AstraZeneca is celebrating a trio of recent advancements for its portfolio in non-small cell lung cancer (NSCLC).
Tagrisso, the company’s targeted tyrosine kinase inhibitor, produced a trial win in unresectable, stage 3 EGFR-mutated NSCLC. Monday, AZ described the drug’s performance in the study as an “overwhelming efficacy benefit.”
Meanwhile, building on its success as a single agent in metastatic EGFR-mutated NSCLC, Tagrisso on Friday bagged an FDA approval for its use alongside chemotherapy.
Also on Monday, AZ and Daiichi Sankyo said the FDA accepted an application for their TROP2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) in previously treated nonsquamous NSCLC. The target action date is Dec. 20, according to Daiichi.
These new developments each contribute to the British pharma’s ambition to have more than half of all lung cancer patients eligible for its medicine by 2030.
First off, as a maintenance therapy in stage 3 EGFR-mutated NSCLC following chemoradiation, Tagrisso significantly reduced the risk of disease progression or death compared with placebo. The improvement in progression-free survival was also “highly clinically meaningful,” according to AZ. The readout came from a phase 3 trial coded LAURA.
Although data on whether Tagrisso can extend patients’ lives remained immature, the study for now showed a favorable trend for the EGFR inhibitor, AZ said. The trial remains ongoing to assess overall survival, and it currently bears an estimated completion date in June 2026, according to ClinicalTrials.gov.
AZ will share the data with global regulatory authorities. Already, Suresh Ramalingam, M.D., from Emory University and principal investigator in the LAURA trial, raised the possibility that Tagrisso could become the first targeted therapy for patients with stage 3 NSCLC.
The positive LAURA readout for Tagrisso followed a recent flop for AZ’s immunotherapy Imfinzi in a slightly different setting. While post-chemoradiotherapy maintenance use of Imfinzi has become the standard treatment in stage 3, unresectable NSCLC, the phase 3 PACIFIC-2 trial found that the PD-L1 inhibitor was no good when used concurrently with chemoradiation.
Even as Tagrisso looks poised to move into stage 3 disease, AZ has dug the trench deeper in metastatic cancer. The approval for Tagrisso and chemotherapy was based on phase 3 data from the FLAURA2 trial, which showed that the combo reduced the risk of disease progression or death by 38% compared with Tagrisso alone. The chemo-containing regimen extended patients’ median progression-free survival by 8.8 months to 25.5 months, according to a blinded independent central review.
Again, overall survival data were not mature. But in an updated analysis performed when 41% of death events required for a final analysis had happened, the Tagrisso-chemo regimen was linked to a preliminary 25% reduction in the risk of death.
Despite the broad approval, AZ has said it expects Tagrisso monotherapy will continue to be the mainstay treatment in first-line EGFR-mutated NSCLC, while the chemo combo will be reserved for patients with high tumor burden.
The combo approval is “especially important for those with a poorer prognosis, including patients whose cancer has spread to the brain and those with L858R mutations,” AZ’s oncology business chief, Dave Fredrickson, said in a statement Monday.
In an update earlier this year, the Tagrisso-chemo regimen was added to the National Comprehensive Cancer Network guidelines for NSCLC with EGFR exon 19 or exon 21 L858R mutations with a category 1 recommendation. However, Tagrisso monotherapy remains the “preferred” first-line therapy, whereas the chemo-containing combo is listed in the “other recommended” category.
The lack of a statistically significant overall survival showing probably put the combo behind the monotherapy, especially given the extra toxicity that comes with chemotherapy.
The combo approval comes as Johnson & Johnson, with a combination of Rybrevant and Yuhan-partnered lazertinib, attempts to challenge Tagrisso after showing its combo cut the risk of progression or death by 30% compared with the AZ standard of care in first-line EGFR-mutated NSCLC. Despite the combo being a chemo-sparing regimen, the addition of Rybrevant on top of an EGFR inhibitor comes with its own side effects.
J&J has filed for an approval in the indication and expects an FDA approval this year, J&J CEO Joaquin Duato said during a conference call last month.
In addition to unresectable stage 3 and stage 4 cancers, AZ is testing Tagrisso as a postsurgical adjuvant therapy in very early-stage nonsquamous NSCLC in the phase 3 ADAURA2 trial. Besides, the phase 3 neoADAURA trial is evaluating Tagrisso before surgery with or without chemo in patients with resectable stage 2 to 3b tumors.
As for Dato-DXd, AZ and Daiichi are only asking for an approval in nonsquamous NSCLC. Although the pivotal TROPION-Lung01 trial showed a statistically significant improvement for the ADC in progression-free survival compared with chemo in an analysis of the overall population, a subgroup analysis only found a benefit for those with nonsquamous tumors. Dato-DXd’s 23% improvement in the nonsquamous subgroup was billed as clinically meaningful, but it didn’t reach statistical significance, according to results shared in October at the European Society for Medical Oncology Congress.
Dato-DXd poses a threat to Gilead Sciences’ Trodelvy, which recently suffered its own setback in lung cancer. A month ago, Gilead announced that its TROP2 ADC failed to show a statistically significant overall survival benefit compared with chemo in the phase 3 EVOKE-1 trial, which has therefore missed its primary endpoint. It’s worth noting that Dato-DXd doesn’t have a statistically significant overall survival win, either. But TROPION-Lung01 is considered positive given its dual primary endpoint design.
As Gilead considers which regulatory direction to take with Trodelvy in NSCLC, there’s a chance that Dato-DXd could become the first TROP2-targeted ADC to reach NSCLC.