ESMO 2019: Comprehensive Genomic Profiling Leverages Data Insights to Improve Patient Care

As scientists worldwide continue to pioneer breakthroughs and change the way we understand and treat advanced cancer, it’s important to stay connected so we can learn from one another. The annual European Society for Medical Oncology (ESMO) Congress is one such opportunity for the cancer community to share the latest developments in oncology research and reflect on how far we’ve come.

And the data that were presented at this year’s ESMO did not disappoint. I was particularly encouraged by advancements in liquid biopsy, difficult-to-treat cancers, and more complex and emerging biomarkers. Comprehensive genomic profiling (CGP) plays an increasingly important role in enabling these studies and improving our collective understanding of how best to stratify patients to therapies and improve outcomes.

FoundationOne®Liquid shows direct clinical utility in lung cancer

Lung cancer has seen the most advancements in personalized medicine and today, there are 16 targeted therapies approved for non-small cell lung cancer (NSCLC).¹ As on-label treatment options have increased, so has the need for expanding access to both tissue and liquid-based CGP. Physicians need to have confidence in the results regardless of specimen type, which is why we are particularly proud that FoundationOne®Liquid, a laboratory test developed by Foundation Medicine, was utilized in Genentech’s phase II/III Blood First Assay Screening Trial (BFAST), the largest prospective global study of its kind.

BFAST is the first global prospective study to use only blood-based next generation sequencing (NGS) to detect specific fusions with the aim of selecting treatment for people with advanced NSCLC, without the need for tissue biopsy. Using FoundationOne Liquid, we were able to find ALK fusions at a rate consistent with what would be expected to be found biologically, and patients with ALK-positive disease had a very high confirmed objective response rate of 87.4 percent to alectinib (Alecensa®). This suggests that ALK fusions detected in the study were not contaminated by “false positives” and makes FoundationOne Liquid the first and only liquid biopsy test to show prospective clinical utility in a global registrational trial for patients with newly diagnosed, metastatic NSCLC. These important findings should give physicians confidence that FoundationOne Liquid has the rigor to find these difficult-to-detect but highly actionable ALK fusions.

Increasingly complex biomarkers are advancing treatment options

CGP is changing our understanding of cancer from an organ-specific disease to a complex disease of the genome. ESMO presentations this year showed how CGP can uncover new, increasingly complex biomarkers to match patients across tumor types with targeted therapy.

New data from the PROfound study, which evaluated AstraZeneca and Merck's PARP inhibitor olaparib (Lynparza®) in pre-treated metastatic castration-resistant prostate cancer (mCRPC) with certain sensitizing mutations, represent the first positive phase III study of biomarker-selected targeted therapy in this population.

Foundation Medicine has collaborated on this study since the beginning. Our genomic data laid the foundation for PROfound, helping inform and develop the specific signature of 15 gene mutations likely to respond to PARP inhibitors that were evaluated in the study. In one large study, these mutations were seen in more than 15 percent of cancers, supporting the value of further studies of PARP inhibitors in other cancer types.²

Tumor Mutational Burden (TMB) data encouraging as studies continue to unfold

Additional Merck, Roche and Bristol-Myers Squibb (BMS) presentations on TMB contributed to our understanding – and the potential promise – of TMB across tumor types.

• Data from several of Merck’s KEYNOTE studies showed that TMB measured by FoundationOne®CDx was predictive of pembrolizumab (Keytruda®) monotherapy response in PDL1-positive NSCLC cases but was not predictive of response to a combination regimen of pembrolizumab and chemotherapy in all comers.

• These data are consistent with another study presented at ESMO that showed that high TMB was not a strong prognostic biomarker in non-immunotherapy-treated patients through an analysis of our clinco-genomic database with Flatiron Health.

• Moreover, Merck demonstrated that TMB could be used to strongly differentiate response rate to pembrolizumab monotherapy amongst 10 selected tumor types in a prospective clinical trial, further supporting TMB’s predictive value for immunotherapy monotherapy-treated patients.

• Additional supporting evidence for the utility of TMB for predicting response to immunotherapy was presented by Genentech in the context of blood-based TMB (bTMB) in its first line NSCLC trial, B-FIRST, which demonstrated it could be used to differentiate response rate to the PD-L1 inhibitor atezolizumab.

• Finally, BMS’s Checkmate-227 showed that TMB was predictive of progression-free survival with nivolumab at AACR last year. Part B of this trial evaluated overall survival (OS). While a link between OS and TMB was not a primary endpoint of the study, the study revealed an OS benefit based on TMB in the immunotherapy arm and the chemotherapy arm, which minimized the power of TMB as a predictor of response to immunotherapy. However, upon closer look, 42 percent of patients were allowed to “cross-over” from the chemotherapy arm to the immunotherapy arm in Checkmate-227, so any measure of OS would be confounded by this.

These notable data emphasize the importance of collaboration and continued research to help further determine the role TMB will play as a predictor of response to immunotherapy across various cancers and its interactions with other biomarkers. While several new studies supported the predictive power of TMB to anti-PD1/PD-L1 monotherapy across several tumor types, a consistent theme emerged from ESMO that additional comprehensive approaches should be explored that can further enhance the utility of an already strong predictive immunotherapy biomarker like TMB.

CGP can enable targeted therapy for rare and hard-to-treat cancers

This year’s conference also reinforced the inherent value of CGP in rare and hard-to-treat cancers. Data from Roche’s CUPISCO study revealed insights about the use of CGP in cancer patients whose disease had spread before diagnosis and for whom no primary tumor origin site was found (known as cancer of unknown primary [CUP]).

CUP patients present with metastatic and often aggressive disease, and aside from the approvals of pan-tumor treatments for MSI-high and NTRK-positive tumors, they have never had a treatment approved specifically for them. Most patients receive non-specific, non-personalized chemotherapy, and outcomes are dismal. CUPISCO results showed that using CGP to assess targetable biomarkers could identify one-third of CUP patients as eligible for precise therapy already available.

While we don’t yet know if this approach improves outcomes, these results point to the opportunity for genomic information to help tailor treatment for a traditionally underserved patient population.

Looking ahead

It’s clear that more and more data about new therapies and biomarkers comes out each day, causing decision-making in oncology to be increasingly challenging. At FMI, we have the opportunity to make this data more accessible and meaningful to the patients and doctors who are making important decisions. This was evidenced by the overflow crowd that showed up at our first ever “live tumor board” that we hosted during ESMO. I want to personally thank all of those involved for putting on such a wonderful presentation. It really showcased the level of analytical rigor and depth of expertise that Foundation Medicine brings to the table to help answer the hardest questions facing oncologists today.

At Foundation Medicine, we are committed to ensuring doctors and their patients have access to the critical information CGP provides, and we are dedicated to advancing research, development and access to personalized treatment options. While at ESMO, I was reminded of – and energized by – the power of collaboration in moving us toward the ambitious goal of improving care for the next generation of cancer survivors.