Experts Take Stock of Critical Clinical Issues in Lung Cancer

In the quest for scientific purity, one should not lose sight of the meaningful end points that can make a difference in patients’ daily lives, said Rogerio C. Lilenbaum, MD, who called into question critics of the phase 3 ADAURA trial during the keynote discussion at the 18th Annual Winter Lung Cancer Conference, a program hosted by the Physicians Education Resource® (PER®), LCC.

Weighing the Advantages of Adjuvant Osimertinib According to ADAURA

In the international, randomized, placebo-controlled, double-blind ADAURA trial, 682 patients with primary nonsquamous stage IB to IIIA non–small cell lung cancer (NSCLC) harboring EGFR exon 19 deletions or L858R mutations were randomized 1:1 to receive 80 mg of osimertinib (Tagrisso) daily or once-daily placebo.¹ Patients received treatment for 3 years, or until disease recurrence or discontinuation criteria were met.

The primary end point was investigator-assessed disease-free survival (DFS) in patients with stage II to IIIA disease. Secondary end points comprised DFS in the overall population; DFS at 2, 3, 4, and 5 years; overall survival (OS), safety, and quality of life.

Early unblinded results of the study demonstrated that adjuvant osimertinib led to a statistically significant improvement in DFS in patients with stage IB/II/IIIA EGFR-mutated NSCLC. The median investigator-assessed DFS had not yet been reached in patients who received osimertinib versus 19.6 months in those who received placebo (HR, 0.17; 95% CI, 0.12-0.23; P < .0001).

In the overall study population, the median DFS was not yet reached versus 27.5 months in the investigative and control arms, respectively (HR, 0.20; 95% CI, 0.15-0.27; P < .0001).

“I’m always a little perplexed by the intensity of the debate [over the ADAURA data] and some of the concerns [with adjuvant osimertinib], although legitimate to some extent, that question the overall conclusion of a trial that cannot just change practice but change lives,” said Lilenbaum, director of the Banner MD Anderson Cancer Center.

Additionally, Lilenbaum questioned whether the field has too conservative an understanding of what constitutes a practice-changing approach based on the mixed reception of the results.

Echoing Lilenbaum, Lecia V. Sequist, MD, MPH, explained that the main criticism of the SELECT trial, which had shown a 2-year DFS benefit with adjuvant erlotinib (Tarceva) versus matched controls in patients with EGFR-mutated NSCLC, had been that the study was not randomized.

“Now there’s a randomized trial, with 680 patients, and the complaint is that we don’t know what the survival is yet,” said Sequist, the Landry Family Associate Professor of Medicine at Harvard Medical School, and director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital. “I think it is hard [for] a person living with lung cancer to have a doctor say that only survival matters and that disease-free intervals don’t matter.”

From a purist standpoint, Sequist acknowledged that OS is the prized end point. However, she added that it is hard to discount such a “tremendous difference in DFS.”

“I do think ADAURA is life-changing for some of our patients,” stated Julie R. Brahmer, MD, MSc, FASCO, co-director of the Upper Aerodigestive Department in the Bloomberg-Kimmel Institute for Cancer Immunotherapy and a professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

“I go back and forth. On the one hand, I believe that such a dramatic DFS hazard ratio has to translate into an OS advantage, but I don’t know that. Maybe it’s the old-school OS mentality that we grew up with in lung cancer [that gives me pause],” said Mark A. Socinski, MD, executive medical director of AdventHealth Cancer Institute.

Moreover, Socinski highlighted the fact that although osimertinib has been termed a well-tolerated drug, the adverse effects of the drug are not to be ignored. For example, 43% of patients experienced grade 1/2 diarrhea while on the trial.

“[Osimertinib] is a well-tolerated cancer drug but trying to go to work on a day-to-day basis with grade 1/2 diarrhea [can be challenging,]” said Socinski.

From a practical standpoint, Brahmer question whether the brain imaging that was required in ADAURA, which is not routinely done in the adjuvant setting in practice, is feasible. Despite the lack of data to drive brain surveillance in resected lung cancer, Sequist stated that the more patients she sees who have a recurrence in the central nervous system that’s 2 cm or 3 cm by the time they are symptomatic, the more she is performing brain surveillance.

“In patients with EGFR and ALK [mutations], the rate of brain metastases is high, and the cost of doing an MRI once a year compared with that seems relatively low,” said Sequist.

Reconciling the Results of ADAURA and PACIFIC

Following the read out of the ADAURA trial, some have questioned whether its preemptive to treat a patient with unresectable stage III EGFR-mutant NSCLC with osimertinib following definitive chemoradiation. Such a strategy could build on the results of the phase 3 PACIFIC trial, which showed an OS benefit with durvalumab (Imfinzi) following chemoradiation in patients with unresectable stage III NSCLC.

“The activation energy to do this is much easier to attain after ADAURA,” said Sequist.

The ongoing phase 3 LAURA trial (NCT03521154) will formally test this question, said Socinski. In the study, patients with unresectable stage III EGFR-mutant NSCLC whose disease has not progressed following chemoradiation will be randomized 2:1 within 6 weeks of completing chemoradiation to receive 40 mg or 80 mg of osimertinib or placebo.²

Treatment will be continued until disease progression, unacceptable toxicity or other discontinuation criteria are met.

“I am glad the LAURA trial is in progress and will read out soon, because those randomized data are really what we need,” said Sequist.

Taking Stock of the Timing of EGFR-Directed TKIs in the Metastatic Setting

The optimal duration of EGFR-directed TKIs in the metastatic setting raised additional discussion, particularly if the patient has been on a drug for several years. For example, if a patient with metastatic disease has been on an EGFR-directed TKI for 5 years, Brahmer questioned whether the best option would be to discontinue the drug or continue treatment indefinitely.

Acknowledging the rarity of the situation, Sequist recalled a patient she and Thomas J. Lynch Jr, MD, of Fred Hutchinson Cancer Research Center, had taken care of who had a great response to expanded access gefitinib (Iressa) in 2003.

“We, for a variety of reasons, did stop her gefitinib about 3 years ago now, and her disease has not woken up or recurred since, so maybe there is a point where you can stop [treatment,]” said Sequist.

Apart from clinical concerns, Brahmer stated that insurance coverage could be a determining factor for some patients.

“I have a [patient] who is beyond 5 years who has done well, but [she] changed [her] insurance, and now her deductible is huge. Even with a drug that has become generic, it still can be an issue for these patients,” said Brahmer.

References

1. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell lung cancer. New Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

2. A global study to assess the effects of osimertinib following chemoradiation in patients with stage III unresectable non-small cell lung cancer (LAURA) (LAURA). ClinicalTrials.gov. Posted May 11, 2018. Updated January 14, 2021. Accessed February 6, 2021. https://clinicaltrials.gov/ct2/show/NCT03521154.