Evolving Lung Cancer Landscape Likely to Involve More Basket Trials

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.

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?

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.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.

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?

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.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.

Your second presentation focused on master protocols in clinical trial designs. What was the take-home message from this lecture?

We still have alterations, such as KRAS; it is in about 25% of patients with adenocarcinoma and that we haven't been successful in targeting. We will continue to target this alteration in clinical trials, to try and find mechanisms that make this tumor so invulnerable to our therapies.By no means am I a statistician, so the designs of clinical trials in this lecture were from the clinician's point of view, and how we can benefit more patients at the same time by designing umbrella, or basket, clinical trials. This is the most cost-effective way to screen many patients and offer therapies to almost everyone.

What are examples of some clinical trials that best exemplify this?

The major part of this talk concentrated on efforts by the NCI in the United States because many of these trials happen to be sponsored by the NCI. Much of the talk concentrated on the international efforts to do so as well, and some of the industry-sponsored clinical trials have adopted this same type of umbrella design. Most of this talk concentrated on results we have seen from these early efforts, and what we hope for in the future.The NCI-MATCH trial is a basket clinical trial, and that means the patients are allocated to therapies on the basis of the molecular alteration of their tumor rather than their tumor type. Specifically, in the case of NCI-MATCH, the patients are selected based on tumors that haven't yet benefitted from the targeted therapy in question.

You are the recipient of the 2018 Addario Lectureship Award, which was presented to you during the 19th Annual ILC Congress. What does this award mean to you?

The other clinical trial is an umbrella trial where patients with the same tumor type and similar histology are allocated to different arms of the trial based on the molecular alteration of the tumor. One example for that in lung cancer is the Lung-MAP clinical trial that was designed to serve patients with squamous lung cancer, but now has expanded into all histologies.It is very important to recognize the efforts of the Bonnie J. Addario Lung Cancer Foundation for patients in the community with lung cancer. One of the primary things that I recognize is the passion that exists within the organization to help patients, their families, and to also help providers get better treatments to those patients.

It is great to be recognized by the Bonnie J. Addario Lung Cancer Foundation. It is a great honor that I take as a task to do better research, better science, and offer better outcomes to our patients.

References

1. Krop IE, Jegede O, Grilley-Olson JE, et al. Results from molecular analysis for therapy choice (MATCH) arm I: Taselisib for PIK3CA-mutated tumors. J Clin Oncol. 2018;36(suppl; abstr 101).
2. Jhaveri KL, Makker V, Wang XV, et al. Ado-trastuzumab emtansine (T-DM1) in patients (pts) with HER2 amplified (amp) tumors excluding breast and gastric/gastro-esophageal junction (GEJ) adenocarcinomas: Results from the National Cancer Institute (NCI) Molecular Analysis for Therapy Choice (MATCH) trial. J Clin Oncol. 2018;36(suppl; abstr 100).
3. Chae YK, Vaklavas C, Cheng HH, et al. Molecular analysis for therapy choice (MATCH) arm W: Phase II study of AZD4547 in patients with tumors with aberrations in the FGFR pathway. J Clin Oncol. 2018;36(suppl; abstr 2503).

<<< 2018 International Lung Cancer Congress