Precision Medicine Highlights from WCLC 2024

Phase 1b FURTHER Trial: Efficacy of Firmonertinib at two dose level in TKI naïve, advanced NSCLC with EGFR PACC mutations¹.

The most common types of EGFR mutations in non-small cell lung cancer (NSCLC) are sensitizing mutations, such as L858R and exon 19 deletions. However, EGFR exon 20 insertions represent a distinct mutation type that confers resistance to conventional EGFR tyrosine kinase inhibitors (TKIs). Based on mutations located in the EGFR P-loop and αC-helix within exons 18–20, these can be classified as EGFR PACC (P-loop and αC-helix compressing) mutations, which account for approximately 12.5% of all EGFR mutations. PACC mutations share structural similarities with exon 20 insertions by narrowing the drug-binding pocket. The most frequent PACC mutation is G719X, followed by S768I and E709X. Additionally, C797S and G742S mutations have been identified as resistance mutations to osimertinib.

In the FURTHER trial, the efficacy of furmonertinib was evaluated for its antitumor activity in patients with EGFR PACC mutations (Cohort 4 - PACC cohort) at two dose levels. Based on blinded independent central review (BICR), the best objective response rate (ORR) was 47.8% in the 160 mg QD group and 81.8% in the 240 mg QD group. Tumor shrinkage was observed across more common mutations, such as G719X and S768I, as well as less frequent mutations like E709X and V774M. Furmonertinib also demonstrated promising CNS activity, with confirmed ORRs of 55.6% in the 160 mg QD group and 42.9% in the 240 mg QD group. Furmonertinib exhibited an acceptable and manageable safety profile, supporting further investigation in EGFR PACC-mutant NSCLC.

Targeting HER2 mutations in NSCLC, phase I/II SOHO-1 trial of BAY 2927088² and phase 1b Beamion-LUNG1 of zongertinib³.

At the 2024 World Conference on Lung Cancer (WCLC), two plenary presentations highlighted the potential of two promising HER2 tyrosine kinase inhibitors (TKIs). Despite advancements, HER2 mutations remain an area of significant unmet need in clinical practice, with the only US FDA-approved therapy for HER2-mutant NSCLC being Enhertu (trastuzumab deruxtecan). HER2 mutations are found in approximately 2–4% of non-small cell lung cancer (NSCLC) cases and are associated with poor prognosis. Notably, the HER2 exon 20 insertion mutation, Y772_A775dup (YVMA), accounts for 75% of all HER2-mutant NSCLC cases.

The SOHO-1 Cohort D study enrolled treatment-naïve patients with HER2-mutant NSCLC. The overall response rate (ORR) per investigator assessment was 72.1%, with a disease control rate (DCR) of 83.7%. The median duration of response (mDoR) was 8.7 months, and the median progression-free survival (mPFS) was 7.5 months. In a subgroup analysis, patients with the HER2 YVMA insertion mutation demonstrated an ORR of 90% and a DCR of 96.7%. The mPFS for patients with the YVMA insertion was 9.9 months, compared to 3.9 months in patients with other HER2 mutations.

Zongertinib, a selective HER2 TKI, demonstrated efficacy in a Phase 1b analysis of pretreated NSCLC patients harboring HER2 tyrosine kinase domain (TKD) mutations. The ORR by central review for the 120 mg dose group was 66.7%, with some patients continuing to show a durable response. Zongertinib also showed intracranial tumor activity, with a confirmed RANO-BM ORR of 33% in the 120 mg group and 40% in the 240 mg group. Both BAY 2927088 and Zongertinib have been granted Breakthrough Therapy Designation by the FDA.

The novel solution for HER2 overexpression (OE) after EGFR TKI or other cancer treatments by transtuzumab deruxtecan (T-DXd) monotherapy from phase 1b DESTINY-Lung03 trial⁴.

T-DXd (trastuzumab deruxtecan) has already received US FDA approval for HER2-positive (IHC 3+) pan-solid tumors. The DESTINY-Lung01 trial supported this HER2-positive indication in NSCLC, with an overall response rate (ORR) of 52.9% in the IHC 3+ subgroup. The phase 1b DESTINY-Lung03 trial is currently evaluating the safety and efficacy of T-DXd-based therapies in HER2-overexpressing (HER2-OE) NSCLC. Here, data from Arm 1D, which assessed T-DXd monotherapy in patients with HER2-OE who experienced disease progression following prior therapy, are reported. In Arm 1D, 52.8% (19/36) of enrolled patients had progressed after receiving EGFR TKIs.

In the overall population, the confirmed ORR was 44.4%. Subgroup analysis revealed that the ORR was 56.3% in the HER2 IHC 3+ group and 35% in the HER2 IHC 2+ group. Additionally, T-DXd demonstrated an ORR of 68.3% in patients previously treated with EGFR TKIs. The median progression-free survival (mPFS) was 8.2 months, and the median overall survival (mOS) was 17.1 months.

These data suggest that T-DXd is associated with improved outcomes compared to the current second-line standard of care (SOC) for HER2-OE NSCLC, particularly in patients with HER2-OE who develop resistance after EGFR TKI therapy. The authors recommend routine HER2 IHC testing in NSCLC, given that HER2-OE represents an actionable biomarker.

The biomarker analysis of PAPILLON trial to find out the clinical benefit of first-line (1L) amivantamab combined with chemotherapy (Ami-chemo) in paitients harboring EGFR exon 20 insertion (ex20ins) ⁵.

Amivantamab is an EGFR-MET bispecific antibody (BsAb) that has been approved by the US FDA in combination with chemotherapy for first-line treatment of NSCLC patients harboring EGFR exon 20 insertions (ex20ins). This biomarker analysis included the evaluation of TP53 co-mutations, ctDNA clearance of EGFR ex20ins, and insertion sites in the helical domain, near loop, and far loop regions to assess the efficacy of the amivantamab-chemotherapy (Ami-chemo) combination.

At baseline, ctDNA detection rates were similar between the two study arms (86% vs. 87%). After six weeks of treatment (C3D1), more patients in the Ami-chemo arm exhibited ctDNA clearance of ex20ins compared to the control arm (55% vs. 31%). Among patients with uncleared ctDNA, the median progression-free survival (mPFS) was 9.8 months in the Ami-chemo group, compared to 4.8 months in the control group. In patients with cleared ex20ins ctDNA, the mPFS was 12.2 months in the Ami-chemo group and 6.8 months in the control group.

Amivantamab-chemotherapy significantly prolonged PFS in both patients with and without TP53 co-mutations (11.1 months and 11.3 months, respectively), compared to the chemotherapy-only group (5.6 months and 8.5 months, respectively). The efficacy of Ami-chemo was consistent across different EGFR ex20ins regions, with mPFS values of 11.3 months in the near loop region, 9.4 months in the far loop region, and 11.1 months in the helical region.

Amivantamab combined with chemotherapy demonstrated superior treatment outcomes compared to chemotherapy alone, particularly in patients with high-risk disease biomarkers, including TP53 co-mutations and various EGFR ex20ins insertion sites.

Concomitant de novo MET amplification with EGFR mutations arises the attention in treatment naïve NSCLC patients since the widely use of next generation sequencing (NGS) in clinical practice. The Phase 2 FLOWER trail evaluated osimertinib with or without savolitinib in de novo MET aberrant, EGFR-mutant NSCLC⁶.

Limited data suggest that de novo MET amplification and MET overexpression (MET IHC 3+ in ≥ 50% of tumor cells) occur in approximately 2%–5% and 11%–15% of treatment-naïve EGFR-mutant (EGFRm) advanced NSCLC, respectively. The phase 2 FLOWER trial included patients with MET aberrations, defined as MET overexpression by IHC 3+ in ≥ 75% of tumor cells or MET amplification determined by FISH (MET gene copy number [GCN] ≥ 5 or MET/CEP7 ratio ≥ 2) or by tissue-based NGS (MET copy number variation [CNV] ≥ 5).

Cohort 1 received osimertinib monotherapy, while Cohort 2 received a combination of osimertinib plus savolitinib. Combination therapy demonstrated a clinically meaningful improvement in the primary endpoint, with an overall response rate (ORR) of 90.5%, compared to 60.9% with osimertinib monotherapy. Although progression-free survival (PFS) data are still immature, a positive trend favoring the combination therapy was observed, with a median PFS of 19.6 months versus 9.3 months for monotherapy.

These findings suggest that the combination of osimertinib and savolitinib has the potential to become a novel first-line treatment option for patients with EGFR-mutant NSCLC who also harbor de novo MET aberrations.

Patterns of progression with lorlatinib and insights into subsequent treatments efficacy in ALK-positive NSCLC⁷.

Although lorlatinib demonstrates remarkable antitumor activity in first-line (1L) ALK-positive NSCLC, with 60% of patients remaining progression-free after 5 years of follow-up, some patients still experience early progression (≤12 months). A comparison of the clinical and molecular characteristics between early progressors and those who remained progression-free after 5 years revealed that a higher proportion of early progressors had unconfirmed ALK positivity and TP53 mutations. However, the EML4-ALK variant subtypes did not distinguish between early progressors and non-progressors.

Among the 149 patients in the lorlatinib arm, 38 (26%) received subsequent therapies. Of these, 61% were treated with another ALK TKI, while others received chemotherapy-based regimens. The duration of treatment (DOT) on the first subsequent systemic therapy was longer for those receiving an ALK TKI compared to non-ALK TKI therapies (12.5 months vs. 6.7 months). The outcomes of subsequent treatments varied, with responses observed regardless of prior lorlatinib DOT or response.

Progression-free survival 2 (PFS2) was longer for patients who received lorlatinib (not reached [NR]) compared to those treated with crizotinib, whose PFS2 was 37.9 months. These PFS2 results indicate that clinical benefit is extended following lorlatinib treatment compared to crizotinib, and this benefit is maintained with subsequent systemic anticancer therapies.

1. Xiuning Le et al., FURTHER (FURMO-002): A Global, Randomized Study of Firmonertinib at Two Dose Levels in TKINaïve, Advanced NSCLC with EGFR PACC Mutations, 2024 WCLC, PL04.07.

2. Xiuning Le et al., Safety and Efficacy of BAY 2927088 in Patients with HER2-Mutant NSCLC: Expansion Cohort from the Phase I/II SOHO-01 Study, 2024 WCLC, PL04.03.

3. Gerrina Ruiter et al., Phase Ib Analysis of Beamion LUNG-1: Zongertinib (BI 1810631) in Patients with HER2-Mutant NSCLC, 2024 WCLC, PL04.04.  

4. Jame CH Yang et al., Trastuzumab Deruxtecan Monotherapy in Pretreated HER2-overexpressing Nonsquamous Non-small Cell Lung Cancer: DESTINY-Lung03 Part 1, 2024 WCLC, OA16.05.

5. Jonathan Goldman et al., PAPILLON: TP53 Co-mutations, Sites of Insertion, and ctDNA Clearance Among Patients With EGFR Ex20ins-mutated Advanced NSCLC, 2024 WCLC, MA12.06.

6. Jin-Ji Yang et al., Osimertinib with or without Savolitinib as 1L in de novo MET aberrant, EGFRm advanced NSCLC (CTONG 2008, FLOWERS): A Phase II trial, 2024 WCLC, PL04.10.

7. Tony S.K. Mok et al., Patterns of progression with lorlatinib and insights into subsequent anticancer therapy efficacy in advanced ALK+ NSCLC, 2024 WCLC, MA06.07.

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