Shooting Cancer Congress Highlights: ESMO 2026

ESMO 2026:

At the ESMO Congress 2026 in Madrid, many of the most relevant results depended on a molecular marker used to select patients, define the therapeutic target or design the treatment itself. Each of these steps involves oncologists, molecular biologists and pathologists.

This issue presents a curated selection of highlights in which biomarker testing plays a central role.

1. Individualized neoantigen therapy in resected high-risk melanoma (INTerpath-001)

Tumor: Resected cutaneous melanoma, stage IIB–IV

Therapy: Intismeran autogene + pembrolizumab vs placebo + pembrolizumab

Biomarker: Patient-specific tumor neoantigens

Testing: Tumor/normal next-generation sequencing

• Intismeran autogene is an mRNA therapy manufactured for each patient. Somatic mutations identified by sequencing the resected tumor are used to select up to 34 neoantigens.
• In the phase 3 INTerpath-001 trial (N=1,137), adding intismeran to adjuvant pembrolizumab reduced the risk of recurrence or death by 42% (RFS HR 0.58; 95% CI 0.45–0.75) at a median follow-up of 24.6 months. Distant metastasis-free survival also improved (HR 0.62).
• OS data are immature. The added toxicity was limited (grade ≥3 treatment-related AEs 14.2% vs 13.4%).
• The first phase 3 evidence for a therapy designed from the patient’s own tumor genome makes tissue quality and sequencing part of the treatment itself.

References

Long GV, et al. ESMO 2026, LBA1. Accepted for publication in N Engl J Med.ù

2. Divarasib vs first-generation KRAS G12C inhibitors in pretreated NSCLC (Krascendo-1)

Tumor: Previously treated advanced NSCLC

Therapy: Divarasib vs sotorasib or adagrasib

Biomarker: KRAS G12C

Testing: NGS-based genomic profiling at diagnosis

• KRAS G12C occurs in about 12–14% of non-squamous NSCLC. Krascendo-1 compared a next-generation inhibitor head-to-head with the approved agents.
• In 338 patients, divarasib improved median PFS (9.8 vs 5.7 months; HR 0.58) and median OS (17.7 vs 12.0 months; HR 0.56), with a higher ORR (58% vs 32%) and less grade ≥3 toxicity.
• About one in five patients carried a KEAP1 co-mutation, a recognized modifier of outcome in KRAS-mutant disease.
• Within the same molecular subgroup, the choice of agent now affects survival, and co-mutation profiling adds prognostic information.

References

Skoulidis F, et al. ESMO 2026, LBA5. N Engl J Med 2026; doi:10.1056/NEJMoa2605703.ù

3. KRAS G12D: a new actionable target in pancreatic cancer

Tumor: Metastatic pancreatic ductal adenocarcinoma (PDAC); NSCLC

Therapy: INCB161734 + chemotherapy; setidegrasib

Biomarker: KRAS G12D

Testing: Variant-level KRAS genotyping (NGS)

• KRAS mutations are present in more than 90% of PDAC, and G12D is the most frequent variant.
• In a phase 1 study of patients treated mostly in the first line, INCB161734 combined with chemotherapy produced an ORR of 89% with mFOLFIRINOX (n=27) and 69% with gemcitabine/nab-paclitaxel (n=26), including unconfirmed responses.
• Two phase 3 trials of the KRAS G12D degrader setidegrasib were presented as trials in progress: one in first-line PDAC with mFOLFIRINOX/NALIRIFOX, and one versus docetaxel in pretreated NSCLC. They follow the survival benefit of the RAS(ON) inhibitor daraxonrasib in second-line PDAC (RASolute 302, ASCO 2026).
• KRAS testing in PDAC is becoming a treatment decision, and identifying the specific variant determines eligibility for allele-specific drugs and trials.

References

Hollebecque A, et al. ESMO 2026, 3137RO.

Setidegrasib: ESMO 2026, 3190TiP (NCT07409272); 2871eTiP (NCT07566052).

4. MTAP deletion: synthetic lethality with MTA-cooperative PRMT5 inhibitors

Tumor: MTAP-deleted solid tumors, notably PDAC and NSCLC

Therapy: Vopimetostat + daraxonrasib; BGB-58067

Biomarker: Homozygous MTAP deletion

Testing: Copy-number analysis by NGS and/or MTAP immunohistochemistry

• MTAP is frequently co-deleted with CDKN2A at 9p21. Its loss causes intracellular accumulation of MTA, which partially inhibits PRMT5 and makes tumor cells selectively sensitive to MTA-cooperative PRMT5 inhibitors.
• In MTAP-deleted, RAS-mutant PDAC, vopimetostat plus daraxonrasib achieved an ORR of 82% (all partial responses) and a 9-month PFS rate of 88.4% in 22 evaluable patients, mostly in the second or third line; a first-line phase 3 trial is planned for 2027.
• In the phase 1 study of BGB-58067 (N=182), MTAP-deficient NSCLC showed a confirmed ORR of 25.3% (38.5% in EGFR wild-type disease), with responses also in untreated brain metastases.
• Because MTAP loss is a homozygous deletion rather than a point mutation, testing must reliably detect copy-number loss, by NGS or by IHC as a surrogate.

References

Spira A, et al. ESMO 2026, 3149P.

BGB-58067: ESMO 2026, 1043P.

5. Dostarlimab and organ preservation in dMMR/MSI-H rectal cancer (AZUR-1)

Tumor: Stage II/III locally advanced rectal cancer

Therapy: Dostarlimab monotherapy with non-operative management

Biomarker: Microsatellite instability / mismatch repair deficiency (MSI-H/dMMR)

Testing: Molecular MSI analysis (PCR or NGS) and/or MMR immunohistochemistry on the diagnostic biopsy

• MSI-H/dMMR tumors are a minority of rectal cancers but are highly sensitive to PD-1 blockade. AZUR-1 included patients with either dMMR or MSI-H tumors.
• Among 154 patients (86% stage III), 71% achieved a clinical complete response with dostarlimab alone. The response was sustained at 12 months in 68% by investigator assessment and 47% by independent central review, and 98% of responders followed for at least 12 months remained in response.
• Because eligibility for organ preservation depends on MSI/MMR status, it must be established on the pre-treatment biopsy. Molecular MSI testing, alongside or after immunohistochemistry, helps make that result reliable before treatment begins.

References

Cercek A, et al. ESMO 2026, LBA87. Ann Oncol 2026; doi:10.1016/j.annonc.2026.10.1280.

6. Atirmociclib after CDK4/6 inhibition in HR+/HER2− advanced breast cancer (FOURLIGHT-1)

Tumor: HR+/HER2− advanced breast cancer after a CDK4/6 inhibitor

Therapy: Atirmociclib (CDK4-selective) + fulvestrant vs investigator’s choice

Biomarker: ESR1 and PIK3CA/AKT1/PTEN alterations

Testing: Molecular re-profiling at progression, including ctDNA

• In the randomized phase 2 FOURLIGHT-1 trial (N=263), atirmociclib plus fulvestrant improved median PFS (9.4 vs 6.6 months; HR 0.60)
• ESR1 alterations were present in 35–41% of patients and PI3K pathway alterations in 37–45%. The benefit was retained in both groups (HR 0.47 and 0.46). The first-line phase 3 FOURLIGHT-3 trial has completed accrual.
• Resistance after CDK4/6 inhibition is molecularly heterogeneous, so re-profiling at progression, preferably by ctDNA, is needed to choose the next line of treatment.

References

Giordano A, et al. ESMO 2026, 1842O. Ann Oncol 2026; doi:10.1016/j.annonc.2026.10.1282.

7. Molecular classification guides therapy in advanced endometrial cancer (KEYNOTE-C93, TroFuse-005)

Tumor: Advanced or recurrent endometrial cancer

Therapy: Pembrolizumab (first line, dMMR/MSI-H); sacituzumab tirumotecan (sac-TMT)

Biomarker: MMR/MSI status within the molecular classification; TROP2 expression

Testing: Molecular classification (POLE sequencing, MMR/MSI, p53); TROP2 immunohistochemistry

• Molecular classification, based on POLE mutation, MMR/MSI status and p53, is now part of the diagnostic work-up of endometrial cancer, and the mismatch repair-deficient subgroup is the one that benefits most from immunotherapy.
• In KEYNOTE-C93 (N=299, centrally confirmed dMMR), first-line pembrolizumab monotherapy outperformed carboplatin-paclitaxel (median PFS 38.2 vs 8.4 months; HR 0.57; 36-month PFS 52.8% vs 30.0%).
• In TroFuse-005 (N=776), the TROP2-directed ADC sac-TMT improved median OS over physician’s choice (19.0 vs 12.1 months; HR 0.68), mainly in tumors with medium-to-high TROP2 expression (HR 0.58 vs 1.07 for low expression).
• A chemotherapy-free first-line option for MMR-deficient disease makes molecular classification at diagnosis essential, including MSI testing and POLE sequencing.

References

Slomovitz BM, et al. ESMO 2026, LBA12.

Lorusso D, et al. ESMO 2026, LBA11.

The highlights selected from ESMO 2026 show that the clinical value of new therapies depends increasingly on what happens before treatment: tumor sequencing for individualized therapies, variant-level KRAS genotyping, detection of MTAP deletions, MSI testing and molecular classification, and ctDNA-based re-profiling. Standardized, timely and comprehensive molecular testing remains a prerequisite for bringing these results into clinical practice.