Santos Breaks Down Key Updates From 2023 in the Management of EGFR-Mutant NSCLC

2023 served as a pivotal year regarding updates in the treatment of patients with EGFR-mutant and ALK-positive non–small cell lung cancer (NSCLC), which included those from the phase 3 ADAURA (NCT02511106), FLAURA2 (NCT04035486), and ALINA trials (NCT03456076), according to Edgardo S. Santos Castillero, MD, FACP.

“Between the 2023 ASCO Annual Meeting, ESMO Congress, and World Lung Cancer Conference, we have a lot of things to discuss in lung cancer,” Santos Castillero, who serves as the medical director at the Oncology Institute of Hope and Innovation in Broward County, Florida, stated.

In an interview with OncLive, Santos expanded on outcomes from pivotal phase 3 trials such as ADAURA and FLAURA2 in patients with EGFR-mutant NSCLC, emphasized the importance of genomic testing in all patients who are diagnosed with NSCLC, and highlighted the impact of combination approaches in these hard-to-treat patient populations.

Santos also serves as a clinical associate professor in thoracic medical oncology at the Charles E. Schmidt College of Medicine, Florida Atlantic University; vice president of the Florida Society of Clinical Oncology (FLASCO); and president of the FLASCO Foundation.

OncLive: What data were presented in 2023 regarding the ADAURA trial?

Santos: Looking to early-stage [disease], especially in the EGFR space, I want to touch on the ADAURA trial, which was presented in June 2023. This clinical trial established osimertinib [Tagrisso] as a standard of care for patients that go for surgery and after surgery have a [sensitizing] EGFR mutation, an exon 19 deletion, or EGFR exon 21 [mutation]. [If that mutation is found] the patient is entitled to receive osimertinib, a third-generation EGFR TKI for 3 years.

This was a phase 3 study evaluating osimertinib vs placebo for 3 years. The patient may or may not receive adjuvant chemotherapy after surgery. This study was positive for overall survival with an impressive HR for overall survival of 0.49.¹ This means that at 5 years, the patient had a chance to be alive by getting osimertinib for 3 years vs those patients that were on placebo. This established osimertinib as a standard of care in the adjuvant setting for patients with stage IB, IIB, and IIIA [disease]. This is the new indication for osimertinib in the adjuvant setting.

Could you expand on the ALINA trial and why it was impactful for patients with NSCLC?

Similar data were presented in another pathway. This was the ALINA trial. This trial had a similar design to the ADAURA trial with the primary end point being disease-free survival and OS, but we need to wait for the final OS data. This trial was very impressive with a powerful HR of 0.24 with DFS benefit in both the stage II and IIIA [population] as well as the stage IB to IIIA [population].2

We are looking forward [to the potential] approval of alectinib [Alecensa], which was the inhibitor used on the ALINA trial in the adjuvant setting. [Osimertinib] already has established OS [data in the adjuvant setting] and [alectinib] now has a very good start with an impressive DFS, which will most likely be approved in the same setting. 

The message for our audience is that every patient with adenocarcinoma that goes for surgery, and in the pathologic stage, must be tested genomically. It is important to be sure that the patient tumor doesn’t have [an] EGFR or ALK [alteration]. Otherwise this therapy must be used in the early-stage setting.

What was seen in 2023 regarding updates in the metastatic setting?

In the metastatic setting, there have been several changes. One that is already reflected in the National Comprehensive Cancer Network [(NCCN) guidelines] is the use of chemotherapy plus Amivantamab-vmjw [Rybrevant] for those patients that have EGFR exon 20 insertion mutations. [We previously had] 2 drugs approved in the metastatic setting for [patients with an] EGFR exon 20 insertion. One was mobocertinib [Exkivity], which is an oral pill and a TKI. The other drug was a bispecific monoclonal antibody, amivantamab, which is a dual monoclonal antibody that attacks MET and EGFR.

After the 2023 ESMO Congress, a landmark study was presented which showed that chemotherapy plus amivantamab was superior [to chemotherapy alone] for patients with EGFR exon 20 insertions. This study was positive for progression-free survival [PFS] and overall response rate. OS is moving in favor of [the combination approach] vs chemotherapy alone. In fact, for chemotherapy, the median OS in the phase 3 PAPILLON study [NCT04538664] was 24.4 months and has not been reached for chemotherapy plus amivantamab.

PFS was strikingly positive and there was a reduction of 62% in the risk of progression of disease or death if the patient had an EGFR exon 20 insertion and received chemotherapy plus amivantamab. Therefore, today, this [regimen] has a become a part of our NCCN guidelines.

Mobocertinib has notably been withdrawn from the United States market recently pending an agreement between the FDA and the manufacturing company [of the drug].

Finally, how has the FLAURA2 trial impacted the treatment landscape for patients with sensitizing EGFR mutations?

We're moving the bar in patients with an EGFR pathway [alteration] with the FLAURA2 study. This was one of the best stories that I saw in 2023. FLAURA2 is [evaluating] the combination of osimertinib plus chemotherapy, in this case a platinum doublet using pemetrexed [Alimta] vs osimertinib alone. The population here had stage IV disease with an EGFR sensitive mutation in exon 19 or exon 21. The randomization in this study was 1:1. Osimertinib plus carboplatin or cisplatin plus pemetrexed followed by maintenance therapy [with] osimertinib plus pemetrexed vs osimertinib alone.

The primary end point of the study was PFS, which was strikingly positive for osimertinib plus chemotherapy at 25.5 months vs 16.7 months for patients on osimertinib alone.3

For the FLAURA2 study, we learned 2 things. Number one is that patients with de novo central nervous system [CNS] metastases did much better on osimertinib plus chemotherapy than osimertinib alone. There was an HR of 0.47 in favor of osimertinib plus chemotherapy vs osimertinib alone [in that population]. For those patients that present without brain metastases, there was no difference between the [2 treatments]. That is one learning from the study.

The other learning is [something we have known]. We know that exon 21 is sensitive [to therapy with osimertinib] but not as sensitive as exon 19 deletion. Therefore, when we expose those patients to an EGFR TKI, those with the exon 19 deletion have better outcomes in terms of PFS or a deeper response. FLAURA2 shows the same. If the patient has exon 21, there was a striking HR for PFS of 0.63. When we analyze that, we can see that there is a separation [of the curves], a bigger delta, between osimertinib alone vs osimertinib plus chemotherapy in this population.

Therefore, I have changed my practice. If I see a patient in my clinic with an EGFR exon 21 [mutation], or an EGFR mutation with brain metastases, my recommendation will be osimertinib plus chemotherapy based on the data from the FLAURA2 trial.

References

1. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR‑mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3
2. Solomon BJ, Ahn JS, Dziadziuszko R, et al. Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S1295-S1296. doi:10.1016/j.annonc.2023.10.051
3. 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