Concurrent MET/EGFR inhibition and third-generation EGFR TKIs

The NEOSTAR trial

Effective treatment options are called for in patients with resectable non-small-cell lung cancer (NSCLC), as more than half of those with stage I to III disease experience relapses [1]. Chen et al. demonstrated in their animal model that tumor PD-L1 upregulation is critical for the spread and survival of metastases [2]. Based on these considerations, several clinical trials are investigating the potential benefits of immunotherapies in the neoadjuvant setting.

The randomized phase II NEOSTAR trial included 44 surgical candidates with stage I to IIIA NSCLC [3]. They were randomized to 3 doses of nivolumab 3 mg/kg on days 1, 15, and 29, or the same nivolumab schedule plus ipilimumab 1 mg/kg on day 1. Surgery was performed within 3 to 6 weeks after the last dose. Major pathological response (MPR), i.e., ≤ 10 % viable tumor cells, was defined as the primary endpoint. It was assumed that nivolumab and/or the combination will produce an MPR rate greater than the one achieved with induction chemotherapy as compared to historical controls. Among the 44 randomized patients, who made up the intent-to-treat (ITT) population, 23 received nivolumab alone, and 21 were treated with nivolumab plus ipilimumab. Thirty-nine patients underwent surgical resection.

Clinical benefits & increased T-cell infiltration

The MPR rate observed in the combination group met the pre-specified trial efficacy boundary. For the ITT population, it was shown that MPRs plus pathological complete responses (pCRs; i.e., 0 % viable tumor cells) occurred in 33 % of patients treated with both nivolumab and ipilimumab (Figure 1). With nivolumab alone, this was 17 %. In the resected population, the combination induced a 44 % MPR plus pCR rate, with pCR accounting for 38 % (MPR plus pCR for nivolumab, 19 %). Overall response rates (ORR) by RECIST according to imaging were 19 % and 22 %, respectively, in the ITT population. One patient in the combination arm (5 %) achieved complete response (CR); in both arms, a total of eight patients (36 %) had partial responses (PRs).

No unacceptable toxicity or increases of perioperative morbidity or mortality were observed. However, the authors noted that nodal immune flares deserve attention in the context of neoadjuvant immunotherapy, as patients might experience seeming radiographic nodal progression due to the emergence of granulomas that need to be distinguished from tumor growth. This is important as potentially curative surgery might be withheld if clinicians fail to differentiate between nodal immune flares and disease progression.

RECIST responses were shown to be positively associated with MPR rates. Elevated baseline PD-L1 expression correlated with radiographic responses and pathological tumor regression. In accordance with the improvement of response rates, immune characterization of surgical samples by flow cytometry revealed that the combined treatment was associated with higher frequencies of CD3-positive tumor-infiltrating lymphocytes as well as tissue resident and effector memory T cells. Moreover, nivolumab plus ipilimumab gave rise to increases of T cell repertoire diversity and reactivity in the tumor.

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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