📬 Lung/Head and Neck/Thymoma Intelligence Digest — Week 2026-W39

A germline EGFR T790M founder variant from Southern Appalachia confers a 25-fold lung cancer risk, and 60-fold in never-smokers

Analyzed across 3,372,531 individuals, the germline EGFR T790M variant was present in 1 of 15,850 overall and up to 1 in 2,000 in parts of Appalachia, carrying an odds ratio of 25.18 (p=1.9×10⁻²⁴) for lung cancer with no association across 17 other cancers and approximately a 60-fold increased risk in never-smokers — described by clinicians as the strongest single germline risk factor in lung cancer so far while cautioning it is rare. Recognition of individuals more likely to carry the variant — including those with family history of lung cancer, multifocal lung cancer, lung nodules or Southeastern US ancestry — may help inform screening and prevention strategies for those at highest risk, pressing the central question of whether a 25-fold germline risk concentrated in one region justifies targeted genetic testing and CT screening for never-smoking carriers outside current guideline age and smoking criteria.

Discussed by: @jennifermarksmd, @YGaritaonaindia, @FordePatrick, @YGaritaonaindia, @HHorinouchi, @NarjustFlorezMD, @HenningWillers

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Sources cited: Germline EGFR T790M mutation and lung cancer risk (Science, 2026) · AAAS Journals

EVOKE-03/KEYNOTE-D46: sacituzumab govitecan plus pembrolizumab misses in PD-L1-high NSCLC with far more toxicity

In this phase III trial of 620 patients with untreated metastatic NSCLC and PD-L1 ≥50%, sacituzumab govitecan plus pembrolizumab versus pembrolizumab alone did not meet the primary endpoint: PFS was 11.8 versus 7.7 months (HR 0.81), not statistically significant per the prespecified boundary, and OS was 21.5 versus 22.8 months (HR 1.07). ORR was 56.6% versus 43.7%, but grade ≥3 treatment-related adverse events were substantially higher at 55.7% versus 16.5%; clinicians concluded that given similar duration of response, lack of OS benefit and substantial toxicity, this combination has no place in clinical practice, and that the strategy fails in an unselected population — with other ADC trials in different PD-L1 subsets and exploring biomarkers pending.

Discussed by: @StephenVLiu, @HHorinouchi, @Tony_Calles, @ChandrakanthMv, @Dr_ElvinaA, @diegoadiazg

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Sources cited: Conference abstract

TAISHAN-302 publishes in NEJM: the B7-H3 ADC tambotatug pelitecan cuts the risk of death by 54% versus topotecan in relapsed SCLC

The 451-patient trial showed median OS 13.3 versus 9.4 months (HR 0.46), median PFS 7.4 versus 2.8 months (HR 0.29) and ORR 59.1% versus 9.7%, with grade ≥3 adverse events lower at 55.4% versus 77.9%; intracranial PFS was 6.1 versus 4.2 months (HR 0.43), intracranial response 32% versus 3%, and ILD occurred in 4.9% with tambotatug pelitecan. Approximately 30% of patients had no smoking history and transformed SCLC was excluded; clinicians flag the China-only design as the main limitation and note that sequencing against tarlatamab remains an open question, framing the central debate as where a B7-H3 ADC sits in the second-line SCLC sequence without head-to-head comparative data.

Discussed by: @GlopesMd, @Tony_Calles, @RManochakian, @StephenVLiu, @jennifermarksmd, @ChandrakanthMv

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Sources cited: Tambotatug Pelitecan in Small-Cell Lung Cancer after Platinum-Based Therapy. (N Engl J Med)

DESTINY-Lung04: first-line T-DXd wins on PFS in HER2-mutant NSCLC but interim OS points the other way and one in five gets drug-related lung disease

DESTINY-Lung04 is the first phase 3 trial to show a benefit for a HER2-directed therapy over standard chemoimmunotherapy as first-line treatment for HER2-mutant NSCLC: PFS was 14.3 versus 8.3 months (HR 0.63), response rate 70% versus 44.5% and DOR 13.7 versus 9.7 months, but interim OS was 29.3 versus 33.1 months (HR 1.15; 95% CI 0.88-1.52), complicated by imbalanced subsequent HER2-directed therapy (48.0% vs 23.3% in the control vs T-DXd arms). Adjudicated drug-related ILD/pneumonitis occurred in 20.8%, with grade ≥3 at 4.4% and grade 5 at 1.8% (4 deaths); clinicians describe the lack of OS translation and safety signals as disappointing and argue that with very well tolerated and similarly active TKIs available, the destiny of T-DXd for now appears to be in the second line.

Discussed by: @Tony_Calles, @HHorinouchi, @StephenVLiu, @M_Torasawa, @BalazsHalmosMD, @ChandrakanthMv, @jennifermarksmd

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Sources cited: Conference abstract

HARMONi-2 reports overall survival: ivonescimab is the first PD-1 x VEGF bispecific to beat pembrolizumab on OS

HARMONi-2 reported median OS of 30.8 versus 22.6 months (HR 0.73; 95% CI 0.57-0.95) in first-line PD-L1-positive NSCLC, with previously reported PFS of 11.1 versus 5.8 months (HR 0.51); the OS benefit was clear in the ≥50% PD-L1 subgroup (HR 0.58) but the HR was 0.85 with a confidence interval crossing 1 in the 1-49% subgroup, and serious treatment-related events were 29.9% versus 21.6%. Every patient was enrolled in China, and clinicians note that pembrolizumab monotherapy is not the contemporary comparator for PD-L1 TPS 1-49% where chemo-immunotherapy is generally standard; separately, the updated HARMONi OS analysis in EGFR-TKI-resistant NSCLC showed 16.8 versus 14.0 months (HR 0.76; 95% CI 0.61-0.95; nominal p=0.0151), consistent in Western patients (17.5 vs 14.0 months, HR 0.76) and Asian patients (16.7 vs 14.0 months, HR 0.76).

Discussed by: @HHorinouchi, @OncBrothers, @GIMedOnc, @BalazsHalmosMD, @Dr_ElvinaA, @M_Torasawa

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Sources cited: Conference abstract

Three first-line regimens now crowd EGFR exon 20 insertion NSCLC, and the discussant says the choice is CNS disease, toxicity and patient preference

All three phase III trials beat platinum doublet on PFS — PAPILLON HR 0.40 (mPFS 11.4 months), WU-KONG28 HR 0.65 (mPFS 10.3 months) and REZILIENT3 HR 0.50 (mPFS 14.5 months) — with no head-to-head winner and no clear OS winner yet. The discussant argued that treatment choice goes beyond efficacy to CNS disease, exon 20 insertion subtype, toxicity, treatment burden, patient preference and subsequent therapy; some clinicians argue sunvozertinib may become preferred as oral monotherapy with lower treatment burden, while others counter that FLAURA2, PAPILLON and REZILIENT3 all point toward the importance of upfront chemotherapy with EGFR inhibition, and that limited data on CNS disease or exon 20 insertion variant mean sequencing is driven more by preference, toxicity and access at this time.

Discussed by: @GlopesMd, @GlopesMd, @ChandrakanthMv, @TejasPatilMD, @jennifermarksmd, @NReguart, @HHorinouchi

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ADAURA at eight years: adjuvant osimertinib's survival curves have not converged five years after treatment ended

In the stage II-IIIA population, 8-year OS was 74% versus 58% (HR 0.53), and in the full stage IB-IIIA population 8-year OS was 79% versus 64% (HR 0.52; 95% CI 0.39-0.71), a 15% absolute gain, with Ex19del showing a stronger OS benefit (HR 0.45) than L858R (HR 0.72); benefit was seen across stages with stage IB HR 0.50, stage II HR 0.60 and stage IIIA HR 0.49. Clinicians argue the durable benefit reframes the question from delay of relapse to cure, while noting that only 43% of placebo-arm patients had access to osimertinib at recurrence, that half of patients on adjuvant osimertinib stopped by approximately 33 months with discontinuation before 12 or 24 months carrying a 2.3x and 2.7x higher risk of recurrence or death, and that patient advocates press on who is under the curve and who might already be cured — centering the debate on optimal osimertinib duration, MRD risk stratification and whether adjuvant chemotherapy can be dropped.

Discussed by: @StephenVLiu, @M_Torasawa, @HHorinouchi, @BalazsHalmosMD, @jillfeldman4, @Latinamd, @RManochakian

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Sources cited: JTO · Conference abstract · OncLive

MDT-BRIDGE reframes resectability as a treatment-modifiable state after two cycles of durvalumab-chemotherapy

In MDT-BRIDGE, of patients with borderline resectable NSCLC, 62% underwent resection (97% R0), with an overall resection rate of 74.6%, pCR 27.3%, 12-month EFS 90.1% in the resectable cohort and 92.3% of patients receiving either surgery or chemoradiotherapy; clinicians argue resectability should be assessed after neoadjuvant chemo-immunotherapy rather than declared upfront. A radiation oncologist raises the ethical concern about the 11 of 50 patients who ended up receiving no local therapy at all and who could have benefited from at least chemoradiotherapy, and the approach is characterized as hypothesis-generating rather than practice-changing given it is single-arm and non-randomized.

Discussed by: @StephenVLiu, @YGaritaonaindia, @GlopesMd, @diegoadiazg, @Latinamd

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PAPILLON's final OS misses in the ITT population but crossover-adjusted analysis shows a 43% reduction in risk of death

In the ITT population, median OS was 34.3 versus 27.9 months (HR 0.87; 95% CI 0.66-1.14; P=0.307), not statistically significant; 76% (97/128) of patients progressing on chemotherapy crossed over to amivantamab, and the crossover-adjusted IPCW analysis gave OS 34.3 versus 22.1 months (HR 0.57; 95% CI 0.39-0.82; nominal p=0.003), with PFS2 28.3 versus 17.5 months (HR 0.59; 95% CI 0.45-0.77) and 3-year PFS2 42% versus 19%. Clinicians note that when crossover exceeds 30%, OS becomes very challenging to demonstrate, and while the ITT OS result is statistically negative and should be described that way, the heavy crossover, strong prior PFS benefit, favorable PFS2 and supportive adjusted OS analyses still support amivantamab plus chemotherapy as a foundational first-line regimen — with PAPILLON also noted to have demonstrated the longest median OS reported to date for exon 20 EGFR-mutant NSCLC.

Discussed by: @GlopesMd, @GlopesMd, @M_Torasawa, @StephenVLiu, @DrSanjayPopat, @Latinamd, @ChandrakanthMv

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FDA cuts tarlatamab monitoring from 22-24 hours to 6-8 hours for the first two doses

On September 14, 2026 the FDA approved a label update reducing the recommended monitoring period for cycle 1 day 1 and day 8 of tarlatamab from 22-24 hours to 6-8 hours, with vital signs and assessment follow-up on days 2 and 9, and a requirement that patients remain within 1 hour of appropriate healthcare for 48 hours following cycle 1 day 1 and day 8. Clinicians describe removing the overnight admission requirement as a change that will increase patient access to treatment, while noting that validated risk assessment tools to identify patients at risk for high-grade cytokine release syndrome remain an unmet need; separately, DeLLphi-309, a randomized phase 2 study of extended-interval dosing, showed similar PFS, OS and toxicity across schedules, providing early support for more flexible dosing.

Discussed by: @GlopesMd, @GlopesMd, @Lung_Cancers, @Latinamd, @RManochakian

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ARROS-1 first-line cohort: zidesamtinib delivers a 94% response rate and 100% intracranial response in TKI-naive ROS1 NSCLC

In 94 TKI-naive patients receiving zidesamtinib 100 mg daily with 15 months of follow-up, ORR was 94% (95% CI 87-98) with 15% complete responses, median PFS not reached, PFS at 6 months 96% and at 12 months 90%, intracranial ORR 100% with intracranial complete response rate 70%, and no CNS progression events among 78 patients without baseline brain metastases — 86% remained in response at 12 months; clinicians note this is single-arm data with maturing follow-up and describe taletrectinib as still the frontline benchmark, with a PFS benchmark from TRUST-I/II of 46 months to beat, against the materially weaker pretreated cohort behind the original approval (44% ORR). Separately, the FDA approved an sNDA updating the taletrectinib label with a 49.7-month median duration of response from TRUST-I in ROS1-positive NSCLC.

Discussed by: @StephenVLiu, @GlopesMd, @DrMirallas, @Latinamd, @Tony_Calles, @ChandrakanthMv, @jennifermarksmd

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Sources cited: Targeted Oncology

IMpower030: perioperative atezolizumab nearly doubles median event-free survival but misses its primary endpoint

In resectable stage IIB-IIIB NSCLC, perioperative atezolizumab plus platinum chemotherapy yielded a median event-free survival of 62.8 versus 34.9 months, with EFS HR 0.77 (95% CI 0.58-1.02) and OS HR 0.77 (95% CI 0.57-1.07), both not statistically significant; pCR was 30.6% versus 8.6% and high rates of surgery were seen in both arms at approximately 90%. Clinicians note that atezolizumab failed where durvalumab, nivolumab and pembrolizumab all succeeded in AEGEAN, KEYNOTE-671, CheckMate 816 and CheckMate 77T, while others attribute the missed endpoint to tighter patient selection reflected in higher resection rates and a placebo arm that performed better than expected.

Discussed by: @StephenVLiu, @HHorinouchi, @ASCOPost, @diegoadiazg, @ChandrakanthMv

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Sources cited: Conference abstract · The ASCO Post

EMPOWER-Lung 01 analysis: KRAS G12C marks exceptional benefit from first-line cemiplimab monotherapy

In PD-L1-high nonsquamous NSCLC, KRAS G12C stood out for benefit from first-line cemiplimab monotherapy, with ORR 74% and PFS approximately 25 months in the largest cohort examining KRAS G12C in this non-squamous setting. The proposed explanation is that G12C is highly associated with smoking, most neoantigenic and favorable to immune checkpoint inhibition — a hypothesis-generating signal described as worth testing prospectively.

Discussed by: @GlopesMd, @RobertoBoreaMD, @ChristianRolfo

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ARTEMIS-008: risvutatug rezetecan nearly doubles overall survival over topotecan, landing the same day as TAISHAN-302

In 461 patients, risvutatug rezetecan delivered median OS 18.5 versus 10.3 months (HR 0.46; 95% CI 0.35-0.62; p<0.0001), PFS 7.2 versus 3.0 months (HR 0.33 by BICR), ORR 58.3% versus 12.6% and disease control rate 90.4% versus 60.2%, with 1-year OS rate 65% versus 43%; grade ≥3 treatment-related adverse events were 60.9% versus 78.2%, with ILD 11.7% versus 1.9% and no grade 4/5 ILD. Clinicians warn that the identical hazard ratios in ARTEMIS-008 and TAISHAN-302 must not be read as equivalence given that TAISHAN-302 reported mOS 13.3 months at 9.2 months follow-up versus ARTEMIS-008 mOS 18.5 months at 12.2 months follow-up, with different populations, study conduct and safety definitions; the higher ILD rate is cited as a reason this ADC is less desirable pending global data that might inform frequency of adverse events in a broader population.

Discussed by: @M_Torasawa, @Lung_Cancers, @Latinamd, @GlopesMd, @jennifermarksmd, @ChandrakanthMv, @Tony_Calles

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First combination of a PD-L1 x VEGF bispecific with a B7-H3 ADC posts a 70.4% response rate in advanced lung cancer

Pumitamig plus elfetabart drozuntecan showed an ORR of 70.4% overall, 92.3% in the first-line setting, 71% with brain metastases and 87.5% after prior DLL3 T-cell engager in advanced SCLC, with 93.0% disease control; however, the signal rests on small cohorts and only 3.2 months of follow-up. Investigators call for longer follow-up to evaluate long-term ADC tolerability and the contribution of the bispecific component, and raise the challenge of seeing how this combination will fit into a first-line era where T-cell engagers are already active.

Discussed by: @DrSanjayPopat, @OncLive, @OncologyMarwarD, @GlopesMd

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Sources cited: OncLive

STARLORD tests SABR to nodes and primary with adjuvant immunotherapy in stage III lung cancer unfit for concurrent chemoradiation

In 26 patients, SABR to nodes up to 40 Gy and to the primary up to 50 Gy plus adjuvant immunotherapy yielded 1-year local control of 92.3%, 1-year OS of 90.9%, 8% acute grade 3 adverse events and no late grade ≥3 toxicities, with worse outcomes in stage IIIC and age ≥75. The discussant grouped STARLORD alongside novel peptide thymosin a1 and the PD-1/VEGF bispecific JS207 as approaches to the question of irradiatable disease in locally advanced lung cancer, though clinicians note that with 26 patients and approximately one year of follow-up the approach remains patient-friendly and feasible but requires more follow-up.

Discussed by: @GlopesMd, @HHorinouchi, @GlopesMd

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Sources cited: Conference abstract

REZILIENT3: zipalertinib plus chemotherapy adds six months of PFS in first-line exon 20 insertion NSCLC at the cost of 80% grade 3+ toxicity

In 279 patients, zipalertinib plus chemotherapy versus chemotherapy alone delivered median PFS 14.5 versus 8.5 months (HR 0.50; 95% CI 0.34-0.73; p=0.00015), ORR 65.0% versus 40.3% (p<0.0001), DoR 14.2 versus 9.9 months and strong CNS activity (PFS HR 0.38; 95% CI 0.21-0.67 in patients with baseline brain metastases); grade ≥3 treatment-related adverse events were 80.7% versus 40.4%, mainly cytopenias, with pneumonitis 5.7% (grade ≥3 2.1%), OS immature (HR 0.72; 95% CI 0.42-1.23) and 64% crossover. Zipalertinib had an 80% dose reduction rate and 17% discontinuation rate; clinicians raise concerns about a death rate almost double that seen in PAPILLON and WU-KONG28 and question whether the toxicity of adding chemotherapy is warranted with such an active drug when it competes with amivantamab and sunvozertinib.

Discussed by: @M_Torasawa, @Latinamd, @BalazsHalmosMD, @ChandrakanthMv, @jennifermarksmd, @phsiao4, @diegoadiazg

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