Lines of therapy

For a patient weighing the FLAURA2 regimen against osimertinib alone, the extra toxicity is front-loaded: the hardest months are the four induction cycles, and once pemetrexed stops the profile returns to that of osimertinib by itself. Kidney function deserves watching during pemetrexed maintenance.

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.

For the first time a new drug has beaten pembrolizumab, the global first-line standard, in a randomised lung cancer trial, and it did so by combining checkpoint blockade with anti-angiogenesis in one molecule. For patients outside China nothing changes yet: the drug is not approved in the West, the trial was single-country, and survival benefit has not been shown. If confirmed in the global HARMONi-3 and HARMONi-7 trials, PD-1 x VEGF bispecifics could replace PD-1 antibodies as the immunotherapy backbone.

Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.

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 newly diagnosed with an advanced grade 2 or 3 neuroendocrine tumour of the gut or pancreas that shows somatostatin receptors on imaging can now receive lutetium dotatate as their first treatment, gaining more than a year of additional disease control and a much higher chance of tumour shrinkage. It does not settle whether radioligand therapy is better than other first-line options such as capecitabine-temozolomide or everolimus, and long-term marrow safety with earlier use needs surveillance.

For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head.