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Tagrisso Poised to Become Standard of Care in Unresectable Stage III EGFR-Mutated NSCLC

Lung cancer treatment

CHICAGO – Patients with EGFR-mutated, unresectable, stage III non-small cell lung cancer may soon have a new treatment option in AstraZeneca's Tagrisso (osimertinib). 

The impressive progression-free survival benefit seen with the EGFR inhibitor compared to placebo in the Phase III LAURA trial received a standing ovation Sunday at the American Society of Clinical Oncology's annual meeting. After seeing the data, Lecia Sequist, a medical oncologist at Massachusetts General Hospital, said she would immediately change the way she treats her patients. 

Tagrisso, a third-generation EGFR inhibitor, has already established a strong foothold in the EGFR-mutated NSCLC treatment landscape. Earlier this year, the US Food and Drug Administration approved Tagrisso combined with chemotherapy in locally advanced or metastatic EGFR-mutated NSCLC patients. The drug is also approved as a first-line treatment for metastatic EGFR-mutated NSCLC, as a later-line treatment for metastatic EGFR T790M-mutated NSCLC, and as an adjuvant treatment for earlier-stage EGFR-mutated NSCLC. 

But these indications leave out a large swath of patients whose EGFR-mutated NSCLC tumors are not metastatic and not surgically resectable due to their involvement of nearby organs or too many lymph nodes, noted Suresh Ramalingam, a medical oncologist at Emory University's Winship Cancer Institute, at a press conference before presenting the study data on Sunday. Anywhere between 60 percent to 90 percent of stage III NSCLC patients aren't candidates for surgical resection, estimated Ramalingam, who was also LAURA's lead investigator. 

Generally, NSCLC patients who fit this description are candidates for AstraZeneca's immune checkpoint inhibitor Imfinzi (durvalumab) after chemotherapy and radiation. But for those NSCLC patients whose tumors harbor EGFR mutations — roughly one-third of unresectable stage III NSCLC — Imfinzi has brought limited benefit, Ramalingam said. 

For all these reasons, EGFR-mutated stage III NSCLC patients whose cancers can't be surgically resected comprise a population with unmet need. 

Within LAURA, 216 patients were randomized to receive either Tagrisso or placebo after definitive chemotherapy and radiation. Patients in the placebo group could cross over to receive Tagrisso if their cancers progressed. 

While more than 80 percent of patients enrolled in the LAURA trial were Asian, AstraZeneca enrolled zero Black patients in the trial, reflecting the persistent disparity in access to precision oncology despite pharmaceutical companies' public-facing initiatives and campaigns on equitable access. 

As of the Jan. 5 data cutoff, the median progression-free survival among 143 patients who received Tagrisso was 39.1 months versus 5.6 months among the 73 patients who received the placebo. After two years of treatment, 65 percent of patients on Tagrisso were still alive without disease progression, whereas the same was true for just 13 percent of patients who received a placebo. 

"Based on these results, osimertinib will become the new standard of care for patients with locally advanced non-small cell lung cancer following definitive chemoradiation," Ramalingam concluded, adding that the results underscore the importance of EGFR mutation testing for early-stage NSCLC. 

While they were in the study, 68 percent of patients who received a placebo developed a new cancer lesion, and 29 percent developed new lesions in the brain. 

In the Tagrisso arm, meanwhile, 22 percent of patients developed new lesions and 8 percent of patients developed new lesions in the brain. Tagrisso also significantly reduced patients' risk of developing new lesions in their lungs. 

Patients who received Tagrisso did have more frequent side effects than those who received placebo, though Ramalingam said most of the side effects were low-grade and none of the safety signals were unexpected. The most common side effect across both arms was radiation pneumonitis. 

In her discussion of the LAURA data following Ramalingam's presentation, Sequist pointed out that side effects, even when they're low-grade, can become problematic when the treatment is meant to be given indefinitely. 

The fact that patients received Tagrisso until their cancers progressed diverged from past trials in this treatment setting, which have historically prespecified a treatment duration time. In practice, this indefinite course of Tagrisso could mean a lifetime of taking the EGFR inhibitor. Oncologists grappled with the implication of this new reality during a discussion of the LAURA results. They discussed, for instance, how best to communicate the realities of lifelong treatment to their patients. Going forward, oncologists also said it would be important to look into new ways of stratifying patients who do and do not need both chemo and radiation before their Tagrisso. 

The progression-free survival benefit in LAURA was consistent across key subgroups. Patients benefited from Tagrisso regardless of whether their cancers harbored EGFR exon 19 deletions or EGFR exon 21 (L858R) mutations. 

Although the overall survival data for LAURA aren't yet mature, Ramalingam pointed to a trend favoring Tagrisso. Those data should be available in the next 18 to 24 months, he said. When those data do come out, however, it will be challenging to parse the survival benefit of Tagrisso versus placebo given the crossover trial design. 

The fact that patients will be eligible for Tagrisso after they progress on placebo will inevitably muddy the overall survival analysis. Regardless, oncologists at ASCO's annual meeting agreed that the crossover design was appropriate in LAURA. "We don't always do that because we're trying to find an overall survival benefit," David Spigel, a medical oncologist at the Sarah Cannon Research Institute, said during the press conference. Spigel lauded the data from LAURA as "outstanding" and noted that the crossover design was "the right thing to do." 

"We need to applaud the study designers and investigators for offering osimertinib to patients who progressed on the placebo arm," he said. 

"To have an 84 percent reduction in the risk of cancer progression or death is meaningful not just to patients but to the providers who are overseeing their care," Spigel continued. "As soon as the label becomes expanded and this becomes available, this will be how patients are treated wherever they can get access to this drug." 

AstraZeneca announced in February that it will share the study data with regulatory authorities.