study, and the trial may also compare whether the treatment is given for a fixed period or for as long as the patient benefits from it^[5].

Will you be tested before the treatment starts?

In some cancers, the immunotherapy is only given to patients whose tumours produce certain levels of a protein known as PD-L1, or whose cancer is determined to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)^[3]. To find this out, doctors need a sample of your cancer, and they may be able to use a sample from a biopsy or an operation you have already had. This testing does not apply to all checkpoint inhibitors^[6]. For atezolizumab, the doctor may need to confirm that the cancer cells produce a certain amount of PD-L1 and that particular genetic mutations known to reduce the medicine's effectiveness are not present^[5].

What is the difference between neoadjuvant and adjuvant immunotherapy?

Adjuvant treatment is given to help prevent the cancer from coming back after surgery. Pembrolizumab is used in this way after surgery to remove melanoma, non-small cell lung cancer or renal cell carcinoma. Neoadjuvant treatment is given before surgery, and in some patients with triple-negative breast cancer, non-small cell lung cancer, head and neck squamous cell carcinoma and urothelial cancer, pembrolizumab can be given both before and after the operation. Whether a combination is offered before surgery, after surgery, in advanced disease, or only after another treatment has stopped working depends on the cancer type – pembrolizumab is mainly used in adults for cancers that are advanced, have spread or returned, are not responding to other treatments, or cannot be removed by surgery^[3].

What should you expect as a participant in a combination trial?

Combination treatments are given differently depending on the medicines involved. Pembrolizumab is given as an infusion into a vein over 30 minutes, every three or six weeks, or as an injection under the skin in the abdomen or thigh given as a 1-minute injection every 3 weeks or a 2-minute injection every 6 weeks; patients can switch between formulations at their next scheduled dose^[3]. Atezolizumab is given as an infusion into a vein every 2, 3 or 4 weeks, or as an injection under the skin every 3 weeks. Depending on the type of cancer, treatment with atezolizumab lasts either for one year or for as long as the patient benefits from it^[5].

These medicines can only be obtained with a prescription, and treatment must be started and supervised by a doctor experienced in the treatment of cancer^[3]. Immunotherapy given alongside another treatment means a schedule with more than one medicine, so ask your cancer team which appointments are infusions and which are for tests. This treatment can cause immune system side effects, and your team should tell you which symptoms to watch for^[7].

What happens if side effects occur during treatment?

Side effects involving the immune system can lead a doctor to stop treatment; they include inflammation of various body organs and endocrine (glandular) disorders^[5]. A doctor may also delay doses if certain side effects occur, or stop treatment altogether if side effects are severe^[3]. Both of these actions are decisions made by the treating physician, so report new symptoms at your appointment or sooner through the contact your team has given you^[5].

Where does your report go, and what rights do you have?

Suspected side effects of a medicine authorised in the European Union are reported to regulators so that they can be assessed centrally^[5]. In the EU, the European Medicines Agency and national competent authorities collect these reports, and you can also ask your doctor or pharmacist how to submit one^[3]. Reading a medicine's public assessment report before joining a study is one way to understand what was already observed in the trials that led to its authorisation^[5].

How do you find a combination trial?

Cancer vaccines and several other immunotherapies are usually only available as part of a clinical trial, so this is often the route to a combination that is not yet authorised^[7]. Trials running in the European Union are listed in the EU clinical trials registers, and studies worldwide can be searched on ClinicalTrials.gov and on the WHO ICTRP^[5]. Trials recruiting in Europe can also be searched on clinicaltrials.eu. Ask your cancer team whether a combination study is open for your type of cancer, because eligibility often depends on the stage of the cancer and on which treatments you have already had^[6].

Which questions should you ask your cancer team?

Before you agree to take part or start a combination that is already authorised, get the practical answers in one place. Whether a checkpoint inhibitor is suitable for you depends on your type of cancer, the stage of the cancer, and whether you have already had certain treatments, so ask your doctor directly^[6].

• Which medicines are in this combination, and who supervises them?^[3]
• Is a test of PD-L1, MSI-H or dMMR status needed before I start?^[3]
• Will the treatment be given before surgery, after surgery, or for advanced disease?^[3]
• Will it be given for a fixed period, or for as long as I benefit from it?^[5]
• Which immune system side effects should I report, and to whom?^[7]

Summary

Combination therapy means giving an immunotherapy together with other cancer medicines, and in the European Union the evidence behind each combination is published by the EMA before it is authorised. Read the numbers with their context: the figures above come from named studies with a defined number of patients and a defined comparison group, and they describe groups, not individuals^[5].

Three practical steps: ask your cancer team which medicines form the combination and how often they are given, check whether a biomarker test is needed before you start, and keep the contact details for reporting new symptoms^[3]. If you are considering a study, search the European and international registers for a trial open to your cancer type, and remember that treatments described in early research reports are not yet available outside a trial^[7].

1. [1] Birnboim-Perach R, Benhar I. Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment. Int J Biol Sci. 2024;20(10):3911-3922. doi:10.7150/ijbs.93697 – (accessed 2 June 2026) — https://www.ijbs.com/v20p3911.pdf
2. [2] Esin E. Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future. Biomed Res Int. 2017;2017:1623679. doi:10.1155/2017/1623679 – (accessed 2 June 2026) — https://pmc.ncbi.nlm.nih.gov/articles/PMC5564060/
3. [3] Keytruda - European Medicines Agency (EMA) (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
4. [4] Combination Therapies in Cancer Treatment: Enhancing Efficacy and Reducing Resistance - Frontiers (accessed 2 June 2026) — https://www.frontiersin.org/research-topics/66212/combination-therapies-in-cancer-treatment-enhancing-efficacy-and-reducing-resistance/magazine
5. [5] Tecentriq - European Medicines Agency (EMA) (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/tecentriq
6. [6] Checkpoint inhibitors - Cancer Research UK (accessed 2 June 2026) — https://www.cancerresearchuk.org/about-cancer/treatment/immunotherapy/types/checkpoint-inhibitors
7. [7] Types of immunotherapy for cancer - Macmillan Cancer Support (accessed 2 June 2026) — https://www.macmillan.org.uk/cancer-information-and-support/treatment/types-of-treatment/immunotherapy/types
8. [8] What are the seven main types of cancer immunotherapy? - CCLG (accessed 2 June 2026) — https://www.cclg.org.uk/news-updates/what-are-seven-main-types-cancer-immunotherapy