📬 Lung/Head and Neck/Thymoma Intelligence Digest — Week 2026-W28

Divarasib beat approved KRAS G12C inhibitors head-to-head in Krascendo 1, a PACIFIC post-hoc analysis linked baseline PPIs and antibiotics to worse durvalumab outcomes, and ASCO updated its stage IV NSCLC living guidelines.

⚡ TL;DR

📄 Publications

Long-Term Follow-Up of JCOG1008, a Randomized Phase II/III Trial of Chemoradiotherapy Comparing 3-Weekly Cisplatin With Weekly Cisplatin in Postoperative Head and Neck Cancer. — 5-year OS 58.7% in the 3-weekly arm and 71.2% in the weekly arm, HR 0.76
Early Detriment Analysis of First-Line Nivolumab plus Ipilimumab-Based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer. — Rapid progression rates were 40% with nivolumab plus ipilimumab versus 26% with chemotherapy
Differential impact of proton pump inhibitors and antibiotics on immunotherapy efficacy after chemoradiotherapy in locally advanced non-small-cell lung cancer: a post-hoc analysis of the PACIFIC trial. — With durvalumab, baseline PPI exposure was associated with shorter PFS (9.4 vs 17.2 months, HR 1.57) and OS (33.0 vs 57.9 months, HR 1.66)

🐦 Twitter / 🦋 Bluesky

Nature Reviews review: refining neoadjuvant and perioperative therapy in resectable NSCLC — pCR is a robust surrogate of durable benefit with 5-year OS above 95% in pCR patients in CheckMate 816
PACIFIC post-hoc: PPIs and antibiotics linked to worse durvalumab outcomes — Median OS was 57.9 vs 33.0 months with baseline PPI use among durvalumab patients (HR 1.66), with no association in placebo
Krascendo 1: divarasib beats approved KRAS G12C inhibitors head-to-head in second-line NSCLC — Divarasib significantly improved PFS and OS versus sotorasib and adagrasib in previously treated advanced KRAS G12C NSCLC
TP53 gain-of-function mutations linked to early osimertinib resistance in EGFR-mutant NSCLC — In 140 patients on first-line osimertinib, TP53 gain-of-function mutations identified a subgroup with significantly shorter PFS despite similar ORR
Acquired EML4-ALK rearrangements drive resistance to KRAS G12C (OFF) inhibitors — Acquired EML4-ALK rearrangements drive resistance to KRAS G12C (OFF) inhibitors by restoring RAS signaling through wild-type KRAS

Full details below ↓

📄 What's Being Published

Manuscripts:

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.2. — Puri Sonam et al., J Clin Oncol

This version of the ASCO living guideline for driver-altered stage IV NSCLC is produced by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. Updates are issued on a regular schedule to reflect new evidence as it emerges.

Clinical bottom line: ASCO's living guideline for driver-altered stage IV NSCLC is refreshed on a continuous schedule to keep pace with rapidly changing evidence.

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Long-Term Follow-Up of JCOG1008, a Randomized Phase II/III Trial of Chemoradiotherapy Comparing 3-Weekly Cisplatin With Weekly Cisplatin in Postoperative Head and Neck Cancer. — Tahara Makoto et al., J Clin Oncol

At 5.6-year follow-up of JCOG1008, 5-year OS was 58.7% in the 3-weekly cisplatin arm and 71.2% in the weekly cisplatin arm (HR 0.76, 95% CI 0.52 to 1.12), confirming noninferiority of the weekly regimen in postoperative high-risk head and neck cancer.

Clinical bottom line: 5.6-year follow-up of JCOG1008 confirms weekly cisplatin plus radiotherapy is noninferior in OS to 3-weekly cisplatin in postoperative high-risk head and neck cancer.

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Early Detriment Analysis of First-Line Nivolumab plus Ipilimumab-Based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer. — Borghaei Hossein et al., Clin Cancer Res

In this analysis of CheckMate 227 and CheckMate 9LA, rapid progression rates were 40% with nivolumab plus ipilimumab versus 26% with chemotherapy. Early detriment was not observed with nivolumab plus ipilimumab plus chemotherapy across subgroups from CheckMate 9LA.

Clinical bottom line: The published CheckMate 227/9LA early-detriment analysis identifies NLR, TMB, PD-L1, albumin, and M-MDSC as predictors of rapid progression on first-line nivolumab plus ipilimumab, an effect avoided by adding chemotherapy.

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🔗 Also discussed on social media →

Impact of preexisting interstitial lung disease on pneumonitis and survival during first-line immune checkpoint inhibitor-based therapy in non-small cell lung cancer. — Matsumoto Kinnosuke et al., Eur J Cancer

Among 1340 patients, 158 (11.8%) had preexisting ILD. Preexisting ILD was independently associated with higher risks of any-grade pneumonitis (adjusted sHR 2.64, 95% CI 1.91–3.65) and grade ≥3 pneumonitis (adjusted sHR 2.18, 95% CI 1.37–3.47), as well as worse OS (adjusted HR 1.36, 95% CI 1.12–1.66).

Clinical bottom line: Preexisting ILD, particularly probable UIP/UIP pattern, marks NSCLC patients at higher risk of pneumonitis and shorter survival on first-line ICI, supporting pretreatment HRCT assessment.

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Differential impact of proton pump inhibitors and antibiotics on immunotherapy efficacy after chemoradiotherapy in locally advanced non-small-cell lung cancer: a post-hoc analysis of the PACIFIC trial. — Brunetti Leonardo et al., Lancet Oncol

In the durvalumab group, baseline PPI exposure was associated with shorter PFS (9.4 vs 17.2 months, HR 1.57, p<0.0001) and shorter OS (33.0 vs 57.9 months, HR 1.66, p<0.0001). Baseline antibiotic exposure was associated with shorter PFS with durvalumab (9.2 vs 15.6 months, HR 1.50, p=0.016) but no significant change in overall survival; neither association was observed in the placebo arm.

Clinical bottom line: In this PACIFIC post-hoc analysis, baseline PPIs and antibiotics were tied to inferior durvalumab outcomes but not placebo, providing the first randomized-trial signal that microbiome-modifying drugs may attenuate curative-intent immunotherapy benefit.

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Excessive vascular integrity restricts anti-tumor immunity. — Trotta Rosa et al., Cell

Wang et al. identify an immune-excluding vasculature in small-cell lung cancer, where excessive vessel integrity drives immune desertification. The commentary proposes "reverse normalization" as a strategy to restore immune access and overcome immunotherapy resistance.

Clinical bottom line: A Cell commentary proposes reverse vascular normalization to restore immune access and overcome immunotherapy resistance in small-cell lung cancer.

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Limited predictive value of PD-L1 TPS for pathological response in NSCLC is not attributable to interobserver variability. — Steinestel Konrad et al., Lung Cancer

PD-L1 TPS remained poorly correlated with residual viable tumor for both single-rater assessment (r = −0.17, p = 0.38) and averaged TPS (r = −0.16, p = 0.39), with no significant difference between these approaches (p = 0.96). The findings indicate this is an intrinsic biomarker limitation rather than a measurement artifact.

Clinical bottom line: PD-L1 TPS poorly predicts pathological response after neoadjuvant chemoimmunotherapy, and this is an intrinsic biomarker limitation rather than interobserver variability.

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Durvalumab plus etoposide-platinum in patients with epidermal growth factor receptor (EGFR)-mutated advanced NSCLC and neuroendocrine transformation after first-line osimertinib: ORCHARD. — Okamoto Isamu et al., Lung Cancer

In this ORCHARD module, confirmed ORR was 43% (80% CI: 24–63), with six partial responses. Median PFS was 4.2 months (95% CI: 3.0–5.6) and median overall survival was 10.2 months (95% CI: 4.3–16.8) in EGFR-mutant NSCLC with neuroendocrine transformation after osimertinib.

Clinical bottom line: Final ORCHARD module data show durvalumab plus etoposide-platinum yields only modest activity (ORR 43%, mOS 10.2 months) in neuroendocrine-transformed EGFR-mutant NSCLC after osimertinib.

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🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

Nature Reviews review: refining neoadjuvant and perioperative therapy in resectable NSCLC

A Nature Reviews discussion positioned pCR as a robust surrogate of durable benefit, citing 5-year OS above 95% in pCR patients from CheckMate 816. Alongside pCR, ctDNA, radiomics, and baseline biomarkers were highlighted as complementary tools to refine patient selection and adapt perioperative strategy, with debate centering on whether these dynamic measures can move perioperative NSCLC toward response-adaptive, biology-guided escalation and de-escalation.

Discussed by: @YGaritaonaindia, @HHorinouchi, @FordePatrick

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PACIFIC post-hoc: PPIs and antibiotics linked to worse durvalumab outcomes

The PACIFIC post-hoc analysis reported in Lancet Oncology generated substantial discussion, with oncologists noting that baseline PPI exposure was linked to shorter PFS (9.4 vs 17.2 months, HR 1.57) and OS (33.0 vs 57.9 months, HR 1.66) among durvalumab-treated patients, with no significant association observed in the placebo arm. Baseline antibiotic exposure similarly corresponded to shorter PFS with durvalumab, prompting direct debate over whether clinicians should review and deprescribe PPIs and recent antibiotics before initiating PACIFIC-style durvalumab consolidation.

Discussed by: @BRicciutiMD, @HabibzadehMD, @dplanchard

→ View representative tweet

Krascendo 1: divarasib beats approved KRAS G12C inhibitors head-to-head in second-line NSCLC

Genentech announced positive phase III Krascendo 1 results showing that the investigational KRAS G12C inhibitor divarasib significantly improved progression-free and overall survival compared with the approved agents sotorasib and adagrasib in previously treated advanced KRAS G12C non-small cell lung cancer, meeting the primary endpoint. Specialists noted divarasib's superiority over first-generation KRAS G12C inhibitors and turned attention to whether a superior second-line result will translate into first-line combination success in Krascendo 2.

Discussed by: @StephenVLiu, @DrSanjayPopat, @FordePatrick, @YGaritaonaindia

→ View representative tweet

TP53 gain-of-function mutations linked to early osimertinib resistance in EGFR-mutant NSCLC

A genomic analysis of 140 patients with EGFR-mutant NSCLC receiving first-line osimertinib found that TP53 gain-of-function mutations identified a distinct subgroup with significantly shorter progression-free survival despite similar objective response rates. This pattern focused debate on whether TP53 gain-of-function status should guide upfront treatment intensification in first-line EGFR-mutant NSCLC.

Discussed by: @OncoAlert, @SandraOrtizCua1

→ View representative tweet

Acquired EML4-ALK rearrangements drive resistance to KRAS G12C (OFF) inhibitors

Clinicians discussed data demonstrating that acquired EML4-ALK rearrangements drive resistance to KRAS G12C (OFF) inhibitors by restoring RAS signaling through wild-type KRAS, representing a therapeutically actionable bypass mechanism. The central question debated was whether combining KRAS G12C and ALK inhibition could overcome this acquired bypass resistance mechanism.

Discussed by: @BRicciutiMD, @DrJNaidoo

→ View representative tweet

CheckMate 73L: nivolumab-based consolidation fails to beat durvalumab in stage III NSCLC

In a phase III trial, nivolumab plus concurrent chemoradiotherapy followed by nivolumab ± ipilimumab failed to improve PFS or OS versus standard concurrent chemoradiotherapy followed by durvalumab in unresectable stage III NSCLC, and both nivolumab-based strategies were associated with increased pneumonitis. Oncologists debated whether CheckMate 73L cements concurrent chemoradiotherapy followed by durvalumab as the durable standard of care in this setting.

Discussed by: @diegoadiazg, @OncodailyLung

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EU approval of trastuzumab deruxtecan as first tumour-agnostic HER2-directed ADC

AstraZeneca and Daiichi Sankyo's trastuzumab deruxtecan received EU approval as the first tumour-agnostic HER2-directed antibody-drug conjugate for previously treated, unresectable or metastatic HER2-positive (IHC 3+) solid tumours without satisfactory options, with clinicians noting strong efficacy in HER2 3+ NSCLC patients across the DESTINY-Lung01 and Lung03 trials. Discussion centered on whether reimbursement and access will constrain the real-world impact of tumour-agnostic trastuzumab deruxtecan in HER2 3+ NSCLC.

Discussed by: @dplanchard, @OncUpdates

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🔥 Top Ranked Tweets

OncoAlert @OncoAlert

RT @DrRishabhOnco: Perioperative immunotherapy has rewritten the treatment landscape of resectable NSCLC. 🫁

Keeping track of what is approved has become surprisingly difficult.

Here’s the simplest way to remember it 👇

🔹 Adjuvant
✅ IMpower010 → Atezolizumab
✅ PEARLS/KEYNOTE-091 → Pembrolizumab

🔹 Neoadjuvant
✅ CheckMate 816 → Nivolumab + platinum chemotherapy

🔹 Perioperative
✅ KEYNOTE-671 → Pembrolizumab + chemotherapy → surgery → pembrolizumab
✅ AEGEAN → Durvalumab + chemotherapy → surgery → durvalumab
✅ CheckMate 77T → Nivolumab + chemotherapy → surgery → nivolumab

@ASCO @myESMO @IASLC @oncoalert

#LungCancer #NSCLC #Immunotherapy #MedTwitter

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