Dr. Ramalingam on How LAURA Established a ‘New Standard of Care’

Samantha Armstrong, MD, of Indiana University, and Karine Tawagi, MD, of the University of Illinois in Chicago, interview Suresh S. Ramalingam, MD, FACP, FASCO, of the Winship Cancer Institute of Emory University, during the 2024 American Society of Clinical Oncology Annual Meeting.

Dr. Ramalingam presented results from the LAURA trial during a plenary session at the meeting, garnering a major reaction, including a standing ovation.

LAURA, a double-blinded and placebo-controlled phase 3 trial, assessed the efficacy and safety of osimertinib in adults with unresectable stage III EGFR-mutated (Ex19del/L858R) non-small cell lung cancer (NSCLC) who received definitive platinum-based concurrent or sequential chemoradiotherapy and did not have progression.

Dr. Ramalingam discussed why it was important to evaluate osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI) with activity in the central nervous system, in patients with EGFR-mutated NSCLC.

“The problem is immunotherapies don’t work for patients with driver mutations like EGFR and ALK and so forth, so we wanted to study the role of EGFR inhibition in the setting. That was the premise of the LAURA study,” he explained.

The study design involved randomizing patients 2:1 to receive osimertinib 80 mg or placebo once a day until progression, as confirmed by a blinded independent central review (BICR), or discontinuation. The primary end point of the study was progression-free survival (PFS) as assessed by BICR.

Drs. Armstrong and Tawagi discussed the results of the study with Dr. Ramalingam, who said he was “very excited to report that osimertinib had a strong improvement in PFS,” with a median PFS of 39.1 months in those receiving the treatment, compared with 5.6 months in those receiving placebo, and a hazard ratio (HR) of 0.16.

“What was important for us to see is it reduces both progression within the chest and at distant metastatic sites, particularly brain [metastases], which was substantially lower for patients who are taking osimertinib compared [with] placebo,” Dr. Ramalingam said.

These results are “very important for our patients,” Dr. Armstrong said.

Drs. Tawagi and Armstrong asked Dr. Ramalingam to discuss why the trial investigators decided to use a placebo as the control arm in the LAURA trial.

“The choice was: Should we consider using durvalumab, which is used for the stage III unresectable patient population? For us, one factor was that when we wrote the trial, durvalumab had not been approved,” he explained.

Another factor in the choice to use placebo was biological in nature.

“Over several years, we’ve learned that even with high PD-L1 expression, patients who have an EGFR mutation don’t respond. The single-agent response rate to PD1 blockade is close to 0,” Dr. Ramalingam said. “We didn’t feel exposing patients to an immunotherapy just for the sake of having that was appropriate.”

There was also an important practical and patient-centered issue that Dr. Ramalingam and colleagues considered when choosing placebo as the control.

“If we had [durvalumab] on the control arm, if patients progress, we have to wait for 2 to 3 months before we can start them with the TKI because of the interaction and toxicities,” he said. “We didn’t think it was appropriate to ask a patient to wait for 3 months so we can start on a TKI when they have a new lesion in the brain or somewhere else.”

Dr. Armstrong commented, “That makes sense. You saved them toxicity as well as a lag time to get them on the proper treatment.”

They also discussed the overall survival data from the trial, which remain preliminary, as the analysis is planned after 60% of the data maturity is obtained.

“Right now, we are at 20% maturity. What is important for people to know is we provided osimertinib to patients in the placebo arm when they had confirmed progression, and 81% of the patients received osimertinib. In fact, another 5% received another third-generation inhibitor. So, practically 86% of the patients received a third-generation TKI,” Dr. Ramalingam said. “And even with that crossover, we’re seeing a favorable survival trend with an HR of 0.81. That’s not significant at this point, but we’ll see where it lands.”

Drs. Armstrong, Tawagi, and Ramalingam discussed the decision to have indefinite therapy for the EGFR-targeted treatment in the LAURA trial.

“This was obviously a topic that the steering committee deliberated a lot, and we came down to this: One, while we would like to believe we’re curing patients with chemo and radiation, what we actually saw in the placebo group is less than 10% of the patients are disease free, or about 10% are disease free at 2 years,” Dr. Ramalingam said. “Practically half the patients experience disease progression within 6 months. This is not looking like a curative setting where you can give therapy for a while and then stop. These patients have cancer in their scans. They have visible radiographic disease. And we know TKIs don’t necessarily cure patients. They keep the cancer suppressed. That’s the reason we said we’re going to give it indefinitely.”

The conversation concluded with an eye toward the future of treatment and what could happen next with targeting other mutations in patients with lung cancer. Overall, when asked to sum up the study results and implications in a single sentence, Dr. Ramalingam said, “This is a new standard of care for unresectable stage III disease for patients with an EGFR mutation.”