Experts Weigh in on Topic of Frontline Osimertinib Alone or With Chemo in EGFR-Mutant NSCLC

At the 25th Annual International Lung Cancer Congress, Jonathan W. Riess, MD, MS, and James Chih-Hsin Yang MD, PhD, debated the benefits of administering osimertinib (Tagrisso) alone or in combination with chemotherapy in the frontline setting for patients with EGFR-mutant NSCLC. Riess kicked off the debate, arguing in favor of osimertinib alone.¹

“Single agent osimertinib is less toxic than osimertinib plus chemotherapy and major patient subsets do not do better with [the combination approach],” Riess stated in his opening argument. “A large percentage of the control arm [in the phase 3 FLAURA2 trial (NCT04035486)] did not receive subsequent systemic anticancer therapy, and significant overall survival [OS] benefit has not yet been demonstrated.

“There’s [also] an opportunity cost of second-line platinum combination therapies,” he pointed out.

In rebuttal, Yang argued that chemotherapy plus osimertinib is a viable option that confers particular benefit for patients with brain metastases, despite potential adverse effects (AEs). “Was there a suggestion of an OS benefit [with osimertinib plus chemotherapy]? Yes. There was also no change in resistance patterns in early progressors, and [upfront administration of the regimen can help patients] avoid central nervous system [CNS] catastrophes. [In light of this, my response is:], why not?”

Overall, the conversation highlighted the ongoing debate and uncertainty in the field regarding the optimal treatment approach for this patient population.

Yang is a professor and the director of both the Graduate Institute of Oncology and the Department of Oncology at the National Taiwan University Hospital in Taipe. Riess is an associate professor of medicine and medical director of Thoracic Oncology at UC Davis Comprehensive Cancer Center in Sacramento, California.

The Original vs the Sequel: Evaluating the FLAURA (NCT02296125) and FLAURA2 Trials

The phase 3 FLAURA trial was designed to determine whether the next-generation EGFR inhibitor osimertinib was the superior frontline therapy for patients with EGFR-mutant NSCLC vs standard first- and second-generation EGFR inhibitors. In FLAURA, the risk of disease progression or death was reduced by 64% (HR, 0.46; 95% CI, 0.37-0.57; P < .0001) with osimertinib (n = 297). Median progression-free survival (PFS) increased by 9 months in the monotherapy vs standard-of-care (SOC) TKI arm (n = 277). Osimertinib also generated a statistically significant and clinically meaningful prolongation of median OS (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).^2,3

“The FLAURA trial conclusively showed that osimertinib as a single agent is the de facto best first line therapy for patients with common EGFR mutations, [such as] exon 19 deletion, and L858R mutations,” Riess stated during the debate.

Following this trial, primary results from FLAURA2 demonstrated that the addition of osimertinib to chemotherapy reduced the risk of disease progression or death by 38% compared with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; P < 0.0001). Moreover, the investigator-assessed PFS increased from 16.7 months (95% CI, 14.1-21.3) for those given osimertinib alone (n = 278) to 5.5 months (95% CI, 24.7–not calculable [NC]) for patients treated with the combination (n = 279).⁴

“I’ll grant Dr Yang the fact that [FLAURA2] met its primary end point, and PFS per investigator assessment was positive...however, I would argue, in terms of PFS, that there are major patient populations where [osimertinib plus chemotherapy] is not beneficial,” Riess says.

Riess went on to cite data presented at the 2024 AACR Annual Meeting, which showed that patients without baseline-detected plasma EGFR mutations did not experience a pronounced PFS benefit with the addition of chemotherapy to osimertinib. In this population, the median PFS was 33.3% (95% CI, 23.8%-NC) vs 30.3% (95 %CI, 25.0-NC) in the combination (n = 65) vs monotherapy arms (n = 48).⁵

“This represents about a quarter of patients in FLAURA2, and the PFS was no different [between the 2 arms] …so why in the world would you give these patients chemotherapy?” Riess posited. “Like the movies, some sequels are better than others…but not FLAURA2,” Riess concluded.

Is a Trend in OS Enough? Disagreement on the Implications of OS Data in FLAURA2

Both Riess and Yang highlighted data from the second interim OS analysis of FLAURA2. At the data cutoff, the median OS with osimertinib plus chemotherapy was not reached (95% CI, 38.0-NC) vs 36.7 months (95% CI, 33.2-NC) with osimertinib alone (HR, 0.75; 95% CI, 0.57-0.97; P = .0280).4 However, Riess pointed out that despite a trend in favor of osimertinib plus chemotherapy, these data were only at 41% maturity.

“It’s not statistically significant by their statistical design, which would require less than 0.000001 to meet statistical significance. So, as of yet, we do not have an OS benefit [with the combination] that is statistically significant, as opposed to FLAURA.

Additionally, Riess noted that approximately 40% of patients in the osimertinib arm who discontinued the study did not go on to receive subsequent anticancer therapy following treatment.

“Does that sound like your patient here with EGFR-mutant lung cancer that often goes on to third-, fourth-, fifth-line therapy, sometimes more?” he asked.

“FLAURA2 was not the only study that showed benefit from adding chemotherapy to the first-line,” Yang stated in his counterargument.

He went on to cite data from the prior NEJ009 study (UMIN000006340) conducted in Japan, which evaluated the standard EGFR TKI gefitinib (Iressa) combined with carboplatin plus pemetrexed vs gefitinib-alone for patients with EGFR-mutant NSCLC. Updated analysis of this trial demonstrated that, at a median follow-up of 84 months, the median PFS2 (corrected PFS2) was 18.0 months (95% CI, 16.3-20.7) vs 20.9 months (95% CI, 18.00- 24.0) in the monotherapy (n = 172) vs combination arms (n = 170), respectively (HR, 0.77; 95% CI, 0.62 to 0.97; P = .027).⁶

However, there was no significant difference in OS between these treatment arms. The mean survival time, 2-year OS rate, and 5-year OS rate were 38.5 months, 69%, and 34%, respectively for the gefitinib group; respective values were 49.0 months, 77.1%, and 39% in the combination group (HR, 0.822; 95% CI, 0.639 to 1.058; P = .127).

“Obviously, this trial didn’t meet the OS [end point], but this was probably due to this study design. You can still see the huge difference between median PFS [across treatment arms],” Yang said. 

Considering CNS Metastases

Adding chemotherapy to osimertinib can also greatly benefit treatment for patients with CNS brain metastases, Yang continued. In a case study of a 58-year-old male patient with stage IV, EGFR-mutant NSCLC in the left upper lobe and adenocarcinoma with brain metastases, treatment with osimertinib alone was not enough to adequately prolong the patient’s survival.

Yang explained that, “At the time that I [started] him on osimertinib, he had small brain metastases and small lymph nodes…1 year later, he had a small, additional metastasis and a few months later, he had rapid progression. A few months later, he had rapid progression, so I gave him chemotherapy. That didn’t work too well, and several months later, he succumbed [to the disease]. That was less than 2 years.

“I was so astonished by this case,” Yang admitted. “This was a patient who I thought I could treat very well with osimertinib, but that didn’t do it.”

This case study reinforces the importance of accurate patient selection in NSCLC, Yang emphasized. “If I met this patient today, I would probably look at chemotherapy upfront, because we know that patients who have brain metastases actually benefit much more than other patients,” he said.

This point is corroborated by data from an exploratory analysis of CNS end points in FLAURA2, which showed that osimertinib plus chemotherapy reduced the risk of CNS progression or death, increased CNS objective response rate, the proportion of patients achieving CNS complete response, and improved durability of CNS responses vs osimertinib alone.⁴

Will Upfront Chemotherapy Reduce the Efficacy of Later-Line Options?

Another common question within the treatment space is whether adding chemotherapy to osimertinib can introduce more genomic alterations and increase tumor heterogeneity.

“If you give platinum-pemetrexed in the first line, you likely don’t have the opportunity to give these combinations where you’re adding another drug that may be better,” Riess explained.

However, Yang cited data from a preliminary cohort of FLAURA2 presented at the 2023 ESMO Asia Congress, which showed that no novel resistance mechanisms were detected with the addition of chemotherapy to osimertinib. Furthermore, 60% of patients in the osimertinib monotherapy arm (n = 53) had at least 1 potential resistance alteration vs 34% with the combination (n = 73). These data suggest that the use of this combination should not impact subsequent targeted second-line treatment options.⁷

Concerns About Upfront Tolerability and Quality of Life

In FLAURA2, the overall incidence of AEs was higher in the osimertinib plus chemotherapy arm vs the osimertinib monotherapy arm, and more common grade 4 AEs were observed, Riess stated, adding that the addition of chemotherapy is clearly adding toxicity to the regimen.

He adds that, “CTCAE criteria for toxicity often underestimates how patients really feel. [One of my patients reported] having rash, fatigue, parenchyma, mouth sores, and shortness of breath, all [of which] she describes with osimertinib alone. Now, add all the potential toxicity that you may get by adding chemotherapy…and you’re looking at cumulative edema, worse fatigue, diarrhea, and kidney dysfunction. That is potentially a lot more toxicity [a patient will experience] over time [only to achieve an] unclear benefit when it comes to OS.”

Yang, however, had a different perspective on the question of upfront tolerability. “I wonder why people pose this question, because every doctor from the United States has told me that, [following progression on] osimertinib, they will continue osimertinib when [administering] chemotherapy. I didn’t hear anybody tell me that [the patient] cannot tolerate it. When you tell me that patients [cannot tolerate this combination in] the first-line, but they can tolerate it in the second-line, I have to wonder…”

Regarding the increase in AEs in FLAURA2, Yang responded that, “I cannot say there were no AEs, but I can say there were no [added] severe AEs effects.”

Riess also pointed out the opportunity cost associated with adding chemotherapy to osimertinib, stating that, “Pemetrexed [itself] is not a long infusion, but [a patient is] getting carboplatin and pemetrexed initially for 4 cycles, so [they’ve got] extra labs, extra visits, and extra infusion time not just in the chair, but checking in and the checking out… It’s about a 9-to-5 job for over a month when you add up that time...there’s a huge opportunity cost of what you could be doing.

“Instead of sitting in an infusion chair, getting labs, and going to more doctor’s visits, [a patient could be] living [their] life doing the things [they] want to do.” 

References

1. Riess JW. Osimertinib is optimal 1L therapy in EGFR mutant NSCLC? Presented at: 25th Annual International Lung Cancer Congress; July 25-27, 2024; Huntington Beach, CA.
2. Yang J. Debate: EGFR Mutations: TKI +/- chemotherapy in first-Line? An important option? Presented at: 25th Annual International Lung Cancer Congress; July 25-27, 2024; Huntington Beach, CA.
3. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
4. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-mutated Advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. Jänne PA, Kobayashi K, Robichaux J, et al. FLAURA2: exploratory analysis of baseline (BL) and on-treatment plasma EGFRm dynamics in patients (pts) with EGFRm advanced NSCLC treated with first-line (1L) osimertinib (osi) ± platinum-pemetrexed. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT017.
6. Miyauchi E, Morita S, Nakamura A, et al. Updated analysis of NEJ009: Gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR. J Clin Oncol. 2022;40(31):3587-3592. doi:10.1200/JCO.21.02911
7. Lee CK, Robichaux JP, Jänne PA, et al. Acquired mechanisms of resistance to first-line (1L) osimertinib with or without platinum-based chemotherapy (CT) in EGFR-mutated (EGFRm) advanced NSCLC: Preliminary data from FLAURA2. Ann Oncol. 2023; 34 (suppl_4): S1661-S1706. doi: 10.1016/annonc/annonc1391