MARIPOSA: long-term results for amivantamab/lazertinib

The EGFR-MET bispecific antibody amivantamab in addition to the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib has shown favorable results as first-line treatment compared to osimertinib in the ongoing randomized, double-blind, phase III MARIPOSA trial. A total of 1,074 patients from 27 countries with advanced non–small-cell lung cancer (NSCLC) and activating EGFR mutations were enrolled in the study. Both the amivantamab/lazertinib arm and the osimertinib arm included 429 patients. After a median follow-up of 22.0 months, amivantamab/lazertinib, as compared to osimertinib, significantly improved progression-free survival (PFS), which was defined as the primary endpoint of the MARIPOSA study (HR, 0.70; p < 0.001) [1, 2]. Also, the analysis revealed a trend regarding overall survival (OS) in favor of the combination (HR, 0.80). Gadgeel et al. presented the results for the two arms after a longer follow-up of 31.1 months at WCLC 2024 [3].

The findings continued to demonstrate advantages of first-line amivantamab/lazertinib over osimertinib. For OS, there was a strong trend with 36-month rates of 61 % vs. 53 % (HR, 0.77; p = 0.019). The Kaplan-Meier curves separated early on and widened over time. Moreover, central nervous system (CNS) control proved durable in the experimental arm. At three years, 51 % vs. 0 % of patients were intracranial responders (Figure 1), and the intracranial PFS rate was double for amivantamab/lazertinib vs. osimertinib (38 % vs. 18 %; HR, 0.82; p = 0.165). Median intracranial duration of response had not been achieved in the experimental arm and was 24.4 months in the control arm.

Likewise, the combination showed benefits with respect to time to treatment discontinuation (26.3 vs. 22.6 months; HR, 0.80; p = 0.014) and time to subsequent therapy (30.0 vs. 24.0 months; HR, 0.77; p = 0.005). A greater proportion of patients in the amivantamab/lazertinib arm remained on study treatment at three years (40 % vs. 29 %), and 45 % vs. 32 % had not yet started their first subsequent therapy. Regarding PFS2, i.e. PFS after the first subsequent therapy, amivantamab/lazertinib led to a significant 27 % risk reduction; after 36 months, 57 % vs. 49 % of patients were progression-free (HR, 0.73; p = 0.004). As the authors noted, amivantamab plus lazertinib improves long-term outcomes compared to osimertinib based on its multi-targeted mechanism.

Figure 1: Duration of intracranial response with amivantamab/lazertinib vs. osimertinib in the MARIPOSA trial

Lazertinib vs. osimertinib in MARIPOSA

The third arm of the MARIPOSA study contains 126 patients treated with lazertinib monotherapy. This group has been included to evaluate the contribution of the individual components of the amivantamab/lazertinib combination. An exploratory analysis comparing lazertinib with osimertinib was reported at WCLC 2024 [4]. MARIPOSA is the first randomized, double-blind trial to prospectively assess two third-generation EGFR TKIs.

The data revealed comparability of the two agents across clinical efficacy endpoints. Objective responses resulted in 85 % vs. 83 % with lazertinib vs. osimertinib (p = 0.57), and median duration of response was approximately 17 months for both arms. Likewise, median PFS did not differ (18.5 vs. 16.6 months; HR, 0.98; p = 0.86), which was also true for high-risk subgroups, i.e. patients with brain metastases (HR, 0.90), detectable circulating tumor DNA at baseline (HR, 0.88), and TP53 co-mutations (HR, 0.85). A preplanned analysis of the time to symptomatic progression demonstrated comparable results (not estimable vs. 29.3 months; HR, 0.85; p = 0.27). For OS, the curves were almost superimposable (HR, 1.00), although these are early results.

In terms of safety, no unexpected signals emerged in either arm. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 for both agents. Serious AEs were reported in 33 % vs. 35 %, with low and comparable rates of treatment-related discontinuations (3 % vs. 5 %). However, the AE profiles differed across the arms due to the specific characteristics of lazertinib that include high selectivity for mutant EGFR and minimal inhibition of HER2 [5-7]. While diarrhea, thrombocytopenia and neutropenia occurred less commonly with lazertinib than with osimertinib, lazertinib had comparatively higher rates of rash, muscle spasms, and paresthesia. Fewer patients on lazertinib developed left-ventricular ejection fraction rates below the lower limit of normal and > 10 % absolute decreases from baseline (1 % vs. 4 %; p = 0.056). The percentage of those with QT interval prolongation > 450 msec was significantly lower in the lazertinib arm (9 % vs. 17 %; p = 0.005).

Consolidation with aumolertinib after CRT

Another third-generation EGFR TKI is aumolertinib that has shown efficacy in both first- and second-line treatment of EGFR-mutant NSCLC [8, 9]. The placebo-controlled phase III POLESTAR study is investigating aumolertinib in patients with locally advanced, unresectable stage III NSCLC harboring sensitizing EGFR mutations who have shown no progression during or after definitive chemoradiotherapy (CRT). In this setting, the PD-L1 inhibitor durvalumab represents the standard of care, although the specific benefit of consolidation immunotherapy regarding EGFR-mutated tumors remains uncertain [10]. POLESTAR included 147 patients who were enrolled at 43 sites across China. The randomization occurred within six weeks after the last dose of CRT. PFS was defined as the primary endpoint. At WCLC 2024, Meng et al. presented a preplanned interim analysis after a median follow-up of 16.4 months for aumolertinib and 14 months for placebo [11]. The modified intention-to-treat set for the efficacy assessment included 92 and 50 patients treated with aumolertinib and placebo, respectively.

Aumolertinib, as compared to placebo, induced a statistically and clinically significant PFS improvement according to blinded independent review (BICR; median PFS, 30.4 vs. 3.8 months; HR, 0.20; p < 0.0001; Figure 2). At 12 months, 69 % vs. 21 % of patients were alive and progression-free. The subgroup analysis showed consistent PFS benefits across the predefined cohorts. Likewise, the objective response rate (ORR) was significantly higher with aumolertinib (57 % vs. 22 %; OR, 4.58; p < 0.0001), as was the disease control rate (96 % vs. 74 %; OR, 8.53; p = 0.0001). Median OS had not been reached in either group. New lesions by BICR were observed in 20.7 % vs. 58.0 % of patients, with brain metastases noted in 7.6 % vs. 16.0 % and lesions of the abdomen and bone in 1.1 % vs. 8.0 % each. For median time to death or distant metastasis, the analysis revealed a significant risk reduction in the experimental arm (HR, 0.21; p < 0.0001). This also applied to CNS PFS (HR, 0.33; p = 0.0270).

The overall safety profile of aumolertinib after CRT was tolerable and manageable. AEs led to treatment interruption and discontinuation in 13.8 % and 2.1 % , respectively. Treatment reductions were necessary in 4.3 %. The most common AEs included increases in blood creatine phosphokinase (all grades, 46 %; grade ≥ 3, 6 %), radiation pneumonitis (all grades, 45 %; no grade ≥ 3 events), and white blood cell count decreases (all grades, 31 %; no grade ≥ 3 events). Overall, these findings suggest aumolertinib as a novel treatment option after CRT for patients with unresectable stage III, EGFR-mutated NSCLC.

Figure 2: Aumolertinib vs. placebo after definitive chemoradiotherapy of unresectable EGFR-mutated stage III NSCLC: progression-free survival

Firmonertinib in NSCLC harboring EGFR PACC mutations

Among third-generation EGFR TKIs, firmonertinib (previously known as furmonertinib) and its major metabolite AST5902 have the distinction of being active against EGFR P-loop and αC-helix compressing (PACC) mutations, while the EGFR wildtype is spared at commonly used dose levels [12]. PACC mutations account for approximately 12.5 % of all EGFR mutations and can be found as single or compound mutations [12, 13]. Similar to exon 20 insertion mutations, they narrow the drug-binding pocket, thus affecting TKI activity. For patients with PACC mutations, no standard-of-care first-line therapies have been established to date. Firmonertinib shows broad activity and selectivity across EGFR mutations [14].

Results from the PACC Cohort of the global FURTHER study evaluating firmonertinib at two dose levels were reported at WCLC 2024 [15]. In this cohort, patients with EGFR-TKI–naïve, advanced NSCLC harboring EGFR PACC mutations were randomized to firmonertinib 160 mg QD or 240 mg QD. Enrollment of patients with asymptomatic brain metastases without prior radiotherapy was allowed. Overall, 31 and 29 individuals received 160 mg and 240 mg, respectively. The cohort contained both first-line and pretreated patients. Among those treated in the first-line setting, 25 and 22 were allocated to the 160 mg and 240 mg groups, respectively. Forty sites in ten countries participated in the FURTHER study. The ORR by BICR constituted the primary endpoint.

Firmonertinib showed promising antitumor activity in a broad range of patients with PACC-mutant NSCLC. In the group treated in the first-line setting, the confirmed ORRs were 34.8 % and 63.6 % by BICR for the 160 mg and 240 mg dose groups, respectively (Table). Disease control was achieved in 91.3 % and 100 %, respectively. Confirmed partial responses occurred in patients with both more frequent (G719X, S768I) and less frequent (E709X, V774M) EGFR PACC mutations, as well as in those with single and compound PACC mutations. The majority of patients demonstrated responses already at first tumor assessment. At the time of the analysis, 90.9 % of responders were still on treatment, with PFS and OS data being immature.

Moreover, firmonertinib showed encouraging CNS activity. In the response-evaluable CNS population, the confirmed CNS ORRs were 55.6 % and 42.9 % for the 160 mg (n = 9) and 240 mg (n = 7) groups, respectively. In the first-line cohort (n = 13), 46.2 % of patients responded. CNS disease control rates ranged from 84.6 % to 88.9 %. The safety profile was acceptable and manageable. According to the data for the entire PACC cohort, reductions were necessary in 12.9 % and 24.1 % of the 160 mg and 240 mg dose groups, respectively, while none of the patients discontinued treatment. TRAEs of clinical interest primarily included diarrhea, liver enzyme elevation, rash and stomatitis. In their entirety, these data support further investigation of firmonertinib as once-daily oral therapy of patients with NSCLC and EGFR PACC mutations.

Osimertinib plus savolitinib: FLOWERS

According to preclinical studies, the coexistence of EGFR mutations and MET amplification/overexpression reduces the sensitivity to EGFR TKIs and is presumably a key mechanism of primary resistance to first-line EGFR TKI monotherapy [16-18]. In treatment-naïve patients with EGFR-mutant NSCLC, de novo MET amplification and MET overexpression are found in 2-5 % and 11-15 %, respectively [19-22]. The open-label, randomized, phase II FLOWERS study was designed to test the combination of osimertinib and the highly selective MET TKI savolitinib as first-line treatment of patients with advanced NSCLC that demonstrated both EGFR mutations and MET aberrations including MET overexpression and/or MET amplification. Twenty-one patients were treated with the combination, while 23 included in the control arm received osimertinib only.

Regarding the primary endpoint, which was the confirmed ORR, osimertinib plus savolitinib showed superiority over os­imertinib monotherapy (90.5 % vs. 60.9 %) after a median follow-up of 8.2 months [23]. Disease control resulted in 95.2 % vs. 87.0 %. Patients treated with the combination experienced deeper and more durable responses; median best reductions in tumor size were -47.7 % vs. -42.2 %, and median duration of response was 18.6 vs. 8.4 months. PFS findings were not mature but trended in favor of osimertinib/savolitinib (19.6 vs. 9.3 months; HR, 0.59), with 12-month PFS rates of 65.5 % vs. 49.0 %.

The safety profiles of the combination and osimertinib monotherapy were as expected, tolerated and manageable. In the osimertinib/savolitinib-treated arm, treatment-related AEs (TRAEs) primarily comprised rash, thrombocytopenia, peripheral edema, and ALT increases. Most TRAEs were grade 1 or 2, and no fatal AE occurred in either cohort. Treatment-related TEAEs leading to dose reduction were observed in 23.8 % vs. 0 %, which also applied to those leading to permanent discontinuation. As the authors pointed out, osimertinib plus savolitinib has the potential to represent a novel first-line option in the setting of advanced NSCLC with both EGFR mutations and de novo MET aberrations.

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