Kim Evaluates New Regimens for EGFR+ Lung Cancer

Edward S. Kim, MD, MBA

Physician-in-Chief

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope Orange County

Irvine, CA

PEERS & PERSPECTIVES IN ONCOLOGY: What was the significance of the FLAURA2 trial (NCT04035486) in patients with sensitizing EGFR mutations?

KIM: The phase 3 FLAURA2 study [investigated] osimertinib [Tagrisso] plus chemotherapy. [Patients had nonsquamous disease] but mixed histology was allowed. They were newly diagnosed with locally advanced or metastatic disease [or] non–curative-intent disease. Patients had to have either one of the common sensitizing mutations [exon 19 deletion or exon 21 L858R mutation] and good performance status. There were stratifications, and they were either treated with osimertinib with the combination vs osimertinib alone [randomly assigned 1:1], and then they got maintenance therapy afterward. The primary end point was progression-free survival [PFS]. The secondary end point was overall survival [OS]…because we’re just doing so well that we can’t do OS. [Median OS] is a long time now [in these patients], and that’s a good thing.

[PFS was evaluated] by blinded radiology review and investigative assessment. The median was 29 months for the combination vs 19.9 months for osimertinib alone [by blinded independent central review] and 25 vs 16 months, respectively, [by investigator assessment].¹ The difference was about the same. The investigators are usually a little more optimistic, [so it’s unusual] to see it this way. But the HR for PFS was 0.62 [95% CI, 0.49-0.79]; it’s pretty good. We like that in the metastatic setting. The fourth generation was less toxic, more potent, and has central nervous system penetration.

PFS in patients with bone or liver metastases at baseline—these are the patients where we’re being more data driven, measuring sites of disease, etc. For patients who had bone and liver metastases up front, the numbers were lower, but the HRs were still in the range of 0.56 [95% CI, 0.40-0.77; for bone metastases to] 0.66 [95% CI, 0.41-1.07; for liver metastases].²

If you had brain metastases, 0.47 was the HR [95% CI, 0.33- 0.66].1 If you didn’t have brain metastases, it was still pretty good [HR, 0.75; 95% CI, 0.55-1.03]. Can we now pick and choose the subsets in which we might use this regimen vs not? It might be the same with sequencing. You might alter PFS now quite a bit by adding it all, if you think PFS is valuable.

How would osimertinib plus chemotherapy compare with osimertinib followed by chemotherapy?

They asked that question on the sequencing. We don’t know. They can anecdotally pull people who have been treated that way and look at that, but it wasn’t one of the arms. It wouldn’t have been done that way, because the company would never [compare] against a non–FDA-approved regimen. Then the question would be: When would you sequence? That’s why you would have it in clinical practice, because you’d have osimertinib treatment, and then they would get [chemotherapy] at progression. This question is more of an OS rather than a PFS question, because the PFS would be the same, but the OS might wash out.

For postprogression outcomes, we look at the [time to second progression]. We want to see how the second-line therapy went. We know we’re already doing [well]. This is why you see the OS still out there, but the [post-progression outcomes] are all good [Table³]. But can you do a little better? And is it worth the tradeoff of a limited number of chemotherapy cycles on top of it? The OS [curve] is crossing a little bit, and at the second interim analysis it’s still not mature [HR, 0.75; 95% CI, 0.57-0.97; P = .0280].

We always want to rebiopsy [after progression] because, with single-agent tyrosine kinase inhibitor [TKI], there is 15% small cell transformation. If you do a liquid biopsy, you will miss it.

What were the outcomes of the MARIPOSA trial (NCT04487080)?

MARIPOSA was a phase 3 trial; here we’ve got the same [setting. Patients must have] had the sensitizing [EGFR] mutations. [The experimental arm was] amivantamab [Rybrevant] plus lazertinib [Lazcluze]. They had to make [the combination arm] open label. [The other 2 arms] were osimertinib and lazertinib. There was a 2:2:1 randomization. The lazertinib [arm] was to see how this does, but the combination compared with osimertinib was what they were looking at. The primary end point was PFS.

The third arm was purely for contributory aspects, so it was not meant to be part of any of the end points. The FDA wanted to see what the activity of single-agent [lazertinib] was. They don’t like to approve 2 nonapproved drugs, so that’s why they added this arm. You can’t [prescribe] lazertinib as a single agent right now. It’s not even a category 2 option in the NCCN [guidelines].

The PFS should look familiar. All this time, we [felt] osimertinib was so great, and now we’ve had 2 consecutive trials that have beaten it. In the EGFR field, we’ve been doing it for 20 years…[and] none of the combinations ever beat these [TKIs]. This was a highly powered study with a good PFS [median, 23.7 vs 16.6 months] and a good HR [0.70, 95% CI, 0.58-0.85; P < .001]—certainly a difference.^4,5

For PFS2 [or] PFS after first the subsequent therapy, in [the amivantamab/lazertinib] arm, 98 started subsequent therapy. [In the osimertinib arm], 137 started subsequent therapy. [In the amivantamab/lazertinib arm, 48 (49%) started TKI and [32 (33%) started chemotherapy. [In the osimertinib arm, 53 (39%)] started chemotherapy and [37 (27%) started TKI]. We see the percentages and how that shaped up, and patients still got better [outcomes with the combination; (HR, 0.75; 95% CI, 0.58-0.98; P = .03)].⁵

In patients with a history of brain metastases [HR, 0.69; 95% CI, 0.53-0.92] vs those without a history of brain metastases [HR, 0.69; 95% CI, 0.53-0.89], we’re seeing the same pattern.4,5 For extracranial PFS by blinded independent central review, [there was an HR of 0.68 (95% CI, 0.56-0.83; P < .001)].⁴ With a median follow-up of 31 months for intracranial PFS, [the HR was 0.82 (95% CI, 0.62-1.09; P = .165)].⁶ You’ll continue to see these subsets [reported]. It’s like that early phase 1 set of patients treated with nivolumab [Opdivo], where there are 7 patients left on it, and their swimmer plots are out at 7 or 8 years.

Updated OS still hasn’t gotten [to maturity at a median follow-up of 31 months]. It shouldn’t stop you from using it.… It looks like [an HR of 0.77 (95% CI, 0.61-0.96; P = .019)]. As in [FLAURA2], the curves [intersect] early. Then as you go out, it starts to separate. So it looks very similar.

[The trial] used the intravenous version [of amivantamab]. I thought one of the coolest things was that the subcutaneous version came out so quickly, so I don’t know what the data would look like with subcutaneous. [However], it is much more convenient for patients, with fewer adverse events [AEs], and all those positive things. But you see [slightly] more AEs here [vs osimertinib]. Thromboembolism is one of the AEs that’s unique there [any grade, 37% with the combination vs 9% with osimertinib].4 It occurred early [in 62%], so the recommendation is to do a little [anticoagulant] prophylaxis in the first 4 months.

_REFERENCES

1. _{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}
2. _{Valdiviezo N, Gray JE, Jänne PA, et al. FLAURA2: impact of tumor burden on outcomes of 1L osimertinib ± chemotherapy in patients with EGFR-mutated advanced NSCLC. J Thorac Oncol. 2024;19(10):S102. doi:10.1016/j.jtho.2024.09.185}
3. _{Valdiviezo N, Okamoto I, Hughes BGM, et al. First-line (1L) osimertinib (osi) ± platinum-pemetrexed in EGFR-mutated (EGFRm) advanced NSCLC: FLAURA2 post-progression outcomes. Ann Oncol. 2024;9(suppl 3):102583. doi:10.1016/esmoop.2024.102583}
4. _{Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614}
5. _{Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1306. doi:10.1016/j.annonc.2023.10.062}
6. _{Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. J Thorac Oncol. 2024;19(suppl 10):S10-S11. doi:10.1016/j.jtho.2024.09.026}