BARCELONA, Spain – This year's theme at the European Society for Medical Oncology's (ESMO) 2019 annual meeting is "translating science into better patient care."
Successes and challenges alike of the translational enterprise were on view at a collaborative session between ESMO and the European Association for Cancer Research, titled "From cancer genomes to combinatorial therapies."
On the one hand, genomics, and the targeted therapies based on it, have led to more than 50 targeted agents targeting roughly 20 molecular alterations to date. And while the clinical benefit of some of those targeted agents is measured on the microscopic scale, others have transformed the outlook for those who benefit from them.
"This is already very big, and it's growing very fast," Rodrigo Dienstmann, a member of the ESMO committee, told the audience in his overview of "how much genomics data have translated into treatment decision."
Currently, he said, roughly 11% of patients can benefit from "genome-targeted" therapies, that directly target mutations such as Bcr-Abl or ALK. Another 17% can benefit from "genome-informed" targeted therapies, which do not directly target a tumor driver mutation but, instead, target vulnerabilities that arise as a result of that mutation. PARP inhibitors, for example, are used in patients with BRCA mutations.
Dienstmann also presented data showing that over the past decade, there has been a linear increase of 0.5% to 1% annually in the proportion of cancer patients that can benefit from targeted therapies.
That increase has been linear, rather than exponential, for reasons that include everything from cost to the fact that targetable alterations are rare. A number of attempts have been made to increase the number of patients who benefit from targeted therapies by integrating matching into clinical trials, but the percentage of patients who benefited has largely been in the single digits, though earlier this year, the WINTHER and I-PREDICT trials managed to achieve 35% and 49% matching, respectively. (See BioWorld, April 29, 2019.)
Though those trials still fall short of the 50% benefit rate (which is lower than the matching rate because not all patients benefit from a targeted agent) that Dienstmann pegged as the minimum he would accept as legitimate for declaring a drug a success, those trials do show that matching is not destined to languish in the single digits.
Dienstmann also said that in the best-case real-world scenario – that is, patients with a mutation in a tumor type that an approved targeted therapy exists for – only 60% to 70% of patients receive those treatments. "What is happening in the community is that patients do not get access even to approved therapies."
Even for those targeted therapies that robustly benefit their patients, though, benefit is almost always temporary. And so, medical oncologists have set their sights on combination treatments.
Here, there is a whole new slew of opportunities for potential to be either fulfilled, or lost in translation.
Daniel Peeper, head of the division of molecular oncology and immunology at the Netherlands Cancer Institute, gave an overview of how to set up trials for success. With more than 1,500 combination trials in his specialty, melanoma, and more than 2,000 combination trials of PD-1 inhibitors, he said, "there are more combinations to be tested that there are patients, as morbid as it sounds."
There are certain strategies for combining drugs that have a convincing rationale – different steps within the same pathway, for example, or inhibiting both a target and feedback loops that can activate that same target.
Peeper gave an overview of three combination strategies that have a high chance of success – for example, exploiting cancer cell addictions, targeting subtypes in heterogenous tumors, and sensitizing tumors to T cells.
But, he argued, approaches such as "my drug plus a PD-1 inhibitor" or "my favorite pathway with everything under the sun" are better considered opportunistic than opportunities.
Fabrice Andre, professor of medical oncology at the Institut Gustave Roussy, who gave an overview of the 2018 progress of the ESMO Precision Medicine Working Group, told the audience that a basic step toward being able to even measure success would be to develop a common approach to it.
Multiple gene sequencing, he said, is "widely used, but there is not validated tool, or common terminology, to report alterations."
As a result, the recommendations of different molecular tumor boards – meetings where oncologists meet and discuss treatment plans for patients based on their mutational profiles – can recommend starkly different treatment strategies for the same profile, based both on the expertise of the board members, and on plain semantics.
The Precision Medicine Working Group, of which Andre is a member, has been working to improve that situation. Last year, the group delivered the ESMO scale of actionability (ESCAT) for genomic alterations, which classifies alterations into categories that can range from blue-ribbon ("Ready for routine clinical use") to rubbish ("No benefit" or "Lack of evidence for actionability").