The 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) gathered over 32.000 oncology professionals from all over the world, highlighting the latest in cancer care treatments.
Although by some referred as to being the “Lung cancer and immuno-oncology (IO) conference”, promising data was shown in several (difficult to treat) tumor indications beyond non-small cell lung cancer (NSCLC), including melanoma, pancreas cancer, renal cell, urothelial cancer and many others. Several treatment options were challenged and some showed results against all odds and current treatment standards – it seemed to be as unpredictable as the weather in the ‘windy city’ that hosted this immense scientific cancer conference. Highlights and some surprising findings are summarized below.
Throughout the conference, the use of (front-line) treatment of pembrolizumab was evident. Numerous KEYNOTE trials were presented during these five days in June, including the Plenary session held on Sunday:
According to Dr. Paz-Ares, the KEYNOTE-407 study provides rationale for a new standard of care for the first-line treatment of metastatic squamous cell NSCLC; pembrolizumab in combination with chemotherapy increased median overall survival (OS) to 15.9 months, compared to 11.3 months when carboplatin and paclitaxel/nab-paclitaxel alone was given. Furthermore, this “step child” orphan indication within lung cancer (as mentioned by Assistant Professor, Dr. Charu Aggarwal), seems to benefit from this IO/chemotherapy combo independent of PD-L1 expression.
Dr. Lopes highlighted that the KEYNOTE-042 study confirms the importance of pembrolizumab as monotherapy as standard of care (SoC) 1st line in locally advanced or metastatic NSCLC PD-L1 expressing patients, even those with much lower PD-L1 expression (tumor proportion score (TPS) ≥ 1%), as noted by an improved OS in all PD-L1 expressing groups (TPS ≥ 1%, 20% and 50%), and lower toxicity.
Later that day, however, Dr. Gandhi presented her thoughts on how these results might be skewed. In her opinion (and later shared by others in the discussion) this benefit is mainly driven by the high PD-L1 subgroup, and not at all clear-cut in the patients with TPS lower than 50%. She advocated the use of PD-L1 as biomarker, despite its imperfectness of being a dynamic biomarker that can change over time and/or treatment. Ways to overcome some of the challenges is to combine with other markers, e.g. mutational tumor burden (mut/Mb). She visualized 5 theoretical treatment scenarios in NSCLC (KEYNOTE-024) based on TPS and mut/Mb:
90% PD-L1: pembrolizumab
0% PD-L1 + 15 mut/Mb: nivolumab + ipilimumab
0 or 20% PD-L1, 4 mut/Mb: pembrolizumab/ platinum/ pemetrexed
20% PD-L1, 4 mut/Mb, liver metastases and EGFR mutant: carboplatin/ paclitaxel/ bevacizumab/ atezolizumab (and in need of an acronym she joked)
20% PD-L1, not-chemo eligible, modest tumor burden, molecular testing not feasible: pembrolizumab
Also in the melanoma setting, pembrolizumab seemed to be the way to go. Among the many presentations that touched upon this topic, included one on the 5-year follow-up data of the KEYNOTE-001 study, the longest follow-up for pembrolizumab to date in any cancer. Here, pembrolizumab had a 5-year OS rate of 34% in patients with previously treated and treatment-naive advanced melanoma, and a 5-year OS rate of 41% in treatment-naive patients, indicating the durable antitumor activity and tolerability of Merck’s PD1i in advanced melanoma.
Moving beyond, although some breaking news expected in the IDO field was obviously missing due to recent failed trials, somewhat paradoxical results were presented in the land of surgery:
As presented by Dr. Méjean, what has been the standard of care in renal cell cancer (RCC) for two decades – i.e. surgery followed by systemic therapy – may not be the best treatment option after all. The necessity of cytoreductive nephrectomy (CN) was brought into question by unexpected results in the randomized CARMENA phase III trial that compared CN + sunitinib (226 patients) vs sunitinib alone (224 patients). The latter showed non-inferior median OS data and numerically greater PFS data. Does this imply that removing the kidney will no longer be essential in the management of advanced RCC, hence changing current practice?
In line with this, secondary surgical cytoreduction (SCC) in ovarian cancer was also put to the test. In the GOG-0213 trial, platinum-sensitive, recurrent ovarian cancer patients were randomized to undergo SCC followed by platinum-based combination chemotherapy, with or without bevacizumab. Dr. Coleman presented that although SCC can be safely performed in this population, it did not improve OS. The patients that didn’t undergo SCC, did three times better as initially thought at the time of designing the study, mostly because bevacizumab was not yet approved, and different outcomes were expected.
The latter notion emphasizes a common feature in the current clinical trial landscape; new drugs are obtaining marketing authorization application (MAA) faster and faster and it is becoming more difficult for drug development pharma and biotech companies to predict what will happen in the next 5 years. Designing your trial and powering your study against a certain arm or therapy type is becoming a bigger struggle. Recently approved drugs or drugs that have moved towards secondary and first line treatments, may lead to disappointing or failed study results as the investigational medicinal product (IMP) turns out to be powered against the wrong chemotherapy/ treatment arm, or eligible patients are hard to find as inclusion criteria are less/ not relevant anymore. It seems that nowadays and even more in the future, tumor indication selection and study design becomes more prudent in early development stages.
Patients (luckily) seem to be moving towards a world in which ‘enrolling in a clinical trial’ may become SoC, while industry are facing tougher competition every day. KEY NOTE here; oncology knowhow is essential to make sure the scientific rationale is translated into a trial design that will ensure the right clinical data are collected, while the study is clinically valuable and attractive for physicians and patients to take part in, operationally feasible, and will suit your business opportunities all at once. Together we can bring cancer cures into reach.