ASCO 2019 round-up

With the American Society of Clinical Oncology (ASCO) conference over for another year, Richard Staines presents a round-up of the most significant developments at this year’s event. Around 40,000 oncologists and other experts descended on Chicago this year, hoping that the ASCO conference would generate some “wow” figures from the latest cancer drugs. And it was AstraZeneca and Merck & Co, with their poly (ADP-ribose) polymerase (PARP) drug Lynparza, that provided one of those moments by showing promise in pancreatic cancer. It is one of the most notoriously difficult cancers to treat because it is usually only detected at the metastatic stage when prognosis is poor -- more than one-half of the 54,300 patients diagnosed in 2018 were metastatic at the time of diagnosis¹. There has also been a dearth of approved treatments, but that could all change thanks to Lynparza, after AZ and US-based Merck & Co turned up some exciting results from their POLO trial in patients with BRCA mutations Results from the trial showed a statistically-significant and “clinically-meaningful” improvement in progression-free survival (PFS) for Lynparza versus placebo, improving the time without disease progression by a median of 7.4 months for patients treated with Lynparza versus only 3.8 months for those on placebo. Lynparza also has the benefit of being an oral medicine, making it convenient for patients to take and meaning healthcare professionals don’t have to worry about organising or administering regular injections at clinics. Doctors at the event also seemed to be interested in the potential of the drug, as although there are no overall survival figures the evidence so far points in the right direction. MacroGenics eyes late-stage breast cancer The small US biotech MacroGenics also caused interest with its follow-up to Roche’s breast cancer drug Herceptin (trastuzumab), called margetuximab. It’s very similar to Herceptin, but the Fc region – the tail of the Y-shaped antibody – has been optimised to produce a stronger immune response compared with the older drug. While the results are statistically significant, the debate at ASCO is whether the effect seen is relevant to the clinic. There are no mature overall survival data at the moment in patients previously treated with Herceptin and HER2-target drugs, from the SOPHIA trial data published at ASCO. But progression free survival was best in a predetermined set of patients who carry the CD16A/158F allele – a median of 6.9 months on margetuximab compared with 5.1 months in the Herceptin comparator group. It’s still a small margin of improvement and the feeling among doctors was that while it may get approved, the clinical benefit in this very sick group of patients may still not be enough for the drug to be popular with prescribers. That said, MacroGenics’ CEO Scott Koenig said the company is developing margetuximab in early stages of the disease, where the difference in performance could be more marked compared with comparator drugs. Premenopausal breast cancer is focus for Novartis While MacroGenics is looking to take on Roche in the late stages of HER2-positive breast cancer, Novartis is targeting the early stages of the disease. Its CDK4/6 inhibitor Kisqali (ribociclib) is already approved in ER-positive, HER2-negative disease but facing intense competition from Pfizer’s Ibrance and Lilly’s Verzenio. But Kisqali is the for first-line use in premenopausal patients for this setting, and results from MONALEESA-7 announced at ASCO will help encourage doctors to prescribe it. Before the event began Novartis announced FDA approval of Piqray (alpelisib), a drug targeting HER2-negative disease with PIK3CA mutations – in SOLAR-1 the drug produced a median progression free survival of 11 months, compared with 5.7 months in a comparator placebo group. Gilead makes case for CAR-Ts Gilead’s Kite Pharma unit had a strong presence at ASCO, giving data about the company’s already-approved CAR-T cell therapy, Yescarta (axicabtagene ciloleucel). Kite came with data from its ZUMA-1 study in refractory diffuse large B-cell lymphoma, which has already been used to approve the therapy in this indication. There was an analysis in older patients in the study, 65 years of age and above, where there was a 92% overall response rate at a median 27.1 months, compared with 81% among patients under 65. After two years, 42% of those over 65 were still responding, compared with 38% in those under 65. In the older group 54% were still alive after two years compared with 49% in the under-65 group. Also at ASCO was data on its investigational KTE-X19, which the company is developing for adults with relapsed or refractory acute lymphoblastic leukaemia. KTE-X19 employs the same T cell construct as Yescarta but as a slightly modified manufacturing process to boost its activity in diseases where there is a large burden of circulating tumour cells such as ALL. Of 41 patients who were evaluable for efficacy after median follow-up of 16 months, 68% achieved either a CR or a CR with incomplete haematological recovery (CRi) while all responders had undetectable minimal residual disease (MRD). Gilead has previously said it intends to file for approval of KTE-X19 before the end of the year in mantle cell lymphoma and ALL. J&J wants to be the Erleada of the pack in prostate cancer Johnson & Johnson’s Janssen unit released data from Erleada (apalutamide) in patients with metastatic castration-sensitive prostate cancer (mCSPC). This will be the first time that we got the chance to see detailed data from the phase 3 TITAN study. Primary endpoints were overall survival and radiographic progression-free survival. Erleada significantly reduced risk of radiographic progression or death by 52%, and the benefit was consistent across subgroups. It also significantly reduced risk of death by 33%. Secondary endpoints also favoured Erleada - there was a significant improvement in median time to cytotoxic chemotherapy, although non-significant improvement in median time to pain progression. The biggest issue safety-wise was a rash seen in 27% of patients although investigator Dr Kim Chi said most cases were Grade 1 or 2. Overall the safety profile was consistent with previous experience of the drug. Erleada is designed to replace Janssen’s older Zytiga, which is threatened by generics, and while the results of TITAN look convincing it’s unclear whether they will convince doctors to prescribe the newer drug instead of much cheaper competitors. Pfizer and Astellas also had data from the phase 3 ENZAMET trial in mCSPC prostate cancer with Xtandi (enzalutamide). An interim analysis showed that among men with mCSPC who received testosterone suppression, those given Xtandi survived longer than those who were also given standard nonsteroidal androgen receptor inhibitor. The verdict at ASCO is that Xtandi could be a new treatment option on the basis of the interim analysis. It could build on Xtandi’s existing indications in non-metastatic and metastatic castration-resistant prostate cancer, in the likely event of a filing with the FDA. Seattle Genetics and Astellas focus on bladder cancer Experts at the conference highlighted that checkpoint inhibitors – Roche’s Tecentriq, Merck & Co’s Keytruda, Astrazeneca’s Imfinzi and Merck KGaA’s Bavencio – are approved in bladder cancer but have issues with low response rates. In urothelial carcinoma rates as low as 13%-21%, and most patients will require further therapy due to lack of response or progression. Enter Seattle Genetics and Astellas, who are jointly developing enfortumab vedotin, an antibody-drug conjugate intended as an option for patients whose disease has progressed despite treatment with platinum therapy and a checkpoint inhibitor. Enfortumab vedotin targets Nectin-4, a therapeutic target highly expressed in multiple solid tumours, and like most other antibody-drug conjugates it works by delivering a toxic payload to cancer cells after locking onto the antigen. The results discussed at ASCO were from one cohort of the EV-201 trial, where patients had been treated with platinum chemo and PD-1/PD-L1 checkpoint inhibitor. Results at this stage show a 44% response rate and a complete response of 12% and 7.6 months median duration of response. These latest data show a median progression-free survival of 5.8 months, and a median overall survival of 11.7 months. Responses were observed across all subgroups and were irrespective of response to PD-1/L1. Study author Daniel Petrylak, a professor of urology at Yale, said results were strong enough to support approval, and that the drug could be a new standard of care in patients not responding to platinum therapy or checkpoint inhibitors. The FDA has already earmarked enfortumab vedotin as a Breakthrough Therapy, clearing the way for a potential fast six-month review after a filing slated for later this year. With the conference wrapped up for another year, the 40,000 oncologists will probably already be booking their hotels for next year’s event, which will be held again in Chicago.   Reference ¹CancerMPact Patient Metrics U.S. Kantar. Available from www.cancermpact.com. Accessed June 10, 2019