Consultants Weigh in on Matter of Frontline Osimertinib Alone or With Chemo in EGFR-Mutant NSCLC

On the twenty fifth Annual Worldwide Lung Most cancers Congress, Jonathan W. Riess, MD, MS, and James Chih-Hsin Yang MD, PhD, debated the advantages of administering osimertinib (Tagrisso) alone or together with chemotherapy within the frontline setting for sufferers with EGFR-mutant NSCLC. Riess kicked off the controversy, arguing in favor of osimertinib alone.¹

“Single agent osimertinib is much less poisonous than osimertinib plus chemotherapy and main affected person subsets don’t do higher with [the combination approach],” Riess said in his opening argument. “A big share of the management arm [in the phase 3 FLAURA2 trial (NCT04035486)] didn’t obtain subsequent systemic anticancer remedy, and vital general survival [OS] profit has not but been demonstrated.

“There’s [also] a possibility price of second-line platinum mixture therapies,” he identified.

James Chih-Hsin Yang MD, PhD

In rebuttal, Yang argued that chemotherapy plus osimertinib is a viable choice that confers specific profit for sufferers with mind metastases, regardless of potential opposed results (AEs). “Was there a suggestion of an OS profit [with osimertinib plus chemotherapy]? Sure. There was additionally no change in resistance patterns in early progressors, and [upfront administration of the regimen can help patients] keep away from central nervous system [CNS] catastrophes. [In light of this, my response is:], why not?”

General, the dialog highlighted the continued debate and uncertainty within the discipline concerning the optimum therapy method for this affected person inhabitants.

Yang is a professor and the director of each the Graduate Institute of Oncology and the Division of Oncology on the Nationwide Taiwan College Hospital in Taipe. Riess is an affiliate professor of drugs and medical director of Thoracic Oncology at UC Davis Complete Most cancers Middle in Sacramento, California.

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

The part 3 FLAURA trial was designed to find out whether or not the next-generation EGFR inhibitor osimertinib was the superior frontline remedy for sufferers with EGFR-mutant NSCLC vs normal first- and second-generation EGFR inhibitors. In FLAURA, the danger of illness development or demise was lowered by 64% (HR, 0.46; 95% CI, 0.37-0.57; P < .0001) with osimertinib (n = 297). Median progression-free survival (PFS) elevated by 9 months within the monotherapy vs standard-of-care (SOC) TKI arm (n = 277). Osimertinib additionally generated a statistically vital and clinically significant prolongation of median OS (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).^2,3

“The FLAURA trial conclusively confirmed that osimertinib as a single agent is the de facto greatest first line remedy for sufferers with frequent EGFR mutations, [such as] exon 19 deletion, and L858R mutations,” Riess said through the debate.

Following this trial, main outcomes from FLAURA2 demonstrated that the addition of osimertinib to chemotherapy lowered the danger of illness development or demise by 38% in contrast with osimertinib monotherapy (HR, 0.62; 95% CI, 0.49-0.79; P < 0.0001). Furthermore, the investigator-assessed PFS elevated from 16.7 months (95% CI, 14.1-21.3) for these given osimertinib alone (n = 278) to five.5 months (95% CI, 24.7–not calculable [NC]) for sufferers handled with the mixture (n = 279).⁴

“I’ll grant Dr Yang the truth that [FLAURA2] met its main finish level, and PFS per investigator evaluation was optimistic…nonetheless, I might argue, by way of PFS, that there are main affected person populations the place [osimertinib plus chemotherapy] isn’t useful,” Riess says.

Riess went on to quote knowledge offered on the 2024 AACR Annual Assembly, which confirmed that sufferers with out baseline-detected plasma EGFR mutations didn’t expertise a pronounced PFS profit with the addition of chemotherapy to osimertinib. On this inhabitants, the median PFS was 33.3% (95% CI, 23.8%-NC) vs 30.3% (95 %CI, 25.0-NC) within the mixture (n = 65) vs monotherapy arms (n = 48).⁵

“This represents a couple of quarter of sufferers in FLAURA2, and the PFS was no completely different [between the 2 arms] …so why on the planet would you give these sufferers chemotherapy?” Riess posited. “Like the flicks, some sequels are higher than others…however not FLAURA2,” Riess concluded.

Is a Development in OS Sufficient? Disagreement on the Implications of OS Information in FLAURA2

Each Riess and Yang highlighted knowledge from the second interim OS evaluation of FLAURA2. On the knowledge 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 Nevertheless, Riess identified that regardless of a development in favor of osimertinib plus chemotherapy, these knowledge have been solely at 41% maturity.

“It’s not statistically vital by their statistical design, which might require lower than 0.000001 to fulfill statistical significance. So, as of but, we wouldn’t have an OS profit [with the combination] that’s statistically vital, versus FLAURA.

Moreover, Riess famous that roughly 40% of sufferers within the osimertinib arm who discontinued the examine didn’t go on to obtain subsequent anticancer remedy following therapy.

“Does that sound like your affected person right here with EGFR-mutant lung most cancers that always goes on to third-, fourth-, fifth-line remedy, typically extra?” he requested.

“FLAURA2 was not the one examine that confirmed profit from including chemotherapy to the first-line,” Yang said in his counterargument.

He went on to quote knowledge from the prior NEJ009 examine (UMIN000006340) performed in Japan, which evaluated the usual EGFR TKI gefitinib (Iressa) mixed with carboplatin plus pemetrexed vs gefitinib-alone for sufferers with EGFR-mutant NSCLC. Up to date evaluation 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) within the monotherapy (n = 172) vs mixture arms (n = 170), respectively (HR, 0.77; 95% CI, 0.62 to 0.97; P = .027).⁶

Nevertheless, there was no vital distinction in OS between these therapy arms. The imply survival time, 2-year OS charge, and 5-year OS charge have been 38.5 months, 69%, and 34%, respectively for the gefitinib group; respective values have been 49.0 months, 77.1%, and 39% within the mixture group (HR, 0.822; 95% CI, 0.639 to 1.058; P = .127).

“Clearly, this trial didn’t meet the OS [end point], however this was in all probability on account of this examine design. You may nonetheless see the large distinction between median PFS [across treatment arms],” Yang stated. 

Contemplating CNS Metastases

Including chemotherapy to osimertinib may tremendously profit therapy for sufferers with CNS mind metastases, Yang continued. In a case examine of a 58-year-old male affected person with stage IV, EGFR-mutant NSCLC within the left higher lobe and adenocarcinoma with mind metastases, therapy with osimertinib alone was not sufficient to adequately extend the affected person’s survival.

Yang defined that, “On the time that I [started] him on osimertinib, he had small mind metastases and small lymph nodes…1 12 months later, he had a small, further metastasis and some months later, he had fast development. A couple of months later, he had fast development, so I gave him chemotherapy. That didn’t work too effectively, and a number of other months later, he succumbed [to the disease]. That was lower than 2 years.

“I used to be so astonished by this case,” Yang admitted. “This was a affected person who I believed I might deal with very effectively with osimertinib, however that didn’t do it.”

This case examine reinforces the significance of correct affected person choice in NSCLC, Yang emphasised. “If I met this affected person immediately, I might in all probability take a look at chemotherapy upfront, as a result of we all know that sufferers who’ve mind metastases truly profit rather more than different sufferers,” he stated.

This level is corroborated by knowledge from an exploratory evaluation of CNS finish factors in FLAURA2, which confirmed that osimertinib plus chemotherapy lowered the danger of CNS development or demise, elevated CNS goal response charge, the proportion of sufferers attaining CNS full response, and improved sturdiness of CNS responses vs osimertinib alone.⁴

Will Upfront Chemotherapy Scale back the Efficacy of Later-Line Choices?

One other frequent query inside the therapy house is whether or not including chemotherapy to osimertinib can introduce extra genomic alterations and enhance tumor heterogeneity.

“When you give platinum-pemetrexed within the first line, you probably don’t have the chance to present these mixtures the place you’re including one other drug which may be higher,” Riess defined.

Nevertheless, Yang cited knowledge from a preliminary cohort of FLAURA2 offered on the 2023 ESMO Asia Congress, which confirmed that no novel resistance mechanisms have been detected with the addition of chemotherapy to osimertinib. Moreover, 60% of sufferers within the osimertinib monotherapy arm (n = 53) had at the least 1 potential resistance alteration vs 34% with the mixture (n = 73). These knowledge recommend that using this mixture mustn’t affect subsequent focused second-line therapy choices.⁷

Considerations About Upfront Tolerability and High quality of Life

In FLAURA2, the general incidence of AEs was greater within the osimertinib plus chemotherapy arm vs the osimertinib monotherapy arm, and extra frequent grade 4 AEs have been noticed, Riess said, including that the addition of chemotherapy is clearly including toxicity to the routine.

He provides that, “CTCAE standards for toxicity typically underestimates how sufferers actually 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 of the potential toxicity that you could be get by including chemotherapy…and also you’re cumulative edema, worse fatigue, diarrhea, and kidney dysfunction. That’s doubtlessly much more toxicity [a patient will experience] over time [only to achieve an] unclear profit with regards to OS.”

Yang, nonetheless, had a special perspective on the query of upfront tolerability. “I ponder why individuals pose this query, as a result of each physician from the US has informed me that, [following progression on] osimertinib, they may proceed osimertinib when [administering] chemotherapy. I didn’t hear anyone inform me that [the patient] can’t tolerate it. If you inform me that sufferers [cannot tolerate this combination in] the first-line, however they will tolerate it within the second-line, I’ve to surprise…”

Concerning the rise in AEs in FLAURA2, Yang responded that, “I can’t say there have been no AEs, however I can say there have been no [added] extreme AEs results.”

Riess additionally identified the chance price related to including chemotherapy to osimertinib, stating that, “Pemetrexed [itself] isn’t an extended infusion, however [a patient is] getting carboplatin and pemetrexed initially for 4 cycles, so [they’ve got] further labs, further visits, and additional infusion time not simply within the chair, however checking in and the trying out… It’s a couple of 9-to-5 job for over a month if you add up that point…there’s an enormous alternative price of what you possibly can be doing.

“As an alternative of sitting in an infusion chair, getting labs, and going to extra physician’s visits, [a patient could be] residing [their] life doing the issues [they] need to do.” 

References

1. Riess JW. Osimertinib is perfect 1L remedy in EGFR mutant NSCLC? Introduced at: twenty fifth Annual Worldwide Lung Most cancers Congress; July 25-27, 2024; Huntington Seashore, CA.
2. Yang J. Debate: EGFR Mutations: TKI +/- chemotherapy in first-Line? An vital choice? Introduced at: twenty fifth Annual Worldwide Lung Most cancers Congress; July 25-27, 2024; Huntington Seashore, CA.
3. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated superior non-small-cell lung most cancers. 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 with out Chemotherapy in EGFR-mutated Superior NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
5. Jänne PA, Kobayashi Ok, Robichaux J, et al. FLAURA2: exploratory evaluation of baseline (BL) and on-treatment plasma EGFRm dynamics in sufferers (pts) with EGFRm superior NSCLC handled with first-line (1L) osimertinib (osi) ± platinum-pemetrexed. Introduced at: 2024 AACR Annual Assembly; April 5-10, 2024; San Diego, CA. Summary CT017.
6. Miyauchi E, Morita S, Nakamura A, et al. Up to date evaluation of NEJ009: Gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung most cancers 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 with out platinum-based chemotherapy (CT) in EGFR-mutated (EGFRm) superior NSCLC: Preliminary knowledge from FLAURA2. Ann Oncol. 2023; 34 (suppl_4): S1661-S1706. doi: 10.1016/annonc/annonc1391