HER2 aberrations and other oncogenic drivers

HER2 mutations are rare as they occur in approximately 2–4 % of NSCLC cases, although they are associated with poor prognosis and increased incidence of brain metastases [1, 2]. As HER2-mutant NSCLC is relatively insensitive to chemo­therapy, there is a substantial unmet need for targeted options [3, 4]. The oral HER2-selective tyrosine kinase inhibitor (TKI) zongertinib binds selectively and covalently to the tyrosine kinase domain (TKD) of both wild-type and mutated HER2 receptors while sparing wild-type EGFR, thereby avoiding associated toxicities [5]. Single-agent zongertinib is being investigated in patients with locally advanced and/or metastatic NSCLC in the ongoing Beamion LUNG-1 and Beamion LUNG-2 trials.

Beamion LUNG-1 is an open-label, phase Ia/Ib dose-escalation study enrolling patients with HER2-aberration–positive advanced solid tumors. In phase Ia, patients with NSCLC (n = 34) experienced an objective response rate (ORR) of 50.0 % and a disease control rate (DCR) of 97.1 % [6]. The zongertinib doses selected for expansion were 120 mg and 240 mg QD.

Zongertinib in pretreated patients

Phase Ib of Beamion LUNG-1 is an ongoing dose-expansion study evaluating single-agent zongertinib in patients with advanced or metastatic HER2-mutant NSCLC with or without prior treatment. At WCLC 2024, Ruiter et al. presented data from Cohort 1 that included pretreated patients with a HER2 TKD mutation after ≥ 1 line of platinum-based combination chemotherapy [7]. They were randomized to either zongertinib 120 mg or 240 mg; after an interim futility analysis, the 120 mg dose was selected for further exploration. The data presented at WCLC pertained to 75 and 57 individuals receiving zongertinib 120 mg and 240 mg, respectively. Most were heavily pretreated, with 28 % and 23 %, respectively, having undergone ≥ 3 treatment lines. Asymptomatic untreated brain metastases were present in 37 % and 46 %, respectively.

After a median follow-up of approximately 13 weeks, the primary endpoint, which was the confirmed ORR by blinded independent review, was met for all patients treated with the 120 mg dose. In this group, the ORR was 66.7 %. The numbers listed in Table 1 represent the results for patients randomized 1:1 for both doses to allow for proper comparison. Tumor shrinkage of any magnitude occurred in 94 %. As two thirds of patients remained on treatment at data cut-off, median duration of response (DOR) and progression-free survival (PFS) findings were immature. Furthermore, zongertinib treatment showed encouraging preliminary intracranial activity, with best overall responses of 33 % and 40 % in the 120 mg and 240 mg cohorts, respectively. Intracranial DCRs were 74 % and 92 %, respectively.

Zongertinib therapy was well tolerated. The majority of treatment-related adverse events (TRAEs) were mild and manageable. Diarrhea was reported as the most frequent TRAE (48 % and 65 % with 120 mg and 240 mg, respectively). Only 1 % and 2 % of events, respectively, were grade 3. None of the patients developed grade 4 diarrhea. Rash ranked second, with all-grade rates of 24 % and 30 % in the two dose groups. Here, no grade ≥ 3 events occurred, and 19 % and 8 % were graded as 1 and 2, respectively. No fatal TRAEs were observed in the study. AEs gave rise to dose reduction in 11 % of patients, and 3 % had AEs leading to treatment discontinuation. In their conclusion, the authors noted that zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated NSCLC harboring a HER2 TKD mutation, including those with brain metastases.

Subanalysis of Beamion-LUNG 1

Opdam et al. reported a subgroup analysis of the Beamion LUNG-01 study that related to the clinical outcomes in the group with asymptomatic brain metastases at baseline [8]. In phase Ia, 26 % of 105 patients with solid tumors showed CNS lesions. Here, preliminary evidence of intracranial activity was observed. The phase Ib cohort comprised a total of 132 individuals 41 % of whom had brain metastases. Zongertinib treatment gave rise to similar ORRs in the groups with and without CNS lesions (70 % and 73 %, respectively), which was also true for the DCRs (94 % and 96 %, respectively). Regarding intracranial activity, the assessment yielded encouraging preliminary findings, with objective response and disease control rates of 37 % and 83 %, respectively. Nine patients (17 %) developed complete responses. The safety profile of zongertinib in patients with brain metastases was similar to that observed in the overall population, with most TRAEs being mild and low rates of dose reductions and discontinuations due to AEs.

The ongoing randomized phase III Beamion LUNG-2 trial is comparing first-line zongertinib 120 mg QD to standard-of-care treatment for patients with HER2-mutant advanced, non-squamous NSCLC (NCT06151574). Approximately 270 patients will be recruited at 160 sites across 30 countries.

SOHO-01: BAY 2927088

The oral, reversible HER2-inhibiting TKI BAY 2927088 has shown anti-tumor activity in the setting of advanced HER2-positive NSCLC [9]. At WCLC 2024, Le et al. presented preliminary safety and efficacy data from the expansion Cohort D of the ongoing open-label, first-in-human, phase I/II SOHO-01 trial [10]. This cohort comprised 44 patients with advanced HER2-mutant NSCLC who were naïve to HER2-targeted agents. Most of them had previously received platinum-based chemotherapy and immunotherapy.

In this pretreated group, BAY 2927088 20 mg BID led to rapid, substantial and durable responses. The ORR per investigator was 72.1 %, and 83.7 % of patients achieved disease control. After a median follow-up of 10.9 months, 36.4 % remained on treatment, with treatment duration > 12 months observed in 31.8 %. Median PFS and median DOR were 7.5 and 8.7 months, respectively. Seventy percent of patients showed the HER2 Y772_A775dup (YVMA) insertion. In this group, 90 % responded, and disease control resulted in 96.7 %; median PFS and median DOR were 9.9 and 9.7 months, respectively.

The safety profile of BAY 2927088 was manageable and consistent with previous reports. Diarrhea was the most common TRAE (all grades, 86.4 %; grade ≥ 3, 25.0 %), followed by rash (all grades, 43.2 %; no grade ≥ 3 events). While no grade 4 TRAEs occurred, one grade 5 event (dyspnea) was reported. None of the patients developed interstitial lung disease (ILD)/pneumonitis. Approximately 32 % had dose reductions due to TRAEs, and in 6.8 %, TRAEs required discontinuation. Taken together, these data support the investigation of BAY 2927088 in the setting of advanced HER2-mutant NSCLC. The global, open-label, phase III SOHO-02 trial is currently exploring first-line treatment with BAY 2927088 vs. the standard of care in patients with activating HER2 mutations (NCT06452277).T-DXd in

T-DXd in HER2-overexpressing NSCLC

HER2 overexpression (IHC 3+/2+) is present in 3-20 % of NSCLCs and has been demonstrated to correlate with poor patient prognosis [11-17]. In the DESTINY-Lung01 study, the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has proven effective in patients with HER2 overexpression, giving rise to ORRs of 34.1 % and 52.9 % in the overall group and in those with IHC 3+ [18]. The ongoing multicenter, open-label, phase Ib DESTINY-Lung03 trial is currently investigating T-DXd in patients with HER2-overexpressing, advanced, non-squamous NSCLC. Enrollment into Parts 1, 3 and 4 of the study occurred after one or two lines of previous treatment, with patients who harbored targetable alterations having received appropriate targeted therapy. In Arm 1D of Part 1, single-agent T-DXd 5.4 mg/kg was administered Q3W to 36 patients. Their prior therapies included targeted agents in 58.3 % (EGFR TKIs, 52.8 %), platinum chemotherapy in 38.9 % and immunotherapy in 22.2 %. Approximately one third of patients had CNS metastases at baseline.

According to the analysis reported at WCLC 2024 by Planchard et al. for Arm 1D of the DESTINY-Lung03 trial [19], the findings corroborated the clinical benefit of T-DXd monotherapy, building on the results observed in the DESTINY-Lung01 study. The confirmed ORR was 44.4 %, and the DCR rate at 12 weeks was 77.8 %. Responses lasted for a median of 11.0 months. Median PFS and overall survival (OS) were 8.2 and 17.1 months, respectively. Exploratory analyses evaluating the efficacy outcomes by HER2 IHC status and prior EGFR TKI exposure showed promising activity across subgroups (Table 2).

No new safety signals were identified. Nausea was the most common drug-related AE (52.8 %), followed by vomiting and fatigue (30.6 % each). Drug-related AEs necessitated dose reductions in 19.4 % and discontinuations in 8.3 %. Adjudicated drug-related ILD/pneumonitis occurred in 5.6 % and was restricted to grade 2. Overall, these data suggest that T-DXd induces improved outcomes over current second-line standard-of-care treatment for metastatic HER2-overexpressing NSCLC. The results reinforce HER2 expression as an actionable biomarker and highlight the need for HER2 IHC testing as part of the routine diagnostic work-up.

Olomorasib plus pembrolizumab and chemotherapy

The combined administration of targeted therapy and chemoimmunotherapy represents an opportunity to further improve upon outcomes in the first-line treatment of patients with advanced NSCLC. Fujiwara et al. presented the first results for the combination of the potent second-generation KRAS^G12C inhibitor olomorasib with pembrolizumab and chemotherapy in patients with KRAS^G12C-mutant advanced NSCLC who were included in Cohort B9 of the phase Ia/Ib LOXO-RAS-20001 study [20]. This group comprised 21 treatment-naïve individuals. Up to one 21-day cycle of any combination of pembrolizumab, pemetrexed, and carboplatin or cis­pla­tin was permitted prior to enrollment, which was the case in 43 % of patients. Prior (neo)adjuvant therapy was allowed, provided that the last dose had been completed ≥ 6 months prior to enrollment. The analysis explored two doses of olomorasib (50 mg and 100 mg BID). PD-L1 positivity was not mandatory; in fact, 91 % of tumors were PD-L1–low or PD-L1–negative.

Olomorasib plus pembrolizumab and chemotherapy demonstrated a manageable safety profile. Cytopenias were consistent with those reported for first-line combinations of chemotherapy with targeted agents. High-grade cytopenias were common but rarely resulted in delay and/or discontinuation of the subsequent chemotherapy cycle. No case of febrile neutropenia occurred. In terms of efficacy, the combination regimen induced an ORR of 50 % and a DCR of 85 %. Responses were seen in patients with PD-L1–low and PD-L1–negative tumors at both dose levels of olomorasib. Tumor shrinkage occurred early on and often deepened over time. Seventy-six percent of patients remained on treatment at data cut-off.

The authors noted that these findings support the feasibility of incorporating second-generation KRAS^G12C inhibitors into standard-of-care first-line chemoimmunotherapy regimens. At present, the global registrational phase III SUNRAY-01 study is assessing olomorasib plus pembrolizumab and chemotherapy in untreated patients with KRAS^G12C-mutant advanced NSCLC.

ROS1-positive NSCLC: data on taletrectinib from TRUST-II

The global phase II TRUST-II study is evaluating the ROS1 inhibitor taletrectinib 600 mg QD in patients with ROS1-positive advanced NSCLC. Cohort 1 enrolled individuals who were ROS1-TKI-naïve, while those in Cohort 2 had already received one line of therapy with a ROS1 TKI. Liu et al. reported results for 55 and 50 patients in cohorts 1 and 2, respectively, both of which contained patients from Asian and non-Asian regions [21]. Brain metastases were present in 34.5 % and 56.0 %, respectively. Eighty percent in the pretreated cohort had previously received crizotinib, whereas 20 % had been treated with entrectinib. The safety population (n = 159) included the two cohorts and an additional patient group that was more heavily pretreated.

The TKI-naïve group achieved a confirmed ORR of 85.2 %. In the cohort with measurable brain metastases at baseline, the intracranial ORR was 66.7 % (Figure 1). TKI-pretreated patients, on the other hand, responded to taletrectinib in 61.7 %, and the intracranial ORR was 56.3 %. Notably, the efficacy of the study drug was not affected by the type of pretreatment (crizotinib vs. entrectinib) nor by patient origin (Asians vs. non-Asians). At the time of the analysis, DOR and PFS were immature for both Cohort 1 and Cohort 2.

The main toxicity observed with taletrectinib was asymptomatic ALT and AST elevations followed by gastrointestinal toxicity including diarrhea, nausea and vomiting that were mostly grade 1 and self-limiting. Dysgeusia and dizziness occurred in 19.5 % and 17.0 %, respectively, with practically all of these events being grade 1 and none being grade ≥ 3. In 37.1 %, treatment-emergent AEs led to dose reduction, and in 1.3 %, discontinuation was necessary due to TRAEs. No fatal TRAEs were reported. In their conclusion, the authors emphasized that with full enrollment of patients in geographically diverse regions, taletrectinib continues to demonstrate meaningful efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-positive NSCLC.

Figure 1: Intracranial responses with taletrectinib in TKI-naïve patients with ROS1-positive NSCLC

Early progressors and subsequent therapy in CROWN

In the setting of ALK-positive NSCLC, the global, phase III CROWN study has revealed prolonged benefit with first-line lorlatinib vs. crizotinib after five years of follow-up [22]. While median PFS had not been reached yet in the experimental arm, this was 9.1 months in the control arm (HR, 0.19). Sixty percent vs. 8 % of patients were progression-free at 60 months. Median time to intracranial progression had not been reached and was 16.4 months, respectively.

Mok et al. compared the clinical and molecular characteristics of early progressors in the experimental arm, i.e. patients who progressed during the first year (n = 28), with those of patients who remained progression-free after five years of treatment (n = 45) [23]. Most clinical features such as age, ECOG performance status and the presence of brain metastases at baseline did not differ notably across the two groups; however, the tumor burden was higher in early progressors than in non-progressors (mean, 84.9 vs. 54.7 mm). At the genomic level, no difference was observed across EML4–ALK variants, whereas higher proportions of early progressors, as compared to non-progressors, had unconfirmed ALK positivity (50 % vs. 22 %) and TP53 mutations (57 % vs. 22 %).

Moreover, the researchers analyzed the nature and results of first subsequent treatment. The data showed that 26 % vs. 74 % of patients had received ≥ 1 subsequent anticancer therapy. Regarding the number of subsequent therapies, a similar pattern emerged between the two arms. Most patients in both arms underwent only one subsequent treatment line (55 % vs. 57 %). Sixty-one percent vs. 93 % received ALK TKIs as their first subsequent anticancer therapy, with alectinib being the most commonly prescribed agent. Chemotherapy with or without anti-angiogenic compounds was administered in 34 % of the lorlatinib group but hardly in any patients of the crizotinib group (4 %). The duration of ALK TKI treatment as first subsequent therapy was similar across the arms (12.5 vs. 15.8 months). PFS2, which was defined as the time from randomization to the date of disease progression with the first subsequent systemic anticancer therapy or death, was significantly longer in the lorlatinib arm (not reached vs. 37.9 months; HR, 0.43; Figure 2). This indicated that the clinical benefit was prolonged following lorlatinib vs. crizotinib and maintained with subsequent systemic anticancer therapies.

Figure 2: Significantly improved progression-free survival 2 after the first subsequent treatment in the lorlatinib and crizotinib arms of the CROWN study

Selpercatinib: no effect of fusion partners

The clinical benefit of the highly selective and potent RET inhibitor selpercatinib has been demonstrated in the phase I/II LIBRETTO-001 study and was confirmed in the phase III LIBRETTO-431 trial [24, 25]. As previous studies have suggested that the efficacy of RET-selective inhibitory drugs in NSCLC might depend on specific RET fusion partners [26, 27], Solomon et al. examined this relationship in a combined cohort of patients from LIBRETTO-001 and LIBRETTO-431 who had known RET fusion partners (n = 415) [28]. The most commonly identified fusion partners were KIF5B-RET (71.6 %) and CCDC6-RET (21.2 %). PFS, ORR and DOR were compared among patients with KIF5B-RET (n = 297), CCDC6-RET (n = 88) or OTHER-RET (n = 30) fusion partners.

The findings indicated that the efficacy of selpercatinib is durable and robust regardless of the type of fusion partner. Although the ORR was higher in the CCDC6-RET group, all groups showed high response rates. Responses were durable, with median DOR not having been reached in the CCDC6-RET cohort compared to 20.3 and 17.6 months in the KIF5B-RET and OTHER-RET groups, respectively. Likewise, PFS was longer for selpercatinib-treated patients from either study vs. chemotherapy with or without pembrolizumab. The authors summarized that these results further support early and comprehensive genomic testing to identify RET fusions and use first-line selpercatinib therapy in patients with advanced RET-positive NSCLC.

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