Key 2025 ASCO® Outcomes

Bottlenecks to Cell Therapy Success in Solid Tumors

As reflected in 2025 ASCO® Annual Meeting theme “Driving Knowledge to Action: Building a Better Future”, innovation with CAR-Ts in solid tumors has been oriented for treatment precision within selected tumors apiece. However, CAR-T cell therapy in solid tumors has progressed from “hopeful” to “complicated” based on the recent presentations made at 2025 ASCO® Annual Meeting.

1. Manufacturing lag kills momentum

• Unmodified CLDN18.2 CAR-T (CT041/Satri-cel) in gastric cancer improved mOS to 7.9 vs. 5.5 months with chemo (HR-0.69, N=156), but a significant proportion of patients (~16%) dropped out during the ~4–6-week vein-to-vein window. Additionally, durability of responses was poor, with half of the responders progressing by 6 months in the Phase I cohort.^1,2

2. Logic gates for safety (finally) show promise

• Hypoxia-activated CEA CAR-Ts hit a 47% ORR (N=15); LOH-gated MSLN CAR-Ts hit 20% (N=5) in NSCLC. Side effects are contained though results remain tumor-specific, and a pH-sensitive HER2 CAR-T in breast cancer fizzled with 0% RR.^3-5

3. Improving delivery method isn’t a magic bullet

• GBM trials tested intra-cranial delivery (to improve cell delivery and potentially reducing systemic toxicity) of dual‐target EGFR/IL13Rα2 CAR-T and CARv3-TEAM-E T (producing anti-EGFR TEAM). Safety was solid, but poor objective responses of around 0–8% (N = 7 to13).^6-7

4. Repeat dosing doesn’t guarantee effectiveness

• Intracranial B7-H3 CAR-T (no lymphodepletion), on day 14 with 6–7 monthly “boosters” improved mOS to 13.5 months in 10 patients, but over 80% experienced tumor inflammation–associated neurotoxicity (TIAN).⁸

5. “Armored” CAR-Ts pack cytokine payloads… and toxicity.

• GPC3-targeted CAR-Ts in HCC and CEA-CAR-Ts in CRC show ORRs of ~42–56% (N<10), but Grade ≥ 3 CRS, colitis and hematologic toxicities spike. Fragile late-stage patients may not survive the super-charged immune storm^9-10

Bottom line: ASCO® Annual Meeting delivered a portfolio of innovative CAR-T constructs that achieved modest advances alongside significant setbacks. Only by resolving these key operational and clinical hurdles will one be able to predict the strategic impact of cell therapies in solid tumors. Look out for our next analysis of key themes.

Taking Immunotherapies Earlier in Cancer Care

2025 ASCO® Annual Meeting spotlighted a wave of momentum in the non-metastatic solid tumor space, with a strong focus on integrating PD-(L)1 inhibitors into existing standards of care to drive meaningful survival gains. A key theme across multiple presentations was the strategic use of molecular enrichment to identify patients most likely to benefit from intensification of current SoC with the addition and extended administration of IO therapies in the peri-op/ adjuvant setting.

1. Integration of clinical-genomic enrichment strategies can improve outcomes with addition of PD-(L)1 adjuvant therapy to current SoC (MATTERHORN, NIVOPOSTOP, ATOMIC)^11-13

• Clinical and pathological risk criteria are critical determinants to identify patients likely to derive maximal benefit from adjuvant ICI treatment strategies:
  • MATTERHORN: Patients with R0 resection receiving Durvalumab + FLOT up to 1 yr demonstrated promising DFS vs comparator (HR 0.7)
  • NIVOPOSTOP: Adjuvant Nivolumab + CRT improved DFS vs CRT in patients with HNSCC at high-risk of relapse, selected based on clinical determinants like extracellular extension and positive margins (3-yr DFS ~63% vs ~53%, HR 0.76).
  • Molecular features are additional levers to be evaluated for potential patient enrichment strategies in the adjuvant setting:
  • ATOMIC: DFS benefit was evident with chemo + extended Atezolizumab (up to 1 yr) vs chemo, in patients with dMMR Stage III colon cancer (~87% vs 77%, HR 0.53).
  • In MATTERHORN study, PD-(L)1 TAP ≥1% showed higher EFS benefit vs PD-(L)1 TAP <1% (HR 0.7 vs 0.77), though NIVOPOSTOP study revealed highest benefit in all-comers (HR ~0.6) in a PD-(L)1 sub-group analysis.

2. ctDNA as a prognostic and potentially, predictive tool may enable patient stratification and early response assessment in peri-operative setting¹⁴

• Peri-operative Durvalumab showed EFS benefit vs NAC regardless of baseline pre-RC ctDNA status, although more compelling outcomes observed in ctDNA- MIBC patients (HR 0.45 vs HR 0.73). In the same study, it was established that ctDNA positivity irrespective of the Tx, worsens DFS (HR 0.09).
• ctDNA was a stronger prognostic marker compared to pCR rates as adjuvant Durvalumab demonstrated similar DFS benefit in ctDNA- patients irrespective of pCR status (NAC ± Durvalumab: pCR vs non-pCR HR 0.42 vs HR 0.5), suggesting that MIBC patients with ctDNA- would benefit from adjuvant Durvalumab.

3. Immune biomarkers, beyond standalone PD-L1 expression levels, may offer innovative approaches to optimize PD-(L)1 treatment decisions in LS-SCLC¹⁵:

• Higher presentation of cytotoxic markers (CD8 density, MHC class I, CD8A expression) along with TIS and STING pathways in Long-Term progressors (LTP) likely favors PD-L1 working mechanism, resulting in improved PFS outcomes.
• LTP in Durva arm experienced a lower proportion of progression outside lungs and mediastinum (16% vs 36% in the ADRIATIC study).
• Similar PD-L1 expression rates between EP and LTP, regardless of the regimen indicate limited application as a standalone predictor of response.
• It remains to be seen, however, if this data can be extrapolated to other diseases – such as immune signature profiling of non-progressors at interim milestones post IO treatment, to help identify patients that could benefit from extended adjuvant treatment?

4. cCR can be an important determinant to identify appropriate MIBC patients that could potentially preserve their bladder¹⁶:

• Post neoadjuvant sacituzumab govitecan (SG)+ Pembrolizumab, 44% patients achieved cCR and demonstrated 1 yr BI-EFS and 1 yr MFS = 100%, with peri-operative SG + Pembrolizumab leading to bladder preservation in 74% patients who refused radical cystectomy, in an early phase trial.

Bottom line:  ASCO® Annual Meeting highlights that the dual-axis approach, neoadjuvant for functional preservation and adjuvant for micrometastatic eradication requires tailored IO integration guided by clinic-pathologic and biomarker profiles of the non-metastatic patients. From a commercial perspective, this creates differentiated peri-operative positioning, unlocks label-extension opportunities, and justifies targeted investment in companion diagnostics and longitudinal outcome monitoring.

Abbreviations: Satri-cel: Satricabtagene autoleucel; ICV: intracerebroventricular; CEA: Carcinoembryonic Antigen; MSLN: Mesothelin; TEAM: T-cell–engaging antibody molecule  ADC- Antibody Drug Conjugate, BIEFS- Bladder Intact Event Free Survival, cCR- Complete Clinical Response, CD8- Cluster of Differentiation 8, CRT- Chemoradiotherapy, ctDNA- Circulating Tumor DNA, DFS- Disease Free Survival, EP- Early Progressors (PFS< 6 months), ICI- Immune Checkpoint Inhibitors, IO- Immuno-oncology, LS-SCLC- Limited Stage Small Cell Lung Cancer, LTP- Long-term Progression Free Survivors (with PFS or censored after >12 months), MFS- Metastasis Free Survival, MHC I- Major Histocompatibility Complex Class I, MIBC- Muscle Invasive Bladder Cancer, NAC- Neoadjuvant Chemotherapy, pCR- Pathological Complete Response, PFS- Progression Free Survival, SoC- Standard of Care, STING- Simulator of Interferon Genes, TAP – Tumor Area Positivity, TIS- T-cell Inflamed Signature, Tx- treatment

References

1. Qi C et al., 2025 ASCO® Annual Meeting Abstract # 4003
2. Peng H et al., 2025 ASCO® Annual Meeting Abstract #4015
3. Wei S et al., 2025 ASCO® Annual Meeting Abstract #8517
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6. Gerstner ER et al., ASCO® ASCO Annual Meeting Abstract #2017
7. Bagley S et al, 2025 ASCO® Annual Meeting Abstract #102
8. Li G et al., 2025 ASCO® Annual Meeting Abstract #2018
9. Fan J et al., 2025 ASCO® Annual Meeting Abstract #4084
10. Schlechter B et al., 2025 ASCO® Annual Meeting Abstract #3581
11. Janjigian Y et al., 2025 ASCO® Annual Meeting Abstract # LBA5
12. Bourhis J et al, 2025 ASCO® Annual Meeting Abstract # LBA2
13. Sinicrope F et al, 2025 ASCO® Annual Meeting Abstract # LBA1
14. Powles T et al, 2025 ASCO® Annual Meeting Abstract # 4503
15. Barbie D et al, 2025 ASCO® Annual Meeting Abstract # 8014
16. Necchi A et al, 2025 ASCO® Annual Meeting Abstract # 4518