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There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
With well over a hundred approved oncology agents and hundreds in development, the space of pairwise combinations runs to tens of thousands, and sequences and schedules multiply it further, while the field can run only a few dozen adequately powered combination trials a year. The combinations that are tested are chosen by commercial ownership and precedent rather than biology: thousands of PD-1/PD-L1 combination trials have been launched, most adding an agent to a checkpoint inhibitor without a predictive biomarker. Analyses of historical combination trials suggest that many 'successes' reflect independent action in different patients rather than synergy, which means better patient selection would achieve the same benefit with fewer drugs. Platform trials, factorial and adaptive designs, ex vivo functional testing, and computational prioritisation from dependency maps and combination screens are the only ways to explore the space at a useful rate.
When two expensive cancer drugs are combined, the price is often the sum of both even though the extra benefit is smaller. A rule for splitting the total value between them is needed.
If a company refuses to supply its approved drug for a well-designed independent trial combining it with a rival's drug, the law would let the trial buy it at manufacturing cost, with results shared back.
Radiotherapy may make immunotherapy work better, but the trials to test this are scattered and often small. One shared platform, run by radiotherapy groups with drugs supplied by several companies, would settle it faster.
Build a shared, not-for-profit clinical unit that runs early combination trials to a standard recipe, so that small companies and academics can test pairs without building their own trial machinery.
Companies fear that testing a combination will hand a competitor a patent. A shared pool where combination patents are cross-licensed by default would remove the fear.
Platform trials that test several companies' drugs against one shared control arm, such as I-SPY 2, Lung-MAP, GBM AGILE and STAMPEDE, are each built from scratch by determined individuals. A permanent non-profit sponsor holding the protocol, control arm, statistics and data, with a standard entry contract for companies, would cut the launch of a new platform from years to months.
Instead of starting a new trial for every drug pair, keep one always-open trial per cancer that new arms can join and leave, sharing the same control group.
Build a large, openly shared dataset of how tumour organoids respond to drug pairs, so that anyone can look up which combinations might work for which tumour type.
A government or charity holds stocks of experimental cancer drugs under standing agreements, so academic doctors can test combinations without negotiating with each company separately.
Three antibody-drug conjugates now used in triple-negative breast cancer carry the same kind of chemotherapy warhead, a topoisomerase inhibitor. Nobody has randomised which to give first or whether the second works after the first; small series suggest it often does not. With two now approved first line, the question decides what a patient gets for the rest of her life.
Trials tell us a drug works but not where it fits among the others. Commit to answering 'which order' from hospital data within a year of each approval.
Record, for every patient, the order of treatments and what happened, so that the most common sequences can be compared and the worst ones flagged.
Most of the delay in testing two companies' drugs together is lawyers negotiating from scratch. A single standard agreement, blessed by regulators, would let them sign in weeks.
Companies with drugs that might work together rarely test them because the legal negotiation takes longer than the trial. A pre-written standard contract would fix that.
Radiotherapy is given to half of all cancer patients but few new drugs are tested alongside it. A permanent trial platform would test drug-plus-radiation pairs systematically.
Rather than building a new trial from scratch for every drug, keep one permanent trial open per cancer where new treatments can be slotted in and dropped out, sharing the same patients, control group and infrastructure.
Train a model on millions of experiments where genes and drugs were altered, so it can predict the effect of a new combination without running the experiment.
If most tumours escape a drug by the same back-up route, blocking that route from the start may prevent resistance rather than chase it.
Companies would put their cancer drugs into a shared licensing pool so that any qualified investigator can test combinations of drugs from different owners under one standard agreement, with royalties split by a fixed formula.
When a tumour evolves resistance to one drug, it sometimes becomes weaker against another. Map these trade-offs systematically so doctors can pick the next drug to exploit them.
Use existing cell-line and organoid data to score thousands of drug pairs, publish the ranking openly, and only test the top of the list in people.
Ask experts and models to predict, in public, which registered combination trials will meet their endpoint. Track who is right, and use the best forecasters to decide what to fund.
Build a shared, openly available AI model that has learned how cancer cells respond to genetic and drug perturbations, so any lab can predict what a new drug or combination might do.
There are far more possible drug combinations than can ever be tried in patients. Test thousands on living samples of real tumours, then feed only the winners into adaptive trials.
Group patients by why their last drug stopped working, then test the combination designed to fix that specific failure, whatever the cancer.
Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.
Combinations used off-label in over 200 patients in clinico-genomic databases can be analysed by target trial emulation. Emulations cannot replace trials, but they can rule out the pairs with no signal and flag those with large effects before money is spent on randomised studies.
Require that approved cancer drugs come with a standard set of data (blood levels, drug interactions, toxicity profile) so anyone can design a safe combination trial without asking the company.
When two cancer drugs are combined, each is usually given at its full single-agent dose, which often proves too toxic. Testing a grid of dose pairs would find combinations that work with tolerable side effects.
One large trial can test aspirin, a statin, metformin and exercise at the same time by randomising each separately, answering four questions for the price of one.
Combination trials usually keep one drug at full dose and push the other as high as patients can bear. Testing a grid of dose pairs would find combinations that work at lower, safer doses.
While patients are treated in a platform trial, their tumour cells grow in a dish and are tested against dozens of drug pairs. The pairs that win in the dish become the next arms.
A rice-grain-sized implant releases microdoses of up to 20 drugs into separate spots of a tumour for one to three days, then is removed so pathologists can see which drug worked in that person's own tumour. First-in-human studies have been done in breast, sarcoma and brain tumours.
Simulate trials of drug combinations in populations of virtual patients to decide which real trials to run, and keep score of how often the simulations were right.
A blood test at six weeks can show whether a treatment is doing anything. Trials should use it to drop failing combinations fast and move patients on.
As results come in, the trial sends more new patients to the arms that are working and fewer to those that are not, so more people benefit and bad arms die faster.
Children's cancers are treated with combinations, but companies study new drugs in children one at a time. Approvals should require the combination study children actually need.
Simulate how two drugs interact in the body and the tumour to pick a starting dose and schedule, instead of guessing from single-drug data.
Regulators should refuse to approve a two-drug combination unless there is evidence that both drugs are doing something, so patients are not exposed to useless extra toxicity and cost.
Adding a new arm to an international platform trial currently needs approval in every country again. A single, pre-agreed process would let arms open in weeks.
Insurers already pay for off-label drug combinations that have never been randomised. Paying only when the patient joins a registry-based randomised comparison, as Medicare did for devices and the Cancer Drugs Fund did for cancer drugs, would turn that spending into evidence at no new drug cost.
Give drug combinations before surgery and measure how much tumour remains at resection; that answer arrives in months. A standing neoadjuvant platform with a shared control arm, as I-SPY 2 runs in breast cancer, would test combinations quickly in lung, bladder, melanoma, head and neck and oesophago-gastric cancer.
Metastatic prostate cancer now has six classes of treatment that work, and no trial has ever compared the orders they can be given in. Every trial adds a drug to the front; none asks what should follow it, so the sequence a man receives is decided by habit and by what was licensed first.
The first drug against the KRAS protein nearly doubled survival in pancreatic cancer in 2026, but on its own it holds the disease for months, not years. Trials are now testing it in combination with a second RAS drug and with chemotherapy, and earlier in the disease; the open questions are which combination, in which order, and what works when the tumour escapes.
When two approved drugs are both reasonable next steps and nobody knows which should come first, let the clinic flip a coin and record what happens.
Hospitals rotate antibiotics to stop bacteria adapting. Cycling between two cancer drugs on a set schedule, rather than using one until it fails, might work the same way.
Patients are randomised at each decision point, not just at the start, so one trial can compare whole treatment sequences rather than single drugs.
When five companies each run a trial against the same standard treatment in the same patients, let them pool the standard-treatment patients so fewer people are randomised to the old drug.
Two drugs might work better given in turns rather than together, with less toxicity. Almost no trial has tested this.
Targeted drugs briefly make cancer cells easier for the immune system to spot. Giving immunotherapy exactly in that window, rather than at the same time, may work better.
Give patients a short course of one of several drug pairs in the gap before surgery and compare what happened inside the tumours. It is the fastest human test of whether a combination does anything.
Low doses of drugs that change how DNA is packaged can make cancer cells display more of what marks them as abnormal, potentially waking up immunotherapy in cold tumours.
Some everyday medicines, such as antibiotics or steroids, seem to blunt immunotherapy. Automatically scanning health records for such harmful pairs would catch them years earlier.
Build a computer model of each patient's cancer and body that simulates how different treatments would go, and prove in a proper trial that choosing treatment with the model helps.
A new combination for relapsed or refractory follicular lymphoma that adds a CD19-directed antibody to the established lenalidomide and rituximab pairing, with the largest progression-free survival hazard ratio reported in the setting.
AMPLIFY delivered the first all-oral, fixed-duration doublet for front-line CLL and supported its approval, giving fit patients a way to avoid both chemotherapy and years of continuous BTK inhibitor. It does not settle whether a doublet or triplet is best, or how AV compares with venetoclax-obinutuzumab. Patients with TP53 aberration were excluded and still need different strategies.
Patients with newly diagnosed metastatic colorectal cancer whose tumour carries a BRAF V600E mutation, which is about 8-12% of cases, should now be offered encorafenib and cetuximab together with FOLFOX from the start rather than after chemotherapy fails; median survival has roughly doubled to about two and a half years. BRAF testing at diagnosis is therefore essential, alongside RAS and mismatch repair testing. The regimen is more toxic than chemotherapy alone.
Almost every patient newly diagnosed with advanced bladder or urothelial cancer should now be offered enfortumab vedotin plus pembrolizumab rather than chemotherapy, with median survival extended from about 16 months to over two and a half years. Neuropathy and skin toxicity need monitoring and dose adjustment, and patients with severe diabetes or pre-existing neuropathy need care. Platinum chemotherapy remains an option for those who cannot receive the combination.
Patients newly diagnosed with EGFR-mutated advanced lung cancer now have a first-line option that improves survival over osimertinib, particularly if they have high-risk features. The trade-off is intravenous (now subcutaneous) infusions and considerably more skin, nail and clotting toxicity, so osimertinib alone remains reasonable for those who prioritise convenience and tolerability. Both this regimen and osimertinib plus chemotherapy (FLAURA2) are approved; there is no direct comparison.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Adding chemotherapy to osimertinib delays progression. Whether it extends life, and whether the same benefit could be had by giving the chemotherapy later to the patients who need it, is what the overall survival analysis and the registry watch on this roadmap are for.
Evidence that the B-cell receptor pathway is worth attacking in follicular lymphoma when a Bruton tyrosine kinase inhibitor is paired with a type II CD20 antibody, after single-agent inhibitors had disappointed in this disease.
Shares An open atlas of collateral sensitivity for every approved targeted drug, Design drug pairs where resisting one makes you vulnerable to the other, Test alternating drug schedules against giving both drugs at once, Combination baskets defined by resistance mechanism rather than by cancer type.
Shares Two-week pre-operative windows to compare combination biology head to head, Whole-patient digital twins validated in prospective randomised trials, A virtual cancer cell that predicts what a drug will do before you test it, A public atlas of drug-pair responses across a thousand patient-derived organoids.
Shares A patent pool for combination method-of-use claims, A regulator-endorsed standard contract for inter-company combination trials, A legal right to obtain marketed cancer drugs at cost for combination trials, A standard cross-company combination agreement that takes weeks, not years, to sign.
Shares Kill combination arms early using circulating tumour DNA, before waiting for scans, RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma, AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients, CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer.
Shares One ethics approval and one consent form for a platform trial across countries, Let the trial learn: response-adaptive allocation across many combination arms, A standing platform trial for every major cancer, funded as infrastructure, A perpetual platform trial in every major cancer, funded as infrastructure.
Shares Test alternating drug schedules against giving both drugs at once, Add the second drug on day one when the escape route is predictable, Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC, MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer.