As would-be competitors eye Tagrisso’s lead in the non-small cell lung cancer (NSCLC) space, the AstraZeneca brand appears to have solidified its position. 

The Food and Drug Administration approved use of the once-daily pill, along with chemotherapy, to treat locally advanced or metastatic EGFR-mutated NSCLC, AstraZeneca announced this week.

The approval, which followed a priority review, was based on data from AZ’s FLAURA-2 Phase 3 trial. As previously reported by MM+M, the trial demonstrated a roughly nine-month progression-free survival (PFS) benefit for the combo versus Tagrisso alone. 

The addition of chemo slashed the risk of disease progression or death by 38% compared to Tagrisso monotherapy, which is already the first-line standard of care for the disease.

As the longest reported PFS benefit in the first-line advanced setting, the Tagrisso combo data set a “new benchmark,” observed Dave Fredrickson, EVP of AstraZeneca’s oncology business unit. 

“This approval reinforces Tagrisso as the backbone of EGFR-mutated lung cancer treatment,” either alone or as part of a drug cocktail, he added.

Clinicians seem to agree. KOL feedback has indicated that Tagrisso, a tyrosine kinase inhibitor (TKI), is likely to hold onto its position as the go-to in the first-line setting, wrote Leerink Partners’ Andrew Berens. 

That’s even as other combinations become available. Johnson & Johnson’s pairing of bispecific Rybrevant with the TKI lazertinib conferred a roughly seven-month PFS benefit over Tagrisso monotherapy, as seen in J&J’s head-to-head MARIPOSA trial in first-line EGFR-mutant NSCLC. 

While those numbers put Rybrevant + lazertinib “in the prescribing discussion,” Berens noted, Tagrisso monotherapy is “still likely to prevail,” largely due to a better safety and tolerability profile, as well as the option to add chemo (i.e., FLAURA-2) if a “more aggressive approach is warranted.”

When chemo is layered onto Tagrisso, patients’ median PFS jumped to 25.5 months versus 16.7 months without, an 8.8-month improvement. Results from blinded review showed a 29.4-month median PFS, a 9.5-month boost over monotherapy. Those numbers are hard to beat.

Dr. Pasi Jänne, a medical oncologist at Dana-Farber Cancer Institute and principal investigator for the FLAURA-2 trial, said having two “highly effective” Tagrisso-based treatment options for advanced EGFR-mutated NSCLC allows physicians to better tailor treatment to the individual’s needs.

Based on the FLAURA-2 data, in December the Tagrisso plus chemo combo was added to the National Comprehensive Cancer Network clinical practical guidelines in oncology as a NCCN Category 1 Other Recommended regimen for patients with EGFR-mutated NSCLC. Additionally, the combo is under review by regulatory authorities in several other countries such as Australia, Canada and Switzerland. 

NSCLC is the most common form of lung cancer, accounting for 80% to 85% of the more than 200,000 people diagnosed with lung cancer annually in the U.S. About 70% are diagnosed with advanced NSCLC and about 15% of NSCLC patients in the U.S. have an EGFR mutation, according to data cited by AstraZeneca.

In addition, the combo’s safety profile was generally manageable and discontinuation rates were low. This has also helped separate Tagrisso-based options from rivals.

For instance, during October’s European Society for Medical Oncology (ESMO) meeting, there had been some lingering debate among oncologists around the seven-month PFS edge seen with Rybrevant plus lazertinib compared to Tagrisso alone. 

However, the full MARIPOSA data, as revealed at the meeting, seemed to settle it. A number of new tolerability and safety issues cropped up with the J&J cocktail, including a higher discontinuation rate as well as venous thromboembolism (VTE), both of which came on top of the combo’s known complications like infusion-related reactions (IRR). 

Furthermore, MARIPOSA’s magnitude of benefit was less than investors had hoped. Coupled with a more complex form of administration — Rybrevant is an infusion drug, which impacts quality of life, while Tagrisso is an oral — the latter program has proven “more resilient than some had feared,” added Berens.

Also, what of the subcutaneous version of Rybrevant, due out later this year? When asked about it, KOLs interviewed by the Leerink team suggested this would not make a difference. 

“SubQ administration may decrease IRR, but would still require a visit to an infusion room, albeit a shorter visit, and would not decrease the EGFR-related effects, such as rash and swelling,” Berens explained. “They noted that a once-daily oral outpatient pill, such as Tagrisso, is still more favorable, and lacks IRRs.”

For Rybrevant plus lazertinib, overall survival (OS) data — not yet statistically significant — is what analysts will be keeping an eye on moving forward, along with future biomarker or subgroup analyses, which could inform which patient segments are most apt to see benefit, the Leerink team wrote.

It appears that Tagrisso has thus far blunted the emerging challenge from J&J. 

“Exiting ESMO, we have a high degree of conviction that Tagrisso monotherapy will remain the standard of care,” Berens concluded at the time. 

Meanwhile, Merus Pharma has also been struggling to carve a niche in the EFGR+ NSCLC therapeutic landscape. The firm is testing a bispecific cancer drug, MCLA-129, in combination with Tagrisso in the first-line EGFR NSCLC setting. However, Phase 1/2 data suggest the bi-specific will have trouble differentiating itself from Rybrevant and may be relegated to later lines of therapy.