Overall Survival Results Reinforce Osimertinib as Standard of Care for EGFRm Stage IB-IIIA NSCLC

Pharmacy Practice in Focus: OncologyJuly 2023
Volume 5
Issue 5

Updated phase 3 trial data provide practice-changing findings.

Lung cancer is a significant burden worldwide, with almost 2 million deaths from the disease each year, explained Roy S. Herbst, MD, PhD, during a news conference at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. Non–small cell lung cancer (NSCLC) represents 80% of lung cancer cases globally, he said.“In [approximately] one-third of those cases, the cancer is found when it can still be resected,” Herbst said. Herbst is the chief of medical oncology and associate director for translational science at Yale School of Medicine and Yale Cancer Center in New Haven, Connecticut. “But even when you resect lung cancer and find it at stage I, the 5-year survival rate is only 65% to 75%.”

Credit: peterschreiber.media - stock.adobe.com

Credit: peterschreiber.media - stock.adobe.com

\That survival rate drops further to 35% to 45% with mutations and node involvement. “More is needed to be done [for this disease],” Herbst said. “Before [the ADAURA] study, all we had was standard of care chemotherapy.”

The global phase 3 ADAURA trial (NCT02511106) was conducted by Herbst and his colleagues at Yale in collaboration with other international cancer centers to assess overall survival (OS) with adjuvant osimertinib (Tagrisso; AstraZeneca) in patients with resected EGFR-mutated (EGFRm) stage IB to stage IIIA NSCLC. Osimertinib is a third-generation, central nervous system (CNS), active EGFR tyrosine kinase inhibitor (TKI) that inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations.

According to Herbst, EGFR mutations are quite common in lung cancer, with prevalence varying around the world. “In the United States, [approximately] 10% to 15% of patients with lung cancer might have this abnormality. In Asia, it can be as high as 40% to 50%,” he said. “One point I’d like to make is that you also have to screen for it to find it. There are also diverse groups and underrepresented groups with these mutations. We’ve got to find these patients and identify these patients.”

EGFR is an “on” and “off” switch, according to Herbst. For patients with this mutation, when EGFR is turned on, the cancer grows.

“Osimertinib is a precision therapy that acts as a ‘key in lock’ that turns EGFR off,” Herbst said. “I started studying these drugs 20 years ago—this is now a third-generation drug. And why is [osimertinib] different? It’s more potent and it targets the most common form of resistance.”

Additionally, osimertinib gets into the brain to block the growth of brain metastases, which are a consequence of lung cancer, according to Herbst. “[Osimertinib] is also less toxic. It’s designed to mitigate the most common toxicities: rash and diarrhea,” Herbst said. “[The results also showed that osimertinib] kept the disease from spreading into the brain, liver, and bones.”

Results of the primary analysis from ADAURA showed osimertinib had clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit when compared with placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC, with or without adjuvant chemotherapy. Following the primary analysis at an updated 2-year follow-up, DFS and CNS DFS benefits with adjuvant osimertinib were sustained (stage II-IIIA DFS HR, 0.23; 95% CI, 0.18-0.30; stage IB-IIIA DFS HR, 0.27; 95% CI, 0.21-0.34; stage II-IIIA CNS DFS HR, 0.24; 95% CI, 0.14-0.42), along with a sustained tolerable safety profile.

According to Herbst, the most recent OS results showed adjuvant osimertinib had an unprecedented, highly statistically significant, and clinically meaningful OS benefit in patients with EGFRm stage IB to stage IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy.

“ADAURA is the first global phase 3 study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB to IIIA NSCLC,” Herbst said. “This reinforces that osimertinib is now the standard of care in this patient population.”

During the trial, investigators enrolled patients 18 years and older, although at the 2 study sites in Japan (the National Cancer Center Hospital East in Kashiwa and Kanagawa Cancer Center in Yokohama) and 1 study site in Taiwan (National Cheng Kung University in Tainan City), patients 20 years and older were eligible for enrollment. Additionally, patients were eligible for trial enrollment with World Health Organization performance status of 0 or 1 with completely resected EGFRm (ex19del/L858R) stage IB, II, or IIIA NSCLC (adjuvant chemotherapy allowed). Patients were randomly assigned 1:1 to receive osimertinib at 80 mg once daily or placebo, until the point of disease recurrence or treatment completion (3 years) or a discontinuation criterion was met.

The primary end point in the trial was investigator-assessed DFS in stage II to stage IIIA disease. Additionally, key secondary end points were DFS in stage IB to stage IIIA, OS, and safety. The study data cutoff was January 27, 2023.

Across all cancer centers, 682 patients were randomly assigned to receive osimertinib (n = 339) or placebo (n = 343). Based on the results, the investigators determined that adjuvant osimertinib significantly improved OS when comparedwith placebo.

“People have asked me, ‘How can you use placebo?’ ” Herbst said. “It’s because there have been no studies that have shown that when you use an EGFR inhibitor in this setting that there’s disease-free survival or overall survival.”

In patients with stage II to stage IIIA disease, the OS HR was 0.49 (95% CI, 0.33-0.73; P =.0004; 100/470 events, 21% maturity), and the 5-year OS rate was 85% with osimertinib vs 73% with placebo. Further, the median follow-up for OS in stage II to stage IIIA was 59.9 months in the osimertinib arm and 56.2 months in the placebo arm.

Among the overall global population included in the study (stage IB-IIIA), OS HR was 0.49 (95% CI, 0.34-0.70; P =.0001; 124/682 events, 18% maturity), whereas the 5-year OS rate was 88% in the osimertinib arm vs 78% in the placebo arm, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). However, median OS was not reached in either the population or treatment group.

“In an exploratory analysis of a secondary end point, [results showed that] across all different variables the point estimate was to the left of 1, meaning generally all groups benefited [regardless of] sex, age, race, [disease] stage, whether they smoked or didn’t smoke, type of EGFR mutation, and—most importantly—whether or not they got adjuvant chemotherapy,” Herbst said. “[Adjuvant chemotherapy] does improve survival a little bit, and it is a decision made by the patient and their physician.”

There were also no new safety signals from previous reports, which had shown osimertinib to be less toxic than other drugs used for this patient population.“

But there are some [adverse] effects of this drug, which is why it’s important that we can now show the patient that they have OS benefit,” Herbst said. “Patients will have some fatigue, rash, diarrhea, and occasionally there’s some interstitial lung disease, but that’s very rare. There were also no deaths in this trial from this drug, although there was 1 death from COVID-19 and pneumonia, but it’s hard to say that that was due to the drug.”

According to Herbst, these results show that the previous DFS results reported at a prior ASCO meeting have indeed translated to significant OS benefits and a sustained tolerable safety profile for osimertinib, making it the standard of care for this patient population.

“We also have to let patients and physicians know that we can’t use this new therapy unless we find these EGFR mutations by screening patients,” Herbst said. “We need to give our best treatments early, and that will prevent deaths from metastases.”


Herbst RS. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC). Presented at: 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Accessed June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047

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