AZ's Etcamah falls short in first-line breast cancer trial

Just a week after getting FDA approval as a frontline treatment for HR-positive, HER2-negative breast cancer, AstraZeneca's Etcamah has missed the mark in a trial designed to expand its label.

The oral SERD, given in combination with Pfizer's CDK4/6 inhibitor Ibrance (palbociclib), was unable to show a statistically significant improvement in progression-free survival (PFS) compared to anastrozole and Ibrance in the closely watched SERENA-4 trial, although there was a "numerical improvement" over the control group.

Etcamah is already approved in the US, Europe, and other markets for use in combination with a CDK4/6 inhibitor as a first-line treatment for locally advanced or metastatic HR-positive, HER2-negative breast cancer with mutations in the ESR1 gene, which are associated with resistance to aromatase inhibitors, based on the SERENA-6 trial.

SERENA-4 – which included an all-comer HR-positive, HER2-negative breast cancer population with and without ESR1 mutations – has been portrayed as a key part of AZ's attempt to position Etcamah as a broadly used first-line treatment option for this form of the disease, and build toward the company's peak sales target of $5 billion a year for the drug.

"Whilst we are disappointed by the SERENA-4 outcome, it sharpens our focus on maximising the number of patients who can benefit from Etcamah today based on SERENA-6 and reinforces the importance of ESR1 testing for patients on first-line therapy," said Susan Galbraith, AZ's head of oncology and haematology R&D.

"Early breast cancer represents an important opportunity, and we remain confident in the long-term potential of Etcamah in the early setting as we advance our broader programme," she added.

AZ's development programme for Etcamah includes the CAMBRIA-1 and CAMBRIA-2 trials, which are exploring adjuvant use of the drug to prevent disease recurrence, as a monotherapy and in combination with CDK4/6 inhibitors.

There are currently two other oral SERDs on the market – Menarini/Stemline's Orserdu (elacestrant) and Eli Lilly's Inluriyo (imlunestrant) – both of which are currently approved as second-line treatments for advanced HR-positive, HER2-negative breast cancer with ESR1 mutations.

Another potential rival is Roche's giredestrant, which has already generated positive results in the adjuvant setting in the phase 3 lidERA trial, but, like Etcamah, disappointed in the frontline persEVERA study, which enrolled a similar population to SERENA-4.

DESTINY-Lung04 delivers mixed results

Alongside the SERENA-4 data, AZ reported encouraging PFS results from its DESTINY-Lung04 study of HER2-targeted antibody-drug conjugate Enhertu (trastuzumab deruxtecan) in HER2-positive non-small cell lung cancer (NSCLC), but the trial also raised questions about its role in this setting.

Daiichi Sankyo-partnered Enhertu achieved a 37%, six-month improvement in median PFS compared to the standard first-line treatment of MSD's PD-1 inhibitor Keytruda (pembrolizumab) and chemotherapy in this type of lung cancer, although, that was somewhat undermined by a trend toward worse overall survival (OS) with the ADC.

OS came in at 33.1 months for the control group and 29.3 months with Enhertu. AZ said the OS results were less than 50% mature at the current readout – reported at the World Conference on Lung Cancer (WCLC) in Seoul, South Korea – adding that "no formal hypothesis testing was performed."

"These results add to the growing body of evidence supporting Enhertu as an important treatment for patients with HER2 alterations and underscore its potential role at the time of metastatic diagnosis, when treatment has the greatest opportunity to improve outcomes," said Galbraith.