PracticeUpdate: Haematology & Oncology

LUNG 29

First-line ceritinib vs platinum-based chemotherapy in advanced ALK- rearranged non-small cell lung cancer The Lancet Take-home message • In a prospective, multicentre phase III study, patients with untreated ALK-rearranged non-small cell lung cancer (NSCLC) were randomised to receive platinum-based chemotherapy (n = 187) or ceritinib (n = 189) to evaluate the safety and efficacy of ceritinib. The primary endpoint was progression-free survival. The ceritinib group had longer median progression-free survival (16.6 months vs 8.1 months; HR, 0.55; P < 00001). Adverse events with ceritinib included diarrhea (85%), nausea (69%), vomiting (66%), and elevated ALT (60%); with chemotherapy, adverse events included nausea (55%), vomiting (36%), and anaemia (35%). • Ceritinib was associated with a significant improvement compared with chemotherapy as a first-line treatment in patients with ALK- rearranged NSCLC. Abstract BACKGROUND The efficacy of ceritinib in patients with untreated anaplastic lym- phoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. METHODS This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cis- platin 75 mg/m 2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m 2 ] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previ- ous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator’s assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded inde- pendent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. FINDINGS Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16.6 months (95% CI 12.6–27.2) in the ceritinib group and 8.1 months (5.8–11.1) in the chemotherapy group (hazard ratio 0.55 [95% CI 0.42–0.73]; p<0.00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotrans- ferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. INTERPRETATION First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-re- arranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 2017 Jan 23;[EPub Ahead of Print], JC Soria, DS Tan, R Chiari, et al.

evolving sort of concept. In the meantime, many patients are getting the drugs. So, what I would suggest is as we give the patients the drugs, we col- lect samples and we’re seeing that. There are more and more, the MoonShot programs, the Parker Foundation, the National Cancer Institute now has multiple supplements that they’re issuing to cancer centres to study this very process. So, we all realise what we need now is take what we know about immune biomarkers from retrospective studies and incorporate them prospectively into studies with clinical annotated follow-up to figure this out. Dr Haffizulla: Absolutely, and maybe having an adaptive trial design as well, too. Dr Herbst: Oh, that would be wonderful. We just need to have enough prior probability to do that. But if we had some sense of what you need, let’s say you have a tumour, and the tumour has no inflammation. You might need to use an agent that’s going to bring T-cells in, or let’s say a tumour has very few mutations. Pick the mutation that you think might be the most likely to cause a response and develop a vaccine. This is what we really need, personalised immunotherapy. Dr Haffizulla: Absolutely. Now how, again, in the spectrum of epitopes that are expressed in that tumour, do you decide which ones are going to initiate the greatest immune response, or which ones matter? I know we’re still in that space of thinking. Dr Herbst: That’s very hard, and I will tell you that in my opinion, just sequencing is not going to be enough. Then you need to do functional studies. You’ve got to actually go back to the lab, and you’ve got to make T-cells that go after that mutant protein. So, you have to engineer the receptor to go after it, and actually see if, in fact, that’s happening in any given patient, so that’s going to be a bit more complicated.

Farzanna Haffizulla, MD, FACP, FAMWA practices general internal medicine in Florida, within her own internal medicine concierge practice. She was previously the National President of the American Medical Women’s Association (AMWA) 2014–2015.

VOL. 2 • NO. 2 • 2017