2023 Data Readouts Enable New Treatment Avenues in Oncogene-Driven NSCLC

In an interview with OncLive^®, Edgardo S. Santos Castillero, MD, FACP, the medical director at the Oncology Institute of Hope and Innovation in Broward County, Florida, discussed key updates in the treatment of targetable non–small cell lung cancer, providing updates from the 2023 ASCO Annual Meeting and ESMO Congress. Santos spotlighted some of the most impactful trials that were discussed during these meetings, including the phase 3 MARIPOSA-2 trial (NCT04988295).

He also explained what combination approaches may prove the most fruitful for the treatment of patients with NSCLC, and highlighted what he thinks the future of targeted therapy may bring, Additionally, Santos provided further insights on the EGFR-mutant paradigm in another interview.

OncLive: Please discuss some of the pivotal studies that have affected the treatment armamentarium in NSCLC.

Santos: At the 2023 ESMO Congress, the landmark MARIPOSA trial [NCT04487080] was presented. This is a complex study, but it is evaluating the use of amivantamab-vmjw [Rybrevant] plus lazertinib [Leclaza]. Lazertinib is a third-generation TKI that is not approved in the United States, though we are trying to combine an EGFR inhibitor plus a bispecific [antibody] like amivantamab. That [combination] was compared with osimertinib [Tagrisso] and lazertinib alone, and this was a blinded study. This [trial was conducted] in the first line for patients with advanced disease and EGFR-sensitive mutations. The study was positive for amivantamab plus lazertinib over osimertinib. There was an impressive progression-free survival of 23.7 months for amivantamab plus lazertinib, which was superior [to that seen with osimertinib alone].¹

What is more important is that we saw a 32% reduction in the risk of extracranial disease progression or death by blinded independent review committee with amivantamab plus lazertinib. What is also important is how the efficacy of amivantamab plus lazertinib [performed] in patients with brain metastases.

This [regimen] showed a very good response in patients with brain metastases; the hazard ratios in patients with or without brain metastases were similar. This [regimen] has not yet been approved by the FDA, but it is moving forward, and we are looking at the near future for approval of the novel combination.

Amivantamab is a monoclonal antibody that has a portion that will attack EGFR and lazertinib is an EGFR TKI. Therefore, we expect more toxicity in the EGFR domain such as rash, diarrhea, dermatitis, stomatitis, and so on. With osimertinib, [we see] expected toxicities. Something that was [new] with the combination was venous thromboembolic events, which was very important to note. There were similar numbers of fatal cases in both groups, but [a higher occurrence of events] were seen in the combination arm, although low in grade.

The combination is being analyzed by regulatory entities. If this combination is approved by the FDA, we will need to use anticoagulation [therapy with this regimen], at least for the first 4 months of therapy.

The phase 3 MARIPOSA-2 trial is being conducted in the second line for patients that progress on osimertinib in the first line. A pertinent question has been how to save a patient whose disease progressed after osimertinib. There are a lot of clinical trials ongoing in that regard. However, one that was also presented at the 2023 ESMO Congress was the MARIPOSA-2 trial. These data have shown that this combination of amivantamab plus chemotherapy could be another alternative.

This combination also showed a central nervous system [CNS] protective effect. The rate of metastases in this population progressing after osimertinib was low.

What combinations showed the most promise in 2023?

[We saw data with] the combination of encorafenib [Braftovi] and binimetinib [Mektovi] in patients with BRAF V600E [mutations]. Encorafenib and binimetinib have already been approved for patients with melanoma with the same kind of mutation. In lung cancer we saw an overall response rate [ORR] of 75%. Moreover, the toxicity profile is very good without the issue of pyrexia which we have seen with other combinations from past approvals by the FDA. [An example is the combination of] dabrafenib [(Tafinlar) and trametinib (Mekinist)] which we have been using for the past 4 years.

Now we have a novel combination with a comparable response rate and a better toxicity profile.

What targeted agents have shifted the treatment armamentarium for patients with NSCLC?

On November 15, 2023, repotrectinib [Augtyro] the novel ROS1 TKI was approved by the FDA. This is a ROS1 inhibitor with a very good ORR and good intracranial ORR. This is important because we need to continue developing drugs that has good CNS penetration. One of the more cumbersome adverse effects of the drug is dizziness.

Additionally, the phase 3 LIBRETTO-431 trial [NCT04194944], which was presented at the 2023 ESMO Congress, established selpercatinib [Retevmo] for patients with RET fusion alterations.

This study compared selpercatinib with chemotherapy with or without pembrolizumab [Keytruda]. Selpercatinib was superior in the intent-to-treat population in patients who received chemotherapy plus immunotherapy and those who received chemotherapy alone establishing selpercatinib as the preferred agent in this space.

Reference

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