Over the last few days some 32,000 oncology professionals from across the globe have gathered in Chicago, USA, for the exchange and debate of the very latest clinical cancer research at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO), 31 May – 04 June. Themed Caring for Every Patient, Learning from Every Patient, several of our clinical investigators are currently on the ground at the meeting to present studies they have either led or have collaborated in as co-authors. ASCO’s pre-meeting release back in April promised us advances in targeted therapies for prostate, pediatric, and pancreatic cancers in particular.
Concerning the latter, Teresa Macarulla, Principal Investigator of our Gastrointestinal and Endocrine Cancer Tumors Group, co-authored a late ‘breaker’, which was selected to first-outing during a Plenary. Results point to a change in clinical practice for the treatment of patients with BRCA-mutated metastatic pancreatic cancer. Namely, PARP inhibitor (PARPi) olaparib as maintenance therapy for these patients. Importantly, findings from this present POLO phase III trial: Olaparib as maintenance treatment following first-line platinum based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer, also published in parallel in The New England Journal of Medicine (1), and were specially selected to feature in ASCO’s Press Program (2).
Also advancing more potent anti-cancer medicines against gastrointestinal cancers, our Director and Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, Josep Tabernero, presented results during an Oral Session (pictured here) that were also hand-picked by ASCO’s Press Program (3) as well as ASCO Post Newsreels for coverage (4). The study explored the promise of immune-based agent, pembrolizumab, combined with chemotherapy for the treatment of patients with advanced gastric or gastroesophageal cancer as first line therapy: the Keynote-062 Phase III Study (see below).
POLO: the promise of PARPi maintenance therapy against BRCA+ Metastatic Pancreatic Cancer
Pancreatic cancer still has a poor prognosis and represents approximately 3% of all newly diagnosed cases. Considering the current survival rates, calculated at 5 years in 9% of these patients, coupled with growing incidence over recent years, it is estimated that pancreatic cancer will be the second cause of death by cancer in the USA by 2030. In Europe, the outlook is equally bleak. As of last year, 2018, it is has been calculated that more lives will be claimed from pancreatic cancer than from breast cancer.
Despite the major research efforts devoted to more effectively combating this notoriously difficult-to-treat tumor type, no biomarker has previously been identified to better indicate which population would most likely benefit from anti-cancer medicines. Up until now.
Presented during a Plenary Session yesterday on the ground at this year’s ASCO Annual Meeting, first author Hedy L. Kinder, University of Chicago, reported the results of the Phase III POLO trial; a multi-center, international study designed to evaluate the efficacy of maintenance therapy with a PARP inhibitor (PARPi) in patients with germline BRCA-mutated metastatic pancreatic cancer.
By showing that maintenance therapy with PARPi olaparib significantly improved progression-free survival (PFS) compared with placebo among these patients, this is the first study with positive results in better tailoring therapy based on a biomarker. Specifically, as the first positive phase III clinical trial of any PARPi in germline BRCA-mutated breast cancer, this could represent new hope and open up new treatment avenues for this patient population. Timed to coincide with the actual Meeting Session, and indicative of the promise of these data as practice changing, results were published in parallel as an Original Article in The New England Journal of Medicine (1).
“This is the very first targeted treatment against pancreatic cancer,” says Teresa Macarulla (pictured above), Principal Investigator of our Gastrointestinal and Endocrine Tumours Group, co-author of the study and VHIO team lead for the ‘local’ recruitment of patients. She concludes, “Approximately 6-8% of patients with pancreatic cancer are carriers of this mutation and could stand to benefit from this therapeutic approach. While these results promise more treatment options for these patients, we must now seek to expand the group of patients who might also gain from olaparib, beyond those who have a germline BRCA1 or BRCA2 mutation.”
This international double-blind, randomised trial, led by Hedy L. Kindler from the University of Chicago (IL, USA), was coordinated by Talia Golan, the Oncology Institute, Sheba Medical Center-Tel Aviv University (Israel), and conducted in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer which had not progressed during first-line platinum based chemotherapy.
The promise of clinical gains for patients with metastatic gastric and gastroesophageal cancers
Immune-based anti-cancer armory is emerging as one of the most promising novel drug contenders across many tumor types. While much work still needs to be done in order to benefit as many patients as they promise, we continue to see encouraging results regarding their efficacy reported in the literature. This is certainly true of pembrolizumab. As an example, this monoclonal antibody has already proven effective in combination with chemotherapy against non-small cell lung cancer, which has since led to further studies exploring its potential in tackling other oncological diseases.
Gastric cancer, which is also a notoriously difficult-to-treat tumor type with a poor prognosis, is the fifth most frequently diagnosed cancer worldwide, claiming an estimated 782,700 lives in 2018 alone. In most countries around the world, the current standard of care for the first-line treatment of advanced gastric cancer is chemotherapy, which has been the case for several years.
Presented yesterday by our Director and first-author, Josep Tabernero (pictured above), during an ASCO Meeting Oral Session, the Phase III KEYNOTE-062 study: Pembrolizumab with or without chemotherapy for advanced gastric of gastroesophageal junction adenocarcinoma, is the first randomized Phase III to evaluate an anti-PD-1 therapy as monotherapy and in combination with chemotherapy as first-line treatments in patients whose tumors express PD-L1 and who are HER2-negative.
This pan-global trial enrolled 763 patients, was divided into three treatment groups. One received chemotherapy alone, another was administered pembrolizumab, and a third group of patients were treated with combination therapy, and patients were treated for an average of no less than eleven months.
Results indicate front-line pembrolizumab as a potential alternative to chemotherapy in treating this particular patient population, with fewer side effects. The investigators also reported meaningful clinical gains in overall survival (OS) among those patients with high levels of PD-L1 expression. Specifically, at two years, 39% of patients with high PD-L1 levels that were treated with pembrolizumab alone were alive, compared with 22% of people who received standard chemotherapy. The trial also evaluated the combination of this agent and standard chemotherapy, and findings showed that this regimen improved survival compared to chemotherapy alone.
Outlining important next steps for future research Josep Tabernero says, “Above and beyond PD-L1, we need to identify more powerful biomarkers that will help us to more precisely predict which patients would be most likely to benefit from this immunotherapy alone as well as in combination with chemotherapy.”
He concludes, “Only then will we continue to unleash the power of the immune system in a greater number of individuals to attack disease. We must therefore strive to deliver the robust immune data required to better guide more precisely matched treatment decisions that benefit an increasing number of patients.”
(1) Talia Golan, Pascal Hammel, Michele Reni, Eric Van Cutsem, Teresa Macarulla, Michael J. Hall, Joon-Oh Park, Daniel Hochhauser, Dirk Arnold, Do-Youn Oh, Anke Reinacher-Schick, Giampaolo Tortora, Hana Algül, Eileen M. O’Reilly, David McGuinness, Karen Y. Cui, Katia Schlienger, Gershon Y. Locker, and Hedy L. Kindler. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. DOI: 10.1056/NEJMoa1903387.