Combination may be ‘new standard’ in EGFR-mutant non-small cell lung cancer
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Key takeaways:
- The amivantamab-lazertinib combination improved PFS compared with osimertinib.
- Results support the potential of this combination to be a standard of care, researchers concluded.
MADRID — The combination of amivantamab and lazertinib improved PFS compared with osimertinib as first-line treatment for EGFR-mutated advanced non-small cell lung cancer, according to study results presented at ESMO Congress.
The combination also induced longer median duration of response, findings of the randomized phase 3 MARIPOSA trial showed.
“Despite advances in EGFR-mutated NSCLC treatment, novel targeted therapies and regimens are needed to address resistance and disease progression, which are nearly inevitable with current treatments,” said Byoung Chul Cho, MD, PhD, medical oncologist and professor in the division of medical oncology at Yonsei Cancer Center in South Korea. “Amivantamab plus lazertinib represents a new standard of care [for] patients with first-line EGFR-mutant advanced NSCLC.”
Approximately 15% to 50% of nonsquamous advanced NSCLC cases harbor EGFR mutations.
Osimertinib (Tagrisso, AstraZeneca), a third-generation EGFR tyrosine kinase inhibitor, is the current standard first-line treatment; however, resistance and disease progression “are nearly inevitable,” Cho said.
Secondary EGFR and MET alterations may contribute to tumor resistance in up to half of cases, Cho said.
Amivantamab (Rybrevant, Janssen) is an EGFR-MET bispecific antibody. Lazertinib (Leclaza; Yuhan, Janssen) is a central nervous system-penetrant EGFR TKI.
These agents in combination exhibited antitumor activity in phase 1 research, and Cho and colleagues hypothesized that these agents used together could proactively address resistance and improve outcomes without use of chemotherapy.
In MARIPOSA, researchers assessed the amivantamab-lazertinib combination vs. osimertinib as first-line treatment for patients with EGFR-mutated locally advanced or metastatic NSCLC.
The trial included 1,074 patients (median age, 63 years; 62% women; 59% Asian; history of brain metastases, 41%).
Researchers randomly assigned them 2:2:1 to amivantamab-lazertinib (n = 429), osimertinib monotherapy (n = 429) or lazertinib monotherapy (n = 216). Baseline characteristics were balanced across treatment groups.
PFS by blinded independent central review served as the primary endpoint. Secondary endpoints included OS, objective response rate, duration of response, safety and PFS after first subsequent therapy.
All patients underwent CNS monitoring.
After median follow-up of 22 months, results showed the combination conferred a 30% reduction in risk for disease progression or death compared with osimertinib (median PFS, 23.7 months vs. 16.6 months; HR = 0.7; 95% CI, 0.58-0.85).
The combination improved PFS regardless of brain metastases history (with history, HR = 0.69; 95% CI, 0.53-0.92; no history, HR = 0.69; 95% CI, 0.53-0.89), and it also improved extracranial PFS (median, 27.5 months vs. 18.5 months; HR = 0.68; 95% CI, 0.56-0.83).
Researchers reported comparable ORRs between groups (86% vs. 85%); however, results showed longer median duration of response among confirmed responders in the combination group (25.8 months vs. 16.8 months).
Interim OS analysis showed a trend toward improved survival with the combination, although the difference did not reach statistical significance (HR = 0.8; 95% CI, 0.61-1.05). At 24 months, 74% of patients assigned the combination and 69% of those assigned osimertinib remained alive.
A higher percentage of patients assigned the combination experienced grade 3 or higher treatment-emergent adverse events (75% vs. 43%) or serious events (49% vs. 33%). Thirty-four patients (8%) assigned the combination and 31 (7%) assigned Osimertinib died due to adverse events.
Higher percentages of combination-treated patients required interruption (83% vs. 39%), reduction (59% vs. 5%) or discontinuation (35% vs. 14%) of any agent.
Rates of most EGFR- and MET-related adverse events appeared higher in the combination group; however, diarrhea occurred more frequently in the osimertinib group.
Researchers also reported a higher rate of venous thromboembolism in the combination group (37% vs. 9%); however, most were grade 1 or grade 2, developed early and could be managed with anticoagulants. Two patients (0.5%) in each group experienced VTE that led to death.
They reported low rates of interstitial lung disease/pneumonitis, with incidence around 3% in each treatment group.
Perspective
Back to TopZosia Piotrowska, MD, MHS
The FLAURA trial established osimertinib as our preferred first-line therapy. Osimertinib is an oral therapy that is generally well-tolerated and leads to a median PFS of about 19 months. Upon progression on osimertinib, most patients undergo a biopsy to look for targetable resistance mechanisms, but the majority receive carboplatin-pemetrexed as second-line therapy.
A number of TKI-based combination strategies have been evaluated in recent years, with the hope of improving our current first-line therapy. As we evaluate these new combinations, we have to keep in mind that our goal is to develop combinations that will improve PFS and OS while avoiding adding excessive toxicities to our current standard of care.
This is a positive study, with a clinically meaningful improvement in PFS. At this interim analysis, the difference in OS was not statistically significant, although you can start to see a slight separation of the curves.
The impact of OS is important to emphasize. If a new regimen extends PFS without improving OS, we risk that patients may spend more of their life on the new regimen, and quality of life becomes even more critical.
With that in mind, it is important to highlight the combination of amivantamab and lazertinib did increase toxicity compared with osimertinib. We also have to remember that amivantamab adds an IV therapy. There also were higher rates of dermatologic toxicities, infusion-related reactions and VTE in the amivantamab-lazertinib arm. We saw higher rates of discontinuation of any agent on the experimental arm and, among those patients who discontinued any agent, 145 of the 147 stopped amivantamab due to toxicity.
So,what was the impact of early amivantamab discontinuation? This will be important to evaluate to understand better whether patients need to continue amivantamab for the duration of first-line therapy. And although many of the dermatologic toxicities were low grade, chronic dermatologic toxicities can have a significant impact, particularly for patients who are remaining on first-line therapy for 2 years or more. We need a better understanding of the impact of this new therapy on patient quality of life, particularly given the long treatment duration. These analyses will be really important to understanding the role of [this] regimen in our clinics.
What will I do with a patient with newly diagnosed EGFR-mutant NSCLC in my clinic?
First-line osimertinib and — if approved, osimertinib/chemotherapy and amivantamab/lazertinib — all represent treatment options that should be discussed. Treatment will need to be individualized based on patient preferences but, for most patients, first-line osimertinib is likely to remain my preferred approach for now given the lack of OS benefit and toxicity concerns with combination regimens.
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Cho BC, et al. Abstract LBA14. Presented at: European Society for Medical Oncology Congress; Oct. 20-24, 2023; Madrid.
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