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ELCC 2025 Highlights

CME

Highlights of the 2025 European Lung Cancer Congress

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: May 27, 2025

Expiration: November 26, 2025

David Planchard
David Planchard, MD, PhD
CME/CE Information

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SOHO-01: Phase I/II Study of BAY 2927088 for Previously Treated HER2-Mutant NSCLC

Now I shift the discussion from EGFR mutations to HER2-mutant NSCLC. HER2 is also an important pathway with mutations occurring in 1% to 4% of patients with NSCLC.33 These mutations are often associated with poor prognosis.34 We often treat patients with advanced NSCLC and HER2 mutations following first-line therapy with ADCs like trastuzumab deruxtecan (T-DXd), which have shown high efficiency in this population.35,36

The phase I/II SOHO-01 trial is evaluating an experimental HER2-targeted tyrosine kinase inhibitor (TKI), BAY 2927088, to treat patients with previously treated advanced NSCLC and HER2-activating mutations.37-39 It is one of the first highly specific TKIs that has been studied in this population and has been granted Breakthrough Therapy designation by the FDA for the treatment of patients with previously treated unresectable or metastatic NSCLC with HER2-activating mutations because of the preclinical and early-phase efficacy data.

The dose-escalation phase of SOHO-01 enrolled patients with advanced NSCLC and EGFR and/or HER2 mutations and progressive disease after ≥1 previous systemic treatment and determined that further study would be performed with a 20-mg twice-daily dose with oral tablets. At ELCC 2025, Girard and colleagues presented data from 2 expansion cohorts of patients with HER2-activating mutations that never received previous HER2-targeted therapy (cohort D; n = 44) or who did have prior HER2-targeted ADC treatment (cohort E; n = 34).40 The primary endpoints were safety, tolerability, and pharmacokinetics with secondary endpoints of ORR, PFS, DoR, and disease control rate.

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SOHO-01: Baseline Characteristics

Both cohort patient populations were typical for patients with HER2-activating mutations. Patients were primarily never smokers (70.5% in cohort D and 64.7% in cohort E) or former smokers (25.0% and 32.4%), and nearly all patients in both cohorts previously received chemotherapy with or without immunotherapy (97.8% and 82.4%).40 In cohort E, most patients also received prior T-DXd therapy, which is considered a SoC in this population. BAY 2927088 was primarily administered as a second-line and third-line treatment across the combined cohorts (68.2% of cohort D and 47.0% of cohort E).

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SOHO-01: ORR by Investigator

The ORRs of this study were impressive, particularly in cohort D because those patients had no previous HER2-targeted therapy. The 70.5% ORR of this population showed good treatment efficacy.40 Even in the patient population that previously received HER2 ADCs, ORR was 35.3%.

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SOHO-01: Treatment Duration and DoR

Cohort D experienced longer treatment durations than cohort E, with 36.4% vs 11.8% of patients undergoing more than 12 months of treatment and median treatment duration of 7.16 months vs 4.83 months.40 Yet both cohorts demonstrated promising data for their respective populations. The DoR of both cohorts was similar (8.7 vs 9.5 months), so it appears that when a patient responds, the response is durable.

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SOHO-01: Treatment-Related Adverse Effects

There were no unexpected adverse effects in the expansion phase of the study.40 The most common adverse effect was diarrhea, which was experienced by most patients of both cohorts as grade ≤3 AEs. Fortunately, no patients discontinued treatment because of diarrhea, but this is an AE that should be anticipated when using BAY 2927088. The next most common AEs were dermatologic or gastrointestinal, including rash and nausea.

Of note, no interstitial lung disease or pneumonitis AEs were reported, which may be an advantage of this drug compared with HER2-targeted ADCs that tend to have significant pulmonary toxicity.41

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SOHO-01: Conclusions

In conclusion, these data from the expansion cohort of SOHO-01 confirmed that BAY 2927088 has notable efficacy and a manageable safety profile for the treatment of patients with NSCLC and HER2-activating mutations after prior systemic treatment.40 BAY 2927088 efficacy was particularly high in patients who were naive to HER2-targeted therapy, although efficacy was still substantial in patients previously treated with HER2-directed ADCs. BAY 2927088 is currently being evaluated as a first-line therapy in the phase III SOHO-02 trial, which is randomizing patients with locally advanced or metastatic NSCLC and HER2 mutations to the experimental agent vs platinum-based chemotherapy (NCT06452277). If the SOHO-02 results are positive, we would likely see FDA approval for this agent.

EMPOWER-Lung 1: Cemiplimab Continuation Plus Chemotherapy After Progression on First-Line Cemiplimab Monotherapy in Advanced NSCLC

Lastly, I discuss the extended results of the phase III EMPOWER-Lung 1 trial that aimed to test cemiplimab monotherapy vs chemotherapy in the first line for patients with advanced NSCLC and high PD-L1 levels.42 This study randomized previously untreated patients with PD-L1 ≥50%, no EGFR, ALK, or ROS1 mutations to cemiplimab or 4-6 cycles of investigator’s choice of chemotherapy.43,44 Positive OS and PFS results led to FDA approval of cemiplimab in this setting.

A retrospective study found that patients with advanced NSCLC benefited from chemotherapy after progression on an immune checkpoint inhibitor with median PFS of 4.1 months.45 This motivated investigators to examine this strategy in the EMPOWER-Lung 1 study. Patients who were randomized to the cemiplimab arm or who had crossed over from the chemotherapy arm and experienced progression on first-line cemiplimab were allowed to continue the immunotherapy with the addition of 4 chemotherapy cycles. The analysis presented at ELCC 2025 was a 5-year follow-up of patients who chose the continued therapy and had received at least 1 dose of chemotherapy.

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EMPOWER-Lung 1 Cemiplimab After Progression: Baseline Characteristics

The median age of patients who continued cemiplimab with chemotherapy (n = 73) was 64 years, which is typical for patients with advanced NSCLC,42 and 20.5% of patients had PD-L1 expression levels >90%, with a majority (57.5%) having levels >60%.

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EMPOWER-Lung 1 Cemiplimab After Progression: Response, PFS, and OS

ORR was similar for the patients after initial cemiplimab monotherapy (35.6%) and after the added chemotherapy (27.4%).42 The DoR was extended to 11.5 months with the second-line chemotherapy and continued cemiplimab, compared with 7.7 months for the first-line cemiplimab. There was also a positive trend in PFS with a median PFS of 6.4 months compared with 4.8 months. 

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EMPOWER-Lung 1 Cemiplimab After Progression: Safety

As expected, the addition of chemotherapy increased rates of AEs like anemia, nausea, and alopecia.42 There were some treatment discontinuations and treatment-related deaths, but overall no new safety signals were observed.

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EMPOWER-Lung 1 Cemiplimab After Progression: Conclusions

Chemotherapy with immunotherapy after first-line immunotherapy is a strategy currently used in clinical practice for the treatment of advanced NSCLC. This exploratory analysis of EMPOWER-Lung 1 suggests that there may be a measurable benefit to this strategy after first-line cemiplimab for patients with advanced NSCLC and PD-L1 ≥50% with no EGFR, ALK, or ROS1 mutations. The median PFS of 6.4 months was also longer than the historical data of platinum-based chemotherapy after progression on an immune checkpoint inhibitor (median PFS of approximately 3-4 months).45

However, these data should be cautiously interpreted, as this extended analysis was not randomized and may include patients with better prognosis who chose to continue cemiplimab with added chemotherapy. There was also no direct comparator treatment in this extended study. Therefore, the promising efficacy results would need to be confirmed in a prospective randomized phase II trial before making this treatment a SoC practice.

Which of the following patient subpopulations with locally advanced or metastatic EGFR-mutated NSCLC and progression on first-line osimertinib may benefit from savolitinib plus osimertinib according to results from the phase II SAVANNAH trial reported at ELCC 2025?

Jane, a 64-year-old woman, was recently diagnosed with metastatic NSCLC with an EGFR mutation (ex19del). 

When discussing first-line treatment options, which of the following results would you tell her was reported from the phase III MARIPOSA trial of amivantamab plus lazertinib vs osimertinib?

An exploratory analysis of the phase III EMPOWER Lung01 trial evaluating continued cemiplimab with 4 cycles of chemotherapy after progression on first-line cemiplimab for patients with advanced NSCLC with PD-L1 ≥50% and no EGFR, ALK, and ROS1 mutations showed which of the following progression-free survival (PFS) results compared with historical PFS with chemotherapy alone after first-line anti–PD-1/PD-L1 therapy?

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