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Expert Point of View: Sarina Anne Piha-Paul, MD, and Benjamin Besse, MD, PhD


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THE INVITED discussants of the presentations on repotrectinib and AMG 510 were enthusiastic about these agents. Sarina Anne Piha-Paul, MD, of The University of Texas MD Anderson Cancer Center, discussed AMG 510, and Benjamin Besse, MD, PhD, Head of the Cancer Medicine Department at the Institut Gustave Roussy Cancer Center in France and Chair of the European Organisation for Research and Treatment of Cancer Lung Cancer Group, discussed repotrectinib.

Sarina Anne Piha-Paul, MD

Sarina Anne Piha-Paul, MD

Benjamin Besse, MD, PhD

Benjamin Besse, MD, PhD

AMG 510: ‘Turning the Tide’ on RAS

DR. PIHA-PAUL said she is “exceedingly happy” to see that targets once considered undruggable [such as RAS] are now being explored as therapeutic options. “We’ve been in a 30-plus–year war on RAS, and I believe we’re finally turning the tide,” she said. Dr. Piha-Paul explained the difficulty of designing a drug that can bind to the RAS protein, which lacks a deep hydrophobic pocket, and block the tight interaction of GTP with RAS. When GTP is bound, there are downstream effects and activation of the MAP kinase pathway. With AMG 510, KRAS is locked into its inactive GDP-bound state and prevents this pathway from being activated in tumors with KRAS G12C mutations.

Although TRIDENT-1 demonstrated “great” responses in NSCLC, with five partial responses now confirmed, the question is why responses were seen in NSCLC alone, with activity less robust in the other tumor types. Dr. Piha-Paul suggested that, similar to the BRAF V600E mutation, histology matters. In melanoma, BRAF inhibitors proved to be powerful, but in colorectal cancer they were “lackluster,” she said. “I’m wondering if this will be the picture for this compound in the future,” she said. “It’s important to see what happens in different tissue histologies with the same mutation when provided a targeted agent.”

Repotrectinib: Need to Test for ROS1 Mutations

AS FOR REPOTRECTINIB, Prof. Besse deemed the drug to be “probably the most potent tyrosine kinase inhibitor today against ROS1,” based largely on its activity in highly refractory patients. He cautioned, however, “We don’t know yet if this will translate to an improved progression-free survival.”

Digging deeper into the responses by dose level, Prof. Besse noted that in five patients who underwent dose escalation after disease progression, two seemed to derive a prolonged benefit from the drug. “This is an argument that probably dose of the drug matters,” he added.

The potency could also raise the risk for more toxicity, Prof. Besse added, and stressed that close monitoring of adverse events is warranted in further investigations. “If we look at the overall picture of ROS1 inhibitor toxicity, repotrectinib seems to be a nice and friendly drug, but we need to follow-up on the dyspnea we saw, which might be related to disease or drug,” he indicated.

“Since we have such potent drugs,” Prof. Besse continued, all patients must be tested for ROS1 mutations. Treatment with current ROS1 inhibitors can prolong survival beyond 4 years, he noted, “and so there may actually be an ethical concern if we do not adequately test these patients.” Uptake in testing has been observed since patients with non–small cell lung cancer (NSCLC) have become more educated and proactive about treatment options. Prof. Besse also commended patient groups such as the ROS1ders for their role in helping to enroll patients in the repotrectinib trial.

DISCLOSURE: Dr. Piha-Paul has received institutional research funding from AbbVie, Aminex, BioMarin, Boehringer Ingelheim, Bristol-Myers Squib, Cerulean Pharma, Chugai, Curis, Five Prime, Flex Bio, Genmab, GlaxoSmithKline, Helix BioPharma Corp, Incyte, Jacobio Pharmaceuticals, MedImmune, Medivation, Merck Sharp and Dohme, Novartis Pharmaceuticals, New Link Genetics/Blue Link Pharmaceuticals, Pieris Pharmaceuticals, Pfizer, Puma Biotechnology, Seattle Genetics, Taiho Oncology, Tesaro, TransThera Biosciences, and Xuanzhu Biopharma. Prof. Besse has received institutional research funding from AbbVie, Amgen, AstraZeneca, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Eli Lilly, GSK, Ignyta, Ipsen, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE Immunopharmaceutics, Pfizer, PharmaMar, Sanofi, Spectrum Pharmaceuticals, Takeda, and Tiziana Pharma.


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