Osimertinib Offers 84% Improvement in PFS Over Standard of Care in Stage III Unresectable EGFR-Driven NSCLC

The targeted therapy osimertinib (Tagrisso, AstraZeneca) improved progression-free survival (PFS) by a whopping 84% over the current standard of care in patients with EGFR-mutated non-small cell lung cancer who are not eligible for surgery.

Suresh Ramalingam, MD | Image credit: Emory University

Findings from the LAURA trial (NCT03521154), to be presented during today’s plenary session at the annual meeting of the American Society of Clinical Oncology (ASCO),¹ seem certain to add another group of patients to those who will be treated with the third-generation tyrosine kinase inhibitor (TKI). Osimertinib is already approved for patients with EGFR-mutated stage IV NSCLC and as an adjuvant therapy in stage IB-IIIA disease.

The immune checkpoint inhibitor durvalumab has been the current standard of care for patients with unresectable NSCLC following chemoradiotherapy. “Now, while this has been used routinely for the past few years, whether this benefits patients with EGFR mutation has been not clear,” Suresh S. Ramalingan, MD, FACP, FASCO, executive director of Winship Cancer Institute of Emory University, said during a press briefing. “In fact, a subset analysis of the pivotal PACIFIC study that showed durvalumab is the new standard of care failed to show a difference in outcomes for patients with EGFR mutation between durvalumab and placebo.”

The phase 3 international phase trial enrolled patients with unresectable stage III NSCLC with EGFR mutations whose disease had not progressed during or after treatment with definitive platinum-based chemoradiotherapy. Patients were randomized 2:1 to receive osimertinib (n = 143) or placebo (n = 73). Disease progression was verified with CT scans and MRI at baseline and intervals.

Median age of the study participants was 62 years in the osimertinib group and 64 years in the placebo group; the osimertinib group was 63% female and the placebo group was 58% female. Most patients were Asian (81% in the osimertinib arm, 85% in the placebo arm), and had never smoked (71% for the osimertinib arm, 67% in the placebo arm).

Findings. Results overwhelmingly favored osimertinib. The median PFS for patients taking osimertinib was 39 months—more than 3 years—for patients taking osimertinib, compared with less than 6 months for those taking placebo. Patients whose cancer progressed while on placebo could switch to osimertinib, and 81% did, Ramalingam said.

Detailed results showed the following:¹

• Osimertinib significantly improved PFS by blinded independent central review compared with placebo (HR, 0.16; 95% CI, 0.10-0.24; P < .001.)
• Interim overall survival analysis (20% maturity) showed a trend in favor of osimertinib: HR 0.81 (95% CI 0.42, 1.56; P = .530)
• Median PFS in the osimertinib group was 39.1 months (95% CI; 31.5, not calculable), compared with 5.6 months (95% CI; 3.7, 7.4) for the placebo group
• The 12-month PFS rate was 74% for osimertinib vs 22% for placebo; the 24-month rate was 65% vs 13% favoring osimertinib
• All-causality adverse events (AEs) were reported in 98% of the osimertinib patients vs 88% of those on placebo; grade 3 or higher events affected 35% vs 12% of patients, and serious AEs were seen in 38% vs 15, respectively. AEs leading to discontinuation were reported in 13% vs 5%
• Pneumonitis was the most common AE, Ramalingam said. He noted that the duration of treatment for osimertinib patients was almost 4 times higher, so this group was more likely to report AEs

Based on these results, Ramalingam said, osimertinib will become the new standard of care “for patients with locally advanced non-small cell lung cancer following definitive chemo radiation, and EGFR mutation testing should be conducted for patients.”

David R. Spigel, MD, chief scientific officer at Sarah Cannon Research Institute, who was on hand to brief the press on the ADRIATRIC trial, noted the significance of the findings for both patients and for their physicians. He praised the study team for offering patients in the placebo arm the opportunity to cross over into the osimertinib arm.

“We don't always do that, because we're trying to find an overall survival benefit. But in this case, it was the right thing to do,” he said. “When patients progress, they don't always get a chance to get that crossover therapy or their next line of therapy. In fact, in lung cancer, about 40% of patients will never make it to the next line of therapy.”

Spigel said the findings would be “practice changing” as soon as there is new indication.

Results were also published today in the New England Journal of Medicine.²

Need for testing. In response to a question from The American Journal of Managed Care^®, Ramalingam addressed barriers to next-generation sequencing or EGFR testing required to access osimertinib, which several physicians at the press briefing said falls short of where it should be.

“There are some practical barriers. And then there are some other barriers that we continue to face, such as insurance coverage being an issue, [or] patients not having access to dedicated teams that can provide the sort of expertise that are needed. We see that specifically the underrepresented minority patients where the gap for not undergoing testing is even wider,” Ramalingam said. He also noted problems such as insufficient tissue being collected for testing, which may someday be solved with the use of liquid biopsy.

“Still, sometimes you have to go back for the second biopsy,” he said. “There is still an awareness issue. I don't think everybody is fully aware of the implications of the value of molecular testing and how critical it is to make treatment decisions for patients.”

Findings for ADRIATIC in LS-SCLC

Consolidation therapy with the durvalumab (Imfinzi, AstraZeneca), given after chemoradiotherapy, allowed patients with limited stage small-cell lung cancer (LS-SCLC) to live almost 2 years longer than similar patients who received chemoradiotherapy alone, according to results presented today at ASCO.³

David R. Spigel, MD | Image credit: SCRI

Spigel presented results for the ADRIATIC trial (NCT03703297) during the plenary session, after others called the findings “practice changing” during a press briefing.

“There really has not been any major advances in the treatment of limited stage small cell lung cancer for several decades,” Spigel said. “The standard of care is concurrent chemoradiotherapy, but despite that, most patients will have relapsed within 2 years and a minority of patients will survive 5 years.”

Lauren Byers, professor and chief, Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center in Houston, Texas, who is well-known for identifying 4 subtypes of SCLC, agreed that ADRIATIC is a landmark trial.

“In this trial, patients with this cancer who received the addition of immunotherapy after traditional chemotherapy and radiation lived longer and were less likely to have their cancer recur,” Byers said. “It's also an important study because of the magnitude of benefit that patients receive for the addition of durvalumab consolidation, with the average improvement in overall survival around 2 years. This is in contrast to many clinical trials in small cell lung cancer, where often the benefit may only be measured in months.”

The trial enrolled 730 patients with LS-SCLC who had finished their course of chemoradiotherapy within the past 6 weeks. Results being presented at this year’s meeting of ASCO include 264 patients randomized to receive durvalumab, a PD-L1 antibody, and 266 who received placebo; an additional cohort received a combination of durvalumab and a CTLA-4 inhibitor, tremelimumab (Imjudo), but Spigel explained those results are not ready.

Spigel explained the ADRIATIC trial’s rationale was based on earlier trials: the PACIFC trial evaluated durvalumab after chemoradiotherapy in stage III NSCLC, while CASPIAN looked at durvalumab with or without tremelimumab following chemotherapy in extensive stage SCLC.

Detailed findings show:³

• At the data cutoff of January 15, 2024, the median OS was 55.9 months for patients who received durvalumab vs 33.4 months for those who received placebo, for an HR of 0.73 (95% CI, 0.57-0.93; P = .0104)
• Median PFS was 17 months for patients who received durvalumab vs 9 months for patients who received the placebo, for an HR of 0.76 (95% CI, 0.61-0.95; P = .0161)
• The 36-month OS rate was 56.5% in the durvalumab group vs 47.6% in the placebo group. The 24-month PFS rate was 46.2% in the durvalumab group and 34.2% in the placebo group
• Rates of severe AEs were 24% in both groups. About 16% of the patients in the durvalumab group stopped treatment due to AEs, compared with 11% in the placebo group
• Pneumonitis was seen in 38% of participants in the durvalumab group, compared with 30% in the placebo group. Grade 3 or 4 pneumonitis was similar between the groups (3.1% in the durvalumab group and 2.6% in the placebo group)

References

1. Ramalingam SS, Kato T, Dong X, et al. Presentation of LBA 4, Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study. J Clin Oncol. Abstract LBA4. Published June 2, 2024. doi: 10.1200/JCO.2024.42.17_suppl.LBA4

2. Lu S, Kato T, Dong X, et al. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. Published online June 2, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2402614

3. Spigel DR, Cheng Y, Cho BC, et al. Presentation of LBA 5, Durvalumab +/- tremelimumab as consolidation therapy for patients with limited-stage small-cell lung cancer (LS-SCLC): Results from the phase 3 ADRIATIC study. J Clin Oncol. Abstract LBA5. Published June 2, 2024. doi: 10.1200/JCO.2024.42.17_suppl.LBA5