by Manasi Vaidya in New York.
AstraZeneca’s Tagrisso (osimertinib) may not find widespread adoption in the adjuvant setting for non-small cell lung cancer (NSCLC), despite positive Phase III data, in the absence of a consensus on whether data indicating a survival benefit is needed.
The Phase III (NCT02511106) ADAURA study data presentation was part of an American Society of Clinical Oncology (ASCO) Virtual Meeting plenary session on 31 May. The company’s stock also moved by 1% after the ASCO presentation, on the following Monday. In April, an independent monitoring committee decision recommended the study be unblinded following “overwhelming efficacy,” with AstraZeneca’s stock increasing by 6%.
The ASCO presentation provided data on Tagrisso’s effect in improving disease-free survival (DFS)—the primary endpoint—compared to placebo when used as adjuvant therapy. While the DFS hazard ratio of 0.21 (p<0.0001) in the overall study population w striking, the data was still inadequate to change treatment practice without mature overall survival (OS) data. OS is a secondary endpoint. There is caution on the translation of DFS into OS benefit due to older studies with first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like AstraZeneca’s Iressa (gefitinib) and Roche’s /Astellas Oncology’s Tarceva (erlotinib) in the adjuvant setting, that failed to do so.
Nonetheless, Tagrisso’s improved efficacy and safety profile in general versus the older EGFR TKIs and the DFS data was adequate to make treatment choices. Moreover, while some patients received prior chemotherapy in the study, its impact on overall efficacy was unclear, but Tagrisso was relatively tolerable as adjuvant therapy.
After study results at ASCO, one analyst said the DFS magnitude in ADAURA exceeded even already bullish market expectations. Prior to the data, another analyst said OS data would be important to convince the field of the drug’s benefit. Nonetheless, a third analyst estimated Tagrisso worldwide sales from $m to approximately $1.5bn prior to the ASCO presentation. Tagrisso sales in 2019 were $3.18bn, as per AstraZeneca’s FY2019 results.
AstraZeneca did not respond to a request for comment.
Necessity of AstraZeneca’s Tagrisso OS data divides expert sentiment
Everyone in the field has different thoughts on the need for OS data in order to inform adjuvant Tagrisso use, said Dr Alex Spira, medical oncologist, Virginia Cancer Specialists, Fairfax.
OS data is necessary before the ADAURA results are adapted to the standard of care (SOC), said Dr Paul Bunn, James Dudley chair in Cancer Research, University of Colorado School of Medicine, Aurora. Although ADAURA was well-designed, it is not known if DFS is as meaningful an endpoint as OS and if the DFS benefit will translate to the latter, Dr Tejas Patil, oncologist, University of Colorado, Anschutz. He gave the example of the Phase III ADJUVANT (NCT01405079) study with Iressa which showed a DFS improvement did not convert into OS. Likewise, Bunn pointed to Phase III (NCT00373425) RADIANT study with Tarceva that also did not show an OS benefit.
However, even though studies with Iressa and Tarceva indicated a DFS improvement, the hazard ratio (HR) in those studies was around 0.6 or 0.7, while the ADAURA trial had an HR of 0.21, said Dr Timothy Burns, medical oncologist, University of Pennsylvania Medical Center Hillman Cancer Center, Pittsburgh. As a result, there is a good chance to see a survival improvement, he said. And even without mature data proving OS benefit, there was a positive trend, said Spira. At 5% data maturity, the Tagrisso HR for OS was 0.4, as per the data presentation.
While OS is an important endpoint for the adjuvant setting, DFS is important enough that Spira said he would strongly consider it for stage II or higher NSCLC patients. At the time of the ASCO presentation, responses were ongoing on the Tagrisso arm and the median DFS was still not reached, while it was 20.4 months on placebo (HR 0.71) in patients with Stage II/IIIA disease. The trial enrolled NSCLC patients with Stage IB-IIIA disease. A pronounced benefit was seen in Stage IIIa patients in ADAURA, but that is a very heterogeneous group of patients, so the efficacy data needs to be broken down as per nodal status, said Patil. Despite the potential for DFS improvement to translate into an OS benefit, it is too early to understand adjuvant Tagrisso’s impact on extending a patient’s life, said Dr Federico Cappuzzo, director, Medical Oncology, AUSL della Romagna-Ravenna, Italy.
If there is an OS improvement between the Tagrisso and placebo groups of even 5% at five years, this would be relevant in terms of clinical significance, said Cappuzzo. A highly statistically significant OS, perhaps around 0.75 or more, would provide convincing evidence to use AstraZeneca’s Tagrisso as adjuvant therapy, said Bunn.
However, patients are already calling to inquire about prescriptions for adjuvant Tagrisso, Burns said, adding he expects it will soon become SOC. If the National Cancer Comprehensive Network (NCCN) guidelines recommend the use of Tagrisso in the adjuvant setting based on the ASCO ADAURA data, that could spur payers to cover its use, said Burns, even before an FDA approval.
Other factors influencing adjuvant Tagrisso use
About half the patients received chemotherapy prior to Tagrisso while others didn’t, which acts as confounding factor, said Cappuzzo. The trial data also does not clarify on the impact of prior chemotherapy on overall efficacy after adjuvant Tagrisso, Cappuzzo and Burns agreed. Nonetheless, the chemotherapy may have given only a 4–10% DFS improvement, said Spira.
Tagrisso is generally well tolerated, with diarrhoea, skin rash and nail changes as the most common adverse events, said Patil. But it may be asking much of patients to be on this drug for three years in the adjuvant setting when chemotherapy alone would have been enough in some patients, said Patil. However, the toxicity of Iressa and Tarceva is higher than Tagrisso, especially in the adjuvant setting, said Burns.
One question that remains is that when used in the metastatic setting, Tagrisso is associated with a progression-free survival improvement of 18–19 months, said Patil. It is not clear whether using adjuvant Tagrisso followed by systemic therapy when a patient has a metastatic relapse, or only observing patients and using Tagrisso in the metastatic setting, is the better strategy, he added.
Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.