Post WCLC 2024 Insights: Recent Advancements in Thoracic Malignancies

NSCLC is the most common type of lung cancer accounting for approximately 85% of all lung cancers (roughly 509,000 incident cases in 2019 [7MM: the US, EU4 and the UK, and Japan]). The real-world treatment trend depicts a significant shift towards targeted and immunotherapies (from only systemic therapies in the past), which is expected to contribute to the evolution of the NSCLC treatment Paradigm. The existing NSCLC treatment is mainly dominated by checkpoint inhibitors such as KEYTRUDA and OPDIVO. Regarding EGFR-positive NSCLC market size, third-generation EGFRs such as AstraZeneca’s TAGRISSO are expected to dominate. In biomarker-specific NSCLC cases, the most number of cases is from PD-L1 followed by KRAS, EGFR. 

The World Conference on Lung Cancer (WCLC) Annual Meeting, one of the important yearly events in lung cancer, took place recently. Discussing the most recent advancements in thoracic malignancy research, over 7,000 delegates attend from over 100 countries. Out of the entire data that was presented for lung cancer, some potential ones targeting a specific patient population, having a novel mechanism of action, or providing a new treatment option are cherry-picked and summarized below.

NSCLC is increasingly becoming a biomarker-driven market. EGFR is one of the profitable biomarker segments, with blockbuster therapies such as TAGRISSO. The total market size of EGFR-mutated NSCLC in the 7MM is expected to reach ~USD 8,500 million by 2032 with TAGRISSO expected to capture the maximum share. TAGRISSO is now the dominant EGFR inhibitor selling nearly USD 6 billion annually. 

Johnson & Johnson’s RYBREVANT (amivantamab-vmjw) is making its name in the EGFR NSCLC segment. Johnson & Johnson was aiming for a first-line label for RYBREVANT in its Phase III MARIPOSA study in combination with lazertinib. Additionally, RYBREVANT will have access to a larger patient cohort through the MARIPOSA-2 study, which accounts for up to 90% of all EGFR mutations in NSCLC. On August 19, 2024, the US Food and Drug Administration approved RYBREVANT + LAZCLUZE for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations based on MARIPOSA trial.

At WCLC 2024, RYBREVANT + LAZCLUZE (lazertinib) MARIPOSA trial data on symptom progression in EGFR-Mutated NSCLC was presented. The MARIPOSA trial compared RYBREVANT + LAZCLUZE to TAGRISSO (osimertinib) in EGFR-mutated NSCLC. The combination showed superior efficacy with the median time to symptomatic progression not reached vs. 29.3 months for osimertinib. At 18 months, symptomatic progression rates were 74% vs. 67%, and at 24 months, 67% vs. 59% for the combination and monotherapy, respectively. Safety profiles were consistent with previous reports, with higher rates of paronychia (68% vs. 28%), infusion-related reactions (63% vs. 0%), and rash (62% vs. 31%) in the combination arm. 

Due to their rarity and the lack of late-stage NSCLC clinical studies, the treatment paradigm for rare NSCLC segments is less clear. However, rare biomarkers like ROS-1, HER2, RET fusion, and NTRK1/2/3 Gene fusion have seen a lot of progress in the past few years. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. Comparing ROS1 TKIs in NSCLC, entrectinib shows superior efficacy to crizotinib in TKI-naive patients, especially for CNS metastases, with a 77% overall response rate (ORR) and 55% intracranial ORR. Lorlatinib demonstrates 62% ORR in TKI-naive and 35% ORR in crizotinib-pretreated patients. Taletrectinib, a novel ROS1 inhibitor, exhibits impressive results with 85.2% confirmed ORR (cORR) in TKI-naive and 61.7% in TKI-pretreated patients. Notably, duration of response (DOR) and progression-free survival (PFS) data remained immature in both cohorts at the time of this analysis. Taletrectinib’s intracranial ORR is 66.7% in TKI-naive and 56.3% in TKI-pretreated groups. Taletrectinib’s safety profile appears favorable, with mostly grade 1 gastrointestinal and neurological toxicities, potentially offering an advantage over other ROS1 TKIs. Taletrectinib is expected to enter the market in 2026 in the US, with projected revenue reaching approximately USD 160 million by 2032. This promising ROS1 inhibitor is expected to compete strongly against existing approved treatments in the ROS1 NSCLC market. Notably, it will face competition from AUGTYRO (repotrectinib), a recently approved therapy anticipated to lead the market with an estimated US revenue of USD 210 million by 2032. Taletrectinib’s market entry is likely to reshape the competitive landscape for ROS1-positive NSCLC treatments in the coming years.

In addition, there have been several advancements in the space of HER2-mutant NSCLC. In an ongoing Phase I/II SOHO-01 study, patients with HER2-mutant NSCLC are showing “rapid, substantial and durable responses” to Bayer’s breakthrough treatment BAY 2927088, according to data presented at WCLC 2024. Furthermore, in the Primary Phase Ib analysis of the Beamion LUNG-1 study, a new oral HER2-specific tyrosine kinase inhibitor called zondergetinib showed encouraging effectiveness in treating patients with HER2-mutant NSCLC. Zongertinib was given Fast Track Designation by the US Food and Drug Administration in November 2023 as an experimental treatment for patients with advanced/metastatic HER2 mutant NSCLC that have progressed after receiving platinum-based therapy.