Kelun-Merck validate TROP2-Keytruda pairing in lung cancer with improved survival

Kelun-Merck's TROP2 ADC Shows Improved Survival in First-Line Lung Cancer

Kelun-Biotech and Merck's TROP2 antibody-drug conjugate (ADC), sacituzumab tirumotecan (sac-TMT), combined with Keytruda, demonstrated significantly improved progression-free survival (PFS) and a 70% objective response rate (ORR) in the Phase 3 OptiTROP-Lung05 study. The trial involved 413 Chinese patients with previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) with certain gene mutations. Median PFS for the combination was not yet reached at a 10.5-month cutoff, compared to 5.7 months for Keytruda alone. Overall survival showed a positive trend. These results, revealed ahead of the ASCO Annual Meeting, suggest a potential new treatment paradigm for first-line NSCLC.

• The Phase 3 OptiTROP-Lung05 study showcased robust efficacy for sac-TMT plus Keytruda in first-line NSCLC. The combination achieved a 70% objective response rate (ORR), which favorably compares to chemo plus Keytruda (56%–58%). Progression-free survival (PFS) was significantly improved, with median PFS not yet reached at 10.5 months, versus 5.7 months for Keytruda alone. A strong PFS was also observed in patients with high PD-L1 expression, confirming superiority over standard-of-care Keytruda.
• The study reported impressive safety and low discontinuation rates for the sac-TMT combination. Treatment-emergent adverse events (Grade 3 or under) occurred in over half of patients receiving sac-TMT, compared to 31% in the Keytruda-only group. Despite these positive results, the market for first-line NSCLC is highly competitive, with other TROP2 ADCs like AstraZeneca’s Dato-DXd and bispecifics like Akeso’s ivonescimab also vying for market share.
• These positive results are significant for Merck, validating its up to $9.3 billion licensing deal with Kelun-Biotech from December 2022. Sac-TMT is considered a key internal program for Merck to drive growth through the Keytruda loss of exclusivity period. Beyond lung cancer, sac-TMT has also shown survival benefits in late-stage endometrial cancer and gastric cancer, highlighting its broad potential across multiple oncology indications.

OptiTROP-Lung05: Efficacy and Safety of Sac-TMT in NSCLC

The TROPION-Lung10 (NCT06357533) represents a landmark phase 3, open-label, multicenter study evaluating first-line datopotamab deruxtecan (Dato-DXd, a TROP2-directed antibody-drug conjugate) plus rilvegostomig (a bispecific anti-PD-1/anti-TIGIT antibody) versus pembrolizumab in approximately 675 patients with advanced/metastatic nonsquamous NSCLC. Patients with PD-L1 TC expression ≥50% and without actionable genomic alterations are randomized 2:1:2 to receive Dato-DXd (6 mg/kg IV Q3W) plus rilvegostomig (750 mg IV Q3W), rilvegostomig alone, or pembrolizumab. The dual primary endpoints focus on PFS by BICR per RECIST v1.1 and OS in the TROP2 NMR biomarker-positive population. The RATIONALE-307 4-year follow-up data demonstrate sustained efficacy of tislelizumab plus chemotherapy combinations in advanced squamous NSCLC, with median OS reaching 26.1 months (arm A: tislelizumab plus paclitaxel/carboplatin) and 23.3 months (arm B: tislelizumab plus nab-paclitaxel/carboplatin) versus 19.4 months with chemotherapy alone, alongside 4-year OS rates of 32.2%, 26.0%, and 19.2% respectively.

The ALEX trial final analysis provides definitive long-term data comparing alectinib versus crizotinib in 303 treatment-naïve patients with ALK-positive NSCLC. After median follow-up of 53.5 months for alectinib, median OS reached 81.1 months (95% CI 62.3-not estimable) versus 54.2 months with crizotinib (HR 0.78; 95% CI 0.56-1.08). Particularly notable benefits emerged in patients with CNS metastases (63.4 versus 30.9 months) and median duration of response extended to 42.3 months with alectinib versus 11.1 months with crizotinib. Long-term safety analysis with median treatment duration of 28.1 months revealed no new or unexpected safety concerns. The F1NE TUNE (LOGiK 2102) phase 2 trial evaluated atezolizumab with carboplatin plus nab-paclitaxel in 52 patients with TTF-1 negative advanced nonsquamous NSCLC, achieving median PFS of 4.9 months and median OS of 13.2 months with a response rate of 56.9%, though the study did not meet its primary endpoint threshold.

Recent safety analyses highlight emerging concerns with targeted therapies, including novel adverse event signals for pralsetinib such as blood calcitonin increases (ROR: 853.54) and myocardial necrosis markers (ROR: 201.79), with hypertension being more prevalent in female and older patients. The CJLSG1901 study demonstrated manageable safety profiles for pembrolizumab plus pemetrexed in older patients, with severe treatment-related adverse events occurring in 25% of patients regardless of PD-L1 status, while achieving overall ORR of 36.7% and median OS of 19.4 months. Meta-analyses confirm superior safety profiles for newer immunotherapy combinations, with atezolizumab showing significantly lower incidence of grade 3-5 adverse events (OR 0.21) and discontinuation rates (OR 0.35) compared to docetaxel.

Sac-TMT + Keytruda: A New Standard in First-Line NSCLC?

Anti-angiogenic therapies have demonstrated significant efficacy improvements over standard chemotherapy in first-line NSCLC treatment. Bevacizumab combined with chemotherapy or tyrosine kinase inhibitors (TKIs) showed substantial benefits in first-line therapy, with hazard ratios of 0.72 for progression-free survival and 0.90 for overall survival compared to chemotherapy or TKIs alone. Meta-analyses of VEGFR-TKI regimens in 12,520 patients revealed significant improvements in progression-free survival (HR 0.839), objective response rates, and disease control rates, though overall survival benefits were not statistically significant (HR 0.960, P=0.060). High-dose bevacizumab demonstrated superior outcomes compared to low-dose regimens, with statistically significant improvements in overall survival, progression-free survival, and objective response rates, establishing anti-angiogenic combinations as strategies that extend overall survival beyond 12 months.

Targeted therapies have shown varying degrees of superiority over conventional treatments depending on molecular subtypes and treatment lines. In ALK-positive NSCLC, ALK inhibitors achieved a median overall survival of 19.14 months with significantly better outcomes than chemotherapy (HR for OS 0.83, HR for PFS 0.43). For squamous NSCLC in the second-line setting, afatinib demonstrated superiority over erlotinib with improved progression-free survival (2.7 vs 1.9 months, HR 0.79) and overall survival (7.9 vs 6.8 months, HR 0.81). However, combination approaches with immune checkpoint inhibitors and multi-targeted TKIs in second-line therapy showed more modest benefits, particularly in patients with EGFR/ALK/ROS1 mutations where median progression-free survival was only 3.17 months.

Immunotherapy and novel drug classes have established new standards of care with distinct safety profiles compared to conventional treatments. Pembrolizumab demonstrated superior overall response rates, overall survival, and more favorable toxicity profiles compared to chemotherapy in both first and second-line settings for patients with high PD-L1 expression. Antibody-drug conjugates represent an emerging class with pooled analysis showing treatment-emergent adverse events in 98.9% of patients, though with manageable toxicity profiles that differ significantly from chemotherapy, with gastrointestinal involvement predominantly in low grades and hematological toxicity more prevalent in severe adverse events. Pemetrexed has shown particular efficacy in nonsquamous histologies with overall favorable toxicity profiles and evidence supporting its use as a strategy to improve overall survival beyond 12 months, particularly in maintenance therapy settings.

A New Frontier for First-Line NSCLC with TROP2 ADC Combo

The recent announcement regarding sacituzumab tirumotecan (sac-TMT) in combination with Keytruda marks a significant moment for the non-small cell lung cancer (NSCLC) treatment landscape. The Phase 3 OptiTROP-Lung05 study, demonstrating significantly improved progression-free survival and a 70% objective response rate in previously untreated patients with specific gene mutations, suggests a powerful new option for a patient population in critical need of more effective first-line therapies. This is particularly impactful given that TROP2-directed antibody-drug conjugates (ADCs) have shown enhanced activity in EGFR-mutant NSCLC, a subgroup where sac-TMT has previously demonstrated promising single-agent efficacy.

This strong clinical performance could redefine the standard of care for these patients, offering a compelling alternative to current regimens. The success of combining a TROP2 ADC with an immunotherapy agent like Keytruda also provides a strong rationale for exploring similar combination strategies across the broader ADC and immuno-oncology pipelines. However, as with all novel therapies, several considerations remain paramount:

• Safety Management: While sac-TMT has a manageable safety profile, TROP2 ADCs are known to cause adverse events such as myelosuppression, mucositis, and interstitial lung disease. Proactive strategies for prevention and management of these toxicities will be crucial for widespread clinical adoption.

• Long-term Outcomes: While the PFS data is impressive and OS shows a positive trend, continued follow-up is essential to fully characterize the long-term survival benefits and durability of response.

• Market Access and Value: The cost-effectiveness of TROP2 ADCs has been a point of discussion in other indications, particularly in regions like China. Demonstrating clear value and optimizing pricing will be key to ensuring broad patient access.

Ultimately, these results underscore the evolving paradigm in NSCLC, where targeted therapies and immunotherapies are increasingly combined to achieve superior outcomes. The data positions sac-TMT as a frontrunner in this new era, but careful navigation of safety, long-term data, and market dynamics will determine its ultimate impact.