Evolving Lung Cancer Landscape Likely to Involve More Basket Trials

Gina Columbus @ginacolumbusonc
Published: Saturday, Jul 28, 2018

Vassiliki A. Papadimitrakopoulou, MD
Vassiliki A.
Papadimitrakopoulou, MD
Lung cancer treatment is poised to include not only more precision medicine approaches, but will also incorporate more basket trials that will evaluate therapies based on molecular aberrations versus tumor types, according to Vassiliki A. Papadimitrakopoulou, MD.

Molecular abnormalities, including EGFR, ALK, ROS1, and BRAF, have been successfully targeted with novel agents in a number of lung cancer subtypes; however, other mutations, such as KRAS, remain difficult to effectively reach.

"The bottom line is that we need to find therapies that match the patients" tumor," said Papadimitrakopoulou, who is the Jay and Lori Eisenberg Distinguished Professor of Medicine and chief of the Thoracic Medical Oncology Section in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.

Clinical trials underway that exemplify the umbrella, or basket, formula include the National Cancer Institute (NCI)-MATCH study, described as a US precision medicine study that involves molecular testing on 6000 patients' tumors. MATCH assigns patients with solid tumors, lymphomas, or multiple myeloma to specific targeted therapies based on molecular alterations.

Findings of 3 arms from the phase II MATCH trial were presented at the 2018 ASCO Annual Meeting. In arm I, the investigational PI3K inhibitor taselisib did not induce any objective responses in a mixed histology cohort of patients with activating PIK3CA mutations. However, 27% of patients were associated with a progression-free survival of 6 months or longer.1

A second arm of the trial, arm Q, showed that treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla) was well tolerated in patients with HER2-amplified tumors that excluded breast cancer and gastric/gastroesophageal adenocarcinoma.2 Partial responses were noted in 3 of 37 patients.

Finally, in arm W of the MATCH trial, the selective FGFR1/2/3 inhibitor AZD4547 demonstrated modest activity across patients with a number of solid malignancies who had FGFR aberrations with an acceptable safety profile.3 Ten percent of patients achieved a partial response on AZD4547.

Papadimitrakopoulou is also the recipient of the 2018 Addario Lectureship Award, awarded by the Bonnie J. Addario Lung Cancer Foundation, for her clinical research in immunotherapy and targeted lung cancer treatments. She received the award during the 19th Annual International Lung Cancer (ILC) Congress.

In an interview with OncLive during the meeting, Papadimitrakopoulou shared insight on how the lung cancer paradigm continues to evolve with the identification of targetable driver mutations, the challenges that remain, and the ongoing clinical trial efforts designed to better reach patients and improve their outcomes.

OncLive: You spoke on the evolution of personalized therapy for patients with non-small cell lung cancer (NSCLC). How has the landscape changed in this regard?

Papadimitrakopoulou: I try to be as simple as possible when I give a lecture, although the landscape for lung cancer has become very complex. We have [matched the patient's tumor] successfully for some of the genotypical alterations for NSCLC, such as EGFR mutations. We have a long way to go because about 50% of our patients do not have alterations that we recognize as drivers. Even within the other 50% of patients who have aberrations, there are some, including KRAS mutations, that are not targetable.

Therefore, it is important to recognize this aspect of treatment of NSCLC; I focused on that during my lecture. I also focused on the fact that immunotherapies are given for all of our patients nowadays but, again, we have no great means of selecting the patients who would benefit the most, and no great means of identifying patients who don't benefit and how to help them.

On the therapies that are available and match driver mutations, what would you say are the most successful ones? Can you also expand on the unmet need with KRAS-mutant NSCLC?

The most successful targeted therapies, of course, are in the area of EGFR-mutated disease. EGFR mutations are the "poster child" for precision medicine in NSCLC. We have seen great evolution in the quality of therapies and the outcomes that we have for patients with osimertinib (Tagrisso). [This has been] emerging as the bigger and better inhibitor that is better tolerated by patients and targets central nervous system disease quite effectively.

It is a similar scenario in ALK gene fusions. We have also seen excellent activity for BRAF mutations and ROS1 fusions. We have also seen emergence of better selective inhibitors for RET fusions and mutations, so we have [seen a] great evolution of the landscape from that point of view.

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