ASCOMOS 2026: Lung Cancer KOL Coverage

Symposium 1A - ADC: The Next Frontier in Lung Cancer. Faculty: Peter Low Bin Jian, Voon Pei Jye, David Lee Dai Wee, David P. Carbone, Herbert HF Loong, Hidehito Horinouchi. 37th Annual Scientific Congress of the Malaysian Oncological Society 2026 & 59th Malaysia-Singapore Congress of Medicine, Kuala Lumpur Convention Centre. Theme: 'Together: Advancing Excellence in Cancer Care.'

In Summary (Actionable Genomic Alterations in NSCLC): 1) Molecular testing is essential in NSCLC. 2) NGS is preferred over single-gene testing. 3) Adjuvant targeted therapies are expanding (ADAURA, ALINA, LIBRETTO-432). 4) LAURA is the standard for stage III EGFR+ NSCLC post chemoradiation. 5) Combination therapy is preferred over monotherapy in metastatic EGFR+ NSCLC. 6) Re-biopsy is essential to guide subsequent therapy. 7) Immunotherapy alone has a limited role in EGFR+ lung cancer. 8) Lorlatinib delivers unprecedented long-term outcomes. 9) ADCs are transforming treatment after progression. 10) Emerging biomarkers in NSCLC are currently in clinical development.

#6 Re-biopsy is essential to guide subsequent therapy. Resistance mechanisms: on-target mutations; bypass pathway activation (MET, HER2, BRAF, PIK3CA, RAS); phenotypic transformation (EMT, histologic/SCLC transformation). ADC / next-line options by target: TROP2-ADC (datopotamab deruxtecan, sacituzumab govitecan); HER2-ADC (trastuzumab deruxtecan); ALK (alectinib); Chemo+IO (IMPOWER150, ORIENT 031, ATLAS). Re-biopsy is essential to guide the next line of systemic therapy.

#8 Lorlatinib delivers unprecedented long-term outcomes (CROWN, 7-year follow-up). No new safety signals; no new emerging ALK resistance mutation. PFS in the ITT population (7-year follow-up): median PFS by investigator was not reached with lorlatinib. Time to intracranial (IC) progression in the ITT population presented.

#9 ADCs are transforming treatment after progression (FDA approved). Datopotamab deruxtecan - TROPION-Lung01 (n=299, Phase 3, >=2L) vs TROPION-Lung05 (N=137, Phase 2, >=3L), TROP-2, advanced/metastatic NSCLC. ORR 26.4% (21.5-31.8) vs 35.8% (27.8-44.4); mDoR 7.1 vs 7.0 mo; mPFS 4.4 vs 5.4 mo; mOS 12.9 vs 13.6 mo; Grade>=3 AEs 25.6% vs 3.6%; adjudicated ILD 8.8% vs 5.1%; AEs leading to discontinuation 8.1% vs 5.1%. Datopotamab deruxtecan demonstrated antitumour activity with no new safety signals; ADC combination strategies are being evaluated in 1L. (Ahn JCO 2025; Sands JCO 2025)

Summary (Uncommon EGFR Mutations): EGFR mutations are diverse; uncommon EGFR mutations can be classical-like or PACC (P-loop and alphaC-helix compressing). Amivantamab + lazertinib has to date the longest OS in PACC; osimertinib or afatinib have been the standard of care. First-line TKIs are now incorporated into the standard of care in EGFR exon 20 insertion NSCLC (choice vs amivantamab/chemo comes down to patient choice, toxicity profiles, loop proximity, and brain metastases). Further studies address combinations (chemo, ADCs, vaccines), resistance mechanisms, and early/resectable disease.

Selected therapeutic agents in atypical EGFR mutations (drug / phase / ORR / mPFS / mDoR / OS) across ACHILLES-TORO1494, XL30-Lu18-09, UNICORN, FURTHER, CHRYSALIS-2 (amivantamab) and others. Amivantamab is FDA/EMA approved based on a LUX-Lung post-hoc analysis; osimertinib is incorporated into guidelines. ALPACCA (NCT07185867): first randomized Phase III trial for PACC mutations comparing firmonertinib vs osimertinib (n~490). (Black Diamond press release; Rotow ASCO 2026)

Therapeutic advances in EGFR exon 20 insertion mutations (timeline 2013-2026): amivantamab; mobocertinib (CHRYSALIS accelerated approval; EXCLAIM); osimertinib 160mg (POSITION20, ORCHARD); PAPILLON; FAVOUR (firmonertinib); sunvozertinib - WU-KONG 1B (accelerated approval, 300mg) and WU-KONG 28 (Phase III vs chemo, 300mg); EXCLAIM-2.

Frontline Phase III trials for EGFR exon 20 insertions: PAPILLON (n=308, amivantamab+chemo), EXCLAIM-2 (n=354, mobocertinib+chemo), WU-KONG 28 (n=324, sunvozertinib monotherapy). ORR: PAPILLON 73%; EXCLAIM-2 32%; WU-KONG 28 84% (mPFS 10.3 mo). WU-KONG 28 toxicities: diarrhoea 84.5%/13.5% (all/G3), rash 51.5%/2.0%, anaemia 46%/6.1%, CPK increase 45%/25.2%; dose interruption 45.4%, dose reduction 40.5%, discontinuation 7.4%. (Girard NEJM 2023; Janne JCO 2025; Heymach ASCO 2026)

Conclusions (HER2 in NSCLC): HER2 is a targetable alteration - HER2 mutation and HER2 3+ overexpression. Trastuzumab deruxtecan is the first approved HER2-directed therapy for HER2-mutant NSCLC (including brain metastases), with a favourable safety profile; confirmatory 1L study ongoing. Zongertinib, a selective HER2 TKI active against HER2-mutant NSCLC (including 1L), is approved. Sevabertinib, a novel HER2 TKI active against HER2-mutant NSCLC including TKI-naive, is approved and being assessed in 1L vs chemo/I-O. Trastuzumab deruxtecan is approved for pretreated HER2 (IHC 3+) NSCLC.

HER2 as an oncogenic driver in NSCLC. Three types of HER2 alteration with oncogenic potential observed across many cancers including NSCLC: HER2 gene mutations (2-4% of NSCLC); HER2 gene amplification (2-30% of NSCLC); HER2 protein overexpression (IHC 2+ 15-30%, IHC 3+ 2-6%). (Oh et al ESMO Open 2024; Yotsukura et al Nat Rev Clin Oncol 2024)

Previous therapies for HER2-altered NSCLC were not very effective - Phase 2 trials showed modest activity of pan-HER (EGFR/HER2) TKIs in HER2-mutant NSCLC. Afatinib ORR 13-19% (mPFS 3.6-3.9 mo); neratinib ORR ~4%; dacomitinib ORR 12% (mPFS 3); mobocertinib ORR 30% (mPFS 6.9); pyrotinib ORR 28-30% (mPFS 5.5); poziotinib ORR 28-44% (mPFS 5.5). Toxicities: diarrhoea, rash, paronychia, mucositis (frequent grade 3 diarrhoea/rash 26-49%).

T-DXd: accelerated tumour-agnostic approval (April 2024) in unresectable/metastatic HER2-positive (IHC 3+) solid tumours who progressed on prior systemic therapy. Efficacy in HER2-positive (IHC 3+) tumours: DESTINY-PanTumor02 (N=111) confirmed ORR 51.4% (41.7-61.0); DESTINY-Lung01 (N=27) 52.9% (27.8-77.0); DESTINY-CRC01 (N=64) 46.9% (34.3-59.8). Median DoR 19.4 / 6.9 / 5.5 mo. Accelerated approval was based on ORR and DoR. Ongoing Phase 1b of T-DXd + pembrolizumab in HER2-expressing NSCLC (NCT04042701).

Take-home messages (Rare Drivers). ALK: lorlatinib has achieved unprecedented disease control in advanced ALK+ NSCLC, potentially turning metastatic cancer into a chronic disease; neladalkib (NVL-655) shows promising activity in patients failing ALK TKI, especially G1202R (in LORIN, ~75% of patients who progressed on lorlatinib were converted to near-stable). RET: the Phase 3 AcceleRET study established pralsetinib as a 1L option for advanced RET+ NSCLC; adjuvant selpercatinib is the new standard of care for resected stage IB-III RET+ NSCLC (role in stage IB less clear). KRAS: 2nd-generation KRAS G12C inhibitors show promising efficacy as monotherapy in 2L and combined with ICI in 1L; both KRAS G12C and pan-RAS inhibitors show promise - all KRAS mutations will soon be targetable.

Patients without a PFS event at 2 years have a 79% probability of being progression-free & alive at 7 years (lorlatinib, CROWN). Estimated proportion of PFS events by year declines (~10%, 5%, 2%, 3%, 3%, 2%), landing at 55% PFS at 7 years. (Mok et al ASCO 2026)

After lorlatinib: what next? Neladalkib (NVL-655) is active against the double on-target mutation (G1202R/L1196M) resistant to approved TKIs including lorlatinib; TRK-sparing (potentially less CNS toxicity); potent intracranial activity. (Lin et al Cancer Discov 2024)

1L ICI + KRAS G12C inhibitor combinations show durable activity - success will likely be determined by toxicity. Pembrolizumab + divarasib: ORR 71%, PFS 19.3 mo (65% grade 3+ TRAE). Pembrolizumab + olomorasib: ORR 90%, PFS 13.2 mo (33% grade 3+ TRAE). Pembrolizumab + adagrasib: PFS 25.2 mo (33% grade 3+ TRAE). Phase 3 designs: pembro/divarasib vs pembro+chemo (PD-L1 unselected); pembro +/- olomorasib, +/- adagrasib, +/- calderasib (PD-L1 high). (Skoulidis et al ASCO 2026; Burns et al JTO 2026; Sacher et al ASCO 2026)