More Umbrella Trials Needed to Advance Precision Medicine in Lung Cancer, Expert Suggests

Vassiliki A. Papadimitrakopoulou, MD

Vassiliki A. Papadimitrakopoulou, MD

Further advancements in precision medicine for patients with non—small cell lung cancer (NSCLC) necessitate the use of more umbrella trials to evaluate therapies based on molecular aberrations versus tumor types, Vassiliki A. Papadimitrakopoulou, MD, suggested during a presentation at the19th AnnualInternational Lung Cancer (ILC) Congress. She shared insight on how the lung cancer paradigm continues to evolve with the identification of targetable driver mutations and on ongoing clinical trial efforts designed to better reach patients and improve their outcomes.

“Umbrella clinical trials [are] the most cost-effective way to screen many patients and offer therapies to almost everyone,” said Papadimitrakopoulou, who is the Jay and Lori Eisenberg Distinguished Professor of Medicine and section chief of thoracic medical oncology in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. She 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 ILC Congress.

Molecular abnormalities, includingEGFR,ALK,ROS1, andBRAF, have been successfully targeted with novel agents in a number of lung cancer subtypes, she said; however, other mutations, such asKRAS,remain difficult to effectively reach.

“EGFRmutations 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…. It is a similar scenario inALKgene fusions. We have also seen excellent activity forBRAFmutations andROS1fusions. We have also seen emergence of better selective inhibitors forRETfusions and mutations, so we have [seen a] great evolution of the landscape from that point of view.,” Papadimitrakopoulou commented. “We still have alterations, such asKRASthat 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.”

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. As of March 13, 2017, the trial was expanded to include 30 different treatments.

“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,” Papadimitrakopoulou explained. The investigators aimed for 25% of enrolled patients to have rare types of cancer.

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 activatingPIK3CAmutations. 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 withHER2-amplified tumors that excluded breast cancer and gastric/gastroesophageal adenocarcinoma.²Partial responses (PRs) 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 hadFGFRaberrations with an acceptable safety profile.³Ten percent of patients achieved a PR on AZD4547.

Papadimitrakopoulou noted that the limitations of the NCI-MATCH trial were that there was a relatively small sample size for each treatment, and so cases of particular histologies may also be limited. Also, many of the patients in the trial were heavily pretreated which could make broad applicability difficult.

“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,” she explained, pointing to the Lung-MAP clinical trial. The trial was originally designed to treat patients with squamous lung cancer only, but now has expanded into all histologies.

The current trial schema is divided into many biomarker-driven as well as non-matched sub-studies. The biomarker driven sub-studies are looking toPI3K, FGFR,andc-METmutations, and more, whereas the non-matched studies are looking at checkpoint inhibitors in patients who have and have not received prior immunotherapy. Patients with known and effectively targeted driver mutations and alterations were excluded from the study unless they had progressed on all standard-of-care tyrosine kinase inhibitor therapies.

Several sub-studies from the Lung-MAP trial have already closed with modest benefits. For example, the FGFR inhibitor AZD4547 was investigated in a phase II study in patients with previously treated squamous NSCLC harboringFGFRalterations or mutations. Of 27 evaluable patients, 1 had a confirmed PR and there was another unconfirmed PR. Thirteen patients also had stable disease. The median PFS was 2.7 months (95% CI, 1.4-4.5) and the median OS was 7.5 months (95% CI, 3.6-9.3).

Many other basket trials are currently being developed and beginning to enroll patients. “Access to novel therapies for patients in ‘rare’ genotypic groups has already produced tangible benefits and the paradigm can be expanded,” Papadimitrakopoulou said.

The TAPUR trial, which is sponsored by ASCO, is a nonrandomized, phase II basket trial designed to describe the antitumor activity of commercially available targeted anticancer drugs that are prescribed for treatment of patients with advanced cancer. Patients with solid tumors, B-cell non-Hodgkin lymphoma, or multiple myeloma harboring a genetic variant known to be a drug target are eligible. Thirteen treatments are currently included in the trial. 

Papadimitrakopoulou noted that with this basket trial, everyone benefits. Patients receive personalized treatment matched to their tumor's genomic profile, physicians receive interpretation of the results which lends to treatment decision-making guidance, payers recieve data on tests and outcomes to inform future coverage decisions, and regulators receive real-world safety data.

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).
4. Aggarwal C, Redman MW, Lara P, et al. Phase II study of the FGFR inhibitor AZD4547 in previously treated patients with FGF pathway-activated stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400D.J Clin Oncol.2017;35(suppl 15; abstr 9055).