Astrazeneca plc’s Tagrisso (osimertinib) seems poised to become standard of care in the adjuvant setting for early stage (IB, II and IIIA) EGFR-mutated non-small-cell lung cancer (NSCLC), thanks to phase III data from the study called Adaura, made public at the American Society of Clinical Oncology (ASCO) meeting.

The Cambridge, U.K.-based firm said the compound, a third-generation, irreversible EGFR tyrosine kinase inhibitor (EGFR-TKI) with clinical activity against central nervous system metastases, turned up statistically significant and clinically meaningful improvement in disease-free survival (DFS) after complete tumor resection with curative intent. Astrazeneca had unblinded the trial for “overwhelming efficacy” at the interim analysis, which presaged a favorable outcome, but the data went well beyond what many had hoped for, said SVB Leerink analyst Andrew Berens, “delivering hazard ratios [HRs] that definitively demonstrate administration of the drug to patients after surgical resection reduces the risk of disease recurrence or death by 79% vs. surgery alone or surgery followed by chemotherapy, with 80% of Tagrisso patients being disease-free at three years vs. 28% in the control arm.”

Overall survival (OS) data have yet to mature but are trending better in the Tagrisso arm, with only nine deaths compared to 20 in the control arm. The findings are “likely to rapidly establish the drug as the standard of care in EGFR-mutated NSCLC patients able to tolerate surgery, with a much longer duration of treatment than we had anticipated,” Berens wrote in a report. He predicted regulatory approval after submission of data in the second half of this year and rapid uptake after launch in 2021.

Astrazeneca will detail the results from Adaura later in the ASCO meeting. Meanwhile, Wall Street was enthused over the related abstract, which showed Tagrisso achieved HRs for DFS of 0.17 (0.12, 0.23) in stage II-IIIA patients (the primary endpoint) and 0.21 (0.16, 0.28) in stage IB-IIIA patients (a key secondary endpoint). For the primary endpoint population, the one-year, two-year and three-year DFS rates in the Tagrisso arm vs. placebo were 97% vs. 61%, 90% vs. 44%, and 80% vs. 28%, respectively. For the patients in the key secondary endpoint population, the one-year, two-year and three-year DFS rates in the Tagrisso arm vs. the placebo arm were 97% vs. 69%, 89% vs. 53%, and 79% vs. 41%, respectively. With a nod to the notorious difficulty of success in the adjuvant setting, Berens pointed to disease-free HRs with Herceptin (trastuzumab, Roche Holding AG) plus chemo in adjuvant breast cancer of 0.48 to 0.60, with Kadcyla (ado-trastuzumab emtansine, Roche Holding AG) of 0.50 (invasive DFS) in the trial called Katherine. Fluorouracil and leucovorin plus oxaliplatin gained an HR 0.77 in colon cancer, and Iressa (gefitinib, Astrazeneca plc) reached 0.60 in adjuvant Chinese NSCLC patients.

Once-daily oral Tagrisso won accelerated approval in November 2015 for metastatic EGFR T790M mutation-positive NSCLC patients who progressed on or after EGFR-TKI therapy. Full approval came in the spring of 2017. First-line clearance came in April 2018. Based on the Adaura data, Berens upped his worldwide adjuvant NSCLC revenues to $5.6 billion from $1.5 billion and raised his price target for Astrazeneca to $65 from $60. Shares (NYSE:AZN) closed May 29 at $54.60, up $1.10.

More lung cancer findings were among datasets rolled out by Astrazeneca at ASCO. Detailed results from an updated analysis of the phase III trial called Caspian showed Imfinzi (durvalumab) in combination with a choice of chemos, etoposide plus either carboplatin or cisplatin, turned up a sustained, clinically meaningful OS benefit for adults with extensive-stage small-cell lung cancer (SCLC) treated in the first-line setting. Caspian met the OS primary endpoint in June 2019, reducing the risk of death by 27% (based on an HR of 0.73; 95% confidence interval [CI] 0.59-0.91; p=0.0047) which formed the basis of the FDA approval in March 2020. Analyst Berens, in a report at the time, said the approval represented “an important addition” in SCLC, where Tecentriq (atezolizumab, Roche Holding AG) is the only approved checkpoint inhibitor. Key opinion leaders he consulted said Imfinzi could have an advantage of Tecentriq, given the dosing flexibility. He pegged U.S. peak revenue at about $413 million and worldwide peak revenue at about $828 million for Imfinzi in SCLC.

After a median follow-up of more than two years, the latest results for Imfinzi plus chemo showed sustained efficacy, maintaining a 25% reduction in the risk of death vs. chemo alone (based on an HR of 0.75; 95% CI 0.62, 0.91; nominal p=0.0032). Updated median OS was 12.9 months vs. 10.5 for chemo.

In a post-hoc analysis, an estimated 22.2% of patients treated with Imfinzi plus chemo were alive at 24 months vs. 14.4% for chemotherapy. For Imfinzi plus chemo, 11% of patients were alive and progression-free at 24 months vs. 2.9% for chemo alone (post-hoc). Imfinzi plus chemo maintained a high confirmed objective response rate (68% vs. 58%) and in a post-hoc analysis, duration of response for Imfinzi at 24 months was 13.5% vs. 3.9% for chemo. At 24 months, 12% of patients in the Imfinzi plus chemo arm remained on Imfinzi treatment.

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