AstraZeneca’s Tagrisso is the standard of care in newly diagnosed, EGFR-mutated non-small cell lung cancer (NSCLC). The company hopes to offer a new combination with chemotherapy, but the lack of patient survival showing may be a problem for that effort.
Compared with Tagrisso monotherapy, the drug’s combination with chemotherapy cut the risk of disease progression or death by 38% in first-line, EGFR-mutant NSCLC, according to data presented at the 2023 World Conference on Lung Cancer (WCLC) in Singapore.
The results “demonstrated a remarkable improvement in progression-free survival” for the combo approach and support the regimen “as a new and promising first-line treatment option,” Pasi A. Jänne, M.D., Ph.D., from the Dana-Farber Cancer Institute, who leads the current phase 3 FLAURA2 trial, said in a statement.
But before the official data release, AstraZeneca had already tempered enthusiasm for the combo.
“We believe Tagrisso monotherapy will remain standard of care in first line, but see the opportunity for FLAURA2 to become a valuable regimen for patients with higher tumor burden,” AZ’s oncology R&D chief Susan Galbraith, Ph.D., said during the company’s second-quarter earnings call in July.
The combo's progression-free survival data were compelling. By investigators’ analysis, the combo extended the median time before disease worsening or death by 8.8 months to 25.5 months versus solo Tagrisso. By an independent review, the median PFS was improved by 9.5 months to 29.4 months.
Both patients with exon 19 deletion and exon 21 mutations, and those with or without smoking history, experienced similar PFS benefits.
However, when it comes to the gold-standard patient survival data, the signal was less clear. At the interim analysis, the combo reduced the risk of death by 10% over Tagrisso alone. What's more, patients in the monotherapy group appeared more likely to be alive than those in the combo arm as the trial grows longer.
The interpretation of overall survival isn’t conclusive at this point as only 27% of deaths had taken place for a final evaluation. But during a WCLC presentation, Yi-Long Wu, M.D., a top lung cancer expert from China’s Guangdong Provincial People's Hospital, said he was not optimistic that FLAURA2 will eventually show an overall survival benefit. He noted that previous Tagrisso studies produced clear life-extension signals early.
The extra toxicity associated with the chemotherapy might have cost the combo a clear overall survival win. Side effects led to a 48% discontinuation rate for any component of treatment in the combo arm, versus 6% for the Tagrisso monotherapy group. The rates of anemia, nausea and neutropenia were markedly higher for the combination.
With this combo approach, AZ appears to believe that doctors might think only patients with a high tumor burden can benefit from the efficacy-safety trade-off because they need a stronger regimen to quickly put the cancer under control.
Feedback from doctors suggested that “Tagrisso’s value proposition extends beyond efficacy, and is significantly driven by safety/tolerability and dosing convenience,” analysts at Leerink Partners wrote in a note in August. While Tagrisso comes in tablets, the chemotherapy is given via intravenous infusion.
A survey conducted by Wu showed that even if Tagrisso and chemo had shown a progression improvement of 10 months, about 80% of 655 members in the Chinese Thoracic Oncology Group would still prefer monotherapy over the combo. More than 70% of patients and their family members said no to chemo combo in that same question.
AZ’s FLURA2 regimen also sets a new bar for rival Johnson & Johnson, which is pairing Yuhan-partnered EGFR inhibitor lazertinib with its own EGFRxMET bispecific antibody Rybrevant. The phase 3 MARIPOSA trial pitting that J&J combo against Tagrisso in first-line NSCLC is expected to read out soon.
Ultimately, the J&J cocktail will face a similar question of whether greater antitumor activity can justify potentially greater toxicity, the Leerink analysts figured. After speaking with doctors, the Leerink team put the PFS benefit bar for the Rybrevant-lazertinib combo at seven months.
That kind of improvement, plus a positive overall survival trend, could make a compelling case for the J&J therapy, the team said. Now, the Tagrisso-chemo combo has set the bar for Tagrisso monotherapy at around nine months.
“Still, the lack of a clear survival trend in FLAURA2 leaves the door open for further improvement,” William Blair analyst Matt Phipps, Ph.D., wrote in a Monday note. “Therefore, a PFS delta of over 10 months with clear separation of overall survival curves is likely needed to garner enthusiasm for the MARIPOSA regimen.”
Editor's Note: The story has been updated with additional information from Yi-Long Wu's presentation and Matt Phipps' note.