Osimertinib OS Data Herald New Frontline Standard for EGFR-Mutant NSCLC

Suresh S. Ramalingam, MD

Frontline treatment with osimertinib (Tagrisso) improved median overall survival (OS) by 6.8 months compared with erlotinib (Tarceva) or gefitinib (Iressa) for patients with metastatic, EGFR-mutant non—small cell lung cancer (NSCLC), despite crossover between arms, according to updated findings from the phase III FLAURA study presented at the ESMO Congress 2019.¹

The median OS in the osimertinib arm was 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0) with erlotinib or gefitinib, representing a 20% reduction in the risk of death with the third-generation EGFR inhibitor (HR, 0.799; 95% CI, 0.647-0.997; P = .0462). At the final data cutoff for the study, 54% of patients remained alive at 36 months in the osimertinib arm compared with 44% in the erlotinib/gefitinib group.

“The survival results are both statistically significant and clinically meaningful with first-line osimertinib for EGFR-mutated patients,” said study author Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University. “The overall survival result you see for the control group in this study is among the highest reported for EGFR-mutated patients. A lot of patients crossed over from the control group to receive osimertinib at progression. And, even with that in play, we see a 6.8-month improvement in survival with osimertinib.”

In April 2018, the FDA approved osimertinib as a frontline treatment for patients with EGFR-mutant NSCLC, based on earlier findings from the FLAURA trial. In addition to meeting both efficacy endpoints, osimertinib has also shown better tolerability than the first-generation TKIs. Grade 3/4 adverse events (AEs) occurred in 34% of patients in the osimertinib group compared with 45% of those receiving erlotinib or gefitinib.²

“The final OS analysis of FLAURA reinforces osimertinib as the standard of care for first-line treatment of patients with EGFR-mutant advanced NSCLC,” said Ramalingam. “Osimertinib presented a favorable and consistent toxicity profile, despite prolonged exposure.”

In the FLAURA trial, 556 treatment-naïve patients with EGFR-positive locally advanced or metastatic NSCLC were randomly assigned to osimertinib (n = 279) or a standard TKI (erlotinib or gefitinib; n = 277). Patients with CNS metastases were allowed on the trial and all patients had exon 19 deletions or L858R mutations. Daily oral therapy was given with 80 mg of osimertinib, 250 mg of gefitinib, or 150 mg of erlotinib.

In the ESMO update,¹ the 12-month OS rate was 89% in the osimertinib arm compared with 83% in the comparator group. The 24-month OS rates were 74% and 59%, for osimertinib and erlotinib/gefitinib, respectively. At 36 months, 28% of patients remained on first-line treatment with osimertinib compared with 9% remaining on erlotinib or gefitinib.

“The results of the FLAURA study clearly show that we should give the best therapy first,” said Ramalingam. “Thirty percent of patients in both arms of the trial did not receive subsequent therapy after progression, and for the vast majority, it is because they died. For those patients, first-line treatment is the only shot they had.”

OS was improved with osimertinib across all key patient subgroups, with the exception of Asian populations where the data were unclear, Ramalingam noted. In Asian patients (n = 347), the HR for OS was 0.995 and in non-Asian patients (n = 209) the HR was 0.542. “In the Asian group, the curves separate early and remain favorable for osimertinib for 36 months,” said Ramaling. “At this time point, I would urge caution, the number of events is low and there’s a high degree of censoring. To us, benefit for osimertinib is seen across all key subgroups.”

In previously reported findings from the New England Journal of Medicine,² the median progression-free survival with osimertinib was 18.9 months (95% CI, 15.2-21.4) versus 10.2 months (95% CI, 9.6-11.1) for erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P <.0001), which was a 54% reduction in the risk of progression or death. The objective response rate with osimertinib was 80% compared with 76% for erlotinib or gefitinib (odds ratio, 1.27; 95% CI, 0.85-1.90; P = .24). The median duration of response with osimertinib was 17.2 months versus 8.5 months in the comparator arm.

The most common all-grade AEs with osimertinib and first-generation TKIs, respectively, were rash or acne (58% vs 78%), diarrhea (58% vs 57%), dry skin (36% vs 36%), paronychia (35% vs 33%), stomatitis (29% vs 20%), and decreased appetite (20% vs 19%). AEs were less likely to lead to treatment discontinuation in the osimertinib arm (13% vs 18% discontinuation rate, respectively).

“Osimertinib is very different from all the other EGFR inhibitors for 3 reasons,” Ramalingam said. “Number 1, it’s highly selective to the EGFR receptor, and therefore has a much better safety profile than the other drugs. Number 2, it has higher penetration in the brain, and therefore is able to induce responses in 70% to 90% of patients with brain metastases, which is a common problem with EGFR-mutated lung cancer. Three, it not only blocks exon 19 and 21 but it also blocks the T790M pathway, which is the most common resistance mechanism for patients treated with first- and second-generation EGFR inhibitors.”

Prior to the frontline approval, osimertinib was also granted approval for use following progression on a first- or second-generation TKI, for those with EGFR T790M-positive NSCLC. This approval and the magnitude of the OS advantage seen in the FLAURA trial should be discussed with patients, in addition to the overall sequence of therapies, advised ESMO expert Pilar Garrido, MD, PhD, from the Ramon y Cajal University Hospital.

“If osimertinib is used as first-line therapy, there is no TKI available when the disease progresses. Patients should be told that osimertinib offers an overall survival advantage and is well tolerated, but when the treatment fails, the only option is chemotherapy,” she said. “Maximizing the duration of chemotherapy-free treatment is important for many patients, but if we want to know the most effective sequence of TKIs we need studies specifically designed for that.”

Further studies are examining treatments that are effective following progression on osimertinib. When it came to sequencing, however, Ramalingam further stressed the need to utilize osimertinib in the frontline setting preferentially. “Not every patient develops T790M,” he said. “If you go with a sequence, only 30% or 35% of patients will get a chance to receive osimertinib. So, you can either give the best drug first or roll the dice, but you’ll lose the opportunity in 2 out of 3 patients to give this therapy. And this is why we feel the best drug should be given first.”

Commenting on the data, invited discussant Pasi A. Jänne, MD, PhD, from the Dana-Farber Cancer Center likened the FLAURA trial to "hitting for the cycle" in baseball, wherein a batter hits a single, double, triple, and home run in a single game. Given the home run OS data in this example, Jänne advised against starting with an older generation TKI for similar reasons noted by Ramalingam.

"This is not optimal clinical care," he said. "We are not smart enough to figure out who will get EGFR T790M and not everyone will be well enough to receive additional treatment. Additionally, tissue or liquid biopsies are not always successful or available and osimertinib has shown a survival benefit."

References:

1. Ramalingam SS, Gray JE, Ohe Y, et al. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Presented at: 2019 ESMO Congress, Barcelona, Spain, September 28 to October 1, 2019. Abstract LBA5_PR.
2. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non—small-cell lung cancer. N Engl J Med. 2018; 378:113-125.

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