📬 Lung/Head and Neck/Thymoma Intelligence Digest — Week 2026-W35

SAFFRON, DESTINY-Lung04, Panku-Lung01 and REZILIENT3 all report positive phase III topline results in EGFR- and HER2-driven NSCLC, KEYNOTE-671 delivers 5-year perioperative pembrolizumab outcomes, eVOLVE-Lung02 is discontinued for futility, and an Annals of Oncology study maps RAS alterations as a resistance route in oncogene-driven lung cancer.

⚡ TL;DR

📄 Publications

Danvatirsen plus pembrolizumab versus pembrolizumab for recurrent and/or metastatic head and neck squamous cell carcinoma (PEMDA-HN): a randomized, phase 2 trial. — ORRs were 15.6% with danvatirsen plus pembrolizumab and 14.3% with pembrolizumab alone (risk difference 1.3, P=1.0)
Five-Year Outcomes of Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer From the Randomized KEYNOTE-671 Study. — Five-year EFS was 49.9% with pembrolizumab versus 26.5% with placebo (HR 0.58)
Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer. — RAS alterations were identified in 35 of 312 patients (11.2%) progressing on first-line osimertinib, with enrichment in KRAS G12D (n=10) and only one KRAS G12C

🐦 Twitter / 🦋 Bluesky

CheckMate 77T biomarker analysis in Nature: ctDNA clearance and tumor-suppressor alterations track perioperative nivolumab benefit — Pre-surgical ctDNA clearance was 66% with nivolumab versus 38% with placebo, and 50% of clearance patients achieved pCR with nivolumab
KEYNOTE-671 at five years: perioperative pembrolizumab nearly doubles EFS and clinicians debate who still needs the adjuvant phase — Five-year EFS was 49.9% versus 26.5% (HR 0.58) and five-year OS 64.6% versus 53.6% (HR 0.74), with no detriment to quality of life
SAFFRON: osimertinib plus savolitinib is the first global phase III to improve both PFS and OS in MET-driven resistance after osimertinib — Savolitinib plus osimertinib significantly improved PFS and OS versus platinum-based chemotherapy in EGFR-mutant NSCLC with MET overexpression/amplification after osimertinib progression
DESTINY-Lung04: first-line T-DXd beats chemotherapy plus pembrolizumab in HER2-mutant NSCLC — First-line T-DXd significantly improved PFS versus pembrolizumab plus chemotherapy in advanced HER2-mutant NSCLC, the first phase 3 trial in which a HER2-directed therapy outperformed the global standard of care in this setting
RAS alterations emerge as a targetable escape route in oncogene-driven lung cancer, with KRAS G12D enriched after osimertinib — RAS alterations were found in 11.2% of patients progressing on first-line osimertinib, with KRAS G12D enriched, and were more frequent at lorlatinib resistance (14.7%)

Full details below ↓

📄 What's Being Published

Manuscripts:

Mesothelioma: Pleural, Version 3.2026, NCCN Clinical Practice Guidelines In Oncology. — Stevenson James et al., J Natl Compr Canc Netw

Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma.

Clinical bottom line: The updated NCCN pleural mesothelioma guideline remains the reference document for evaluation and treatment of the 85% of mesotheliomas that arise in the pleura.

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Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.3. — Wheatley Price Paul et al., J Clin Oncol

Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis. The major new change adds sunvozertinib monotherapy as a first-line option for EGFR exon 20 insertion NSCLC, alongside platinum-doublet chemotherapy plus amivantamab; in WU-KONG28, sunvozertinib versus carboplatin-pemetrexed produced a median PFS of 10.3 versus 7.5 months (HR 0.65).

Clinical bottom line: The ASCO living guideline now names sunvozertinib monotherapy as a guideline-backed chemotherapy-free frontline option for EGFR exon 20 insertion NSCLC, alongside chemotherapy plus amivantamab, with no head-to-head data to separate them.

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Danvatirsen plus pembrolizumab versus pembrolizumab for recurrent and/or metastatic head and neck squamous cell carcinoma (PEMDA-HN): a randomized, phase 2 trial. — Saba Nabil F et al., Clin Cancer Res

69 patients were randomized and 66 treated (45 with danvatirsen plus pembrolizumab, 21 with pembrolizumab alone); in the final analysis, ORRs were 15.6% and 14.3%, respectively (risk difference 1.3, P=1.0). Treatment-emergent adverse events were more frequent in the combination arm (97.8% vs 85.7%).

Clinical bottom line: Adding the STAT3-targeting antisense oligonucleotide danvatirsen to first-line pembrolizumab added toxicity without improving response in recurrent/metastatic HNSCC, so STAT3 inhibition needs a different combination strategy rather than this one.

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Five-Year Outcomes of Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer From the Randomized KEYNOTE-671 Study. — Wakelee H et al., Ann Oncol

797 participants were randomized to pembrolizumab (n=397) or placebo (n=400), with a median time from randomization to data cutoff of 60.4 months. Five-year EFS was 49.9% (95% CI, 44.6–55.0) in the pembrolizumab arm and 26.5% (95% CI, 21.7–31.5) in the placebo arm (HR 0.58; 95% CI, 0.48–0.69), and five-year OS was 64.6% (95% CI, 59.5–69.2) versus 53.6% (95% CI, 48.3–58.6), respectively (HR 0.74; 95% CI, 0.59–0.92), with no detriment to quality of life.

Clinical bottom line: At five years, perioperative pembrolizumab nearly doubles event-free survival and continues to improve overall survival without harming quality of life, confirming it as a standard of care for resectable stage II–IIIB(N2) NSCLC.

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Therapeutic targeting of RAS-mediated resistance in oncogene-driven lung cancer. — Facchinetti F et al., Ann Oncol

RAS alterations were identified in 35 of 312 patients (11.2%) progressing on first-line osimertinib, with enrichment in KRAS G12D (n=10) and only one KRAS G12C; in ALK-positive disease, RAS alterations were more common at lorlatinib resistance than after second-generation inhibitors (14.7% vs 5%, p=0.0444). In two patient-derived models with acquired KRAS mutations (G12D and G12R), combining osimertinib with the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib demonstrated marked synergistic activity in vitro and in vivo.

Clinical bottom line: RAS alterations account for roughly 10% of resistance across oncogene-driven lung cancers, and the preclinical synergy of osimertinib with zoldonrasib or daraxonrasib is a concrete rationale for taking these combinations into patients.

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🔗 Also discussed on social media →

🗂 Every paper considered this week, including the ones that didn’t make it →

🗣️ 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).

CheckMate 77T biomarker analysis in Nature: ctDNA clearance and tumor-suppressor alterations track perioperative nivolumab benefit

Pre-surgical ctDNA clearance was 66% with nivolumab versus 38% with placebo, and 50% of patients who achieved clearance attained a pCR with nivolumab. In tumors harboring KEAP1/STK11/CDKN2A/SMARCA4 alterations — historically associated with poor prognosis — EFS was still prolonged with nivolumab (HR 0.48). Clinicians described the correlative package — ctDNA clearance, post-surgical MRD, whole-exome sequencing, and patient-reported outcomes all reported together — as the standard phase 3 trials should aim for, though the question of whether these liquid biomarkers are ready to guide individual treatment decisions or remain hypothesis-generating remains unresolved.

Discussed by: @HosseinBorghaei, @StephenVLiu, @HHorinouchi, @EladSharonMD, @OncoAlert

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KEYNOTE-671 at five years: perioperative pembrolizumab nearly doubles EFS and clinicians debate who still needs the adjuvant phase

At five years, perioperative pembrolizumab produced EFS of 49.9% versus 26.5% (HR 0.58) and OS of 64.6% versus 53.6% (HR 0.74) with no detriment to quality of life. Clinicians framed this as immunotherapy doubling EFS at five years, with roughly 1 in 10 patients potentially cured with added immunotherapy, and argued that strong benefit in patients without pCR makes adjuvant immunotherapy prudent. Open questions remain about who requires neoadjuvant-only versus perioperative therapy, whether the adjuvant phase is needed and for how long, and whether PD-L1, pCR, or ctDNA/MRD can guide patient selection.

Discussed by: @kazuki_nozawa, @BalazsHalmosMD, @StephenVLiu, @HHorinouchi, @Dr_ElvinaA, @Dr_Oncologista, @EladSharonMD

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SAFFRON: osimertinib plus savolitinib is the first global phase III to improve both PFS and OS in MET-driven resistance after osimertinib

SAFFRON randomized 338 patients with EGFRm locally advanced or metastatic NSCLC and MET overexpression or amplification progressing after first- or second-line osimertinib to osimertinib 80 mg QD plus savolitinib 300 mg BID versus platinum-doublet chemotherapy, becoming the first global phase 3 trial to demonstrate both PFS and OS benefit in this setting. MET amplification is recognized as the most common resistance mechanism after first-line osimertinib, occurring in roughly 10–24% of patients. The result led clinicians to call rebiopsy and MET testing at osimertinib progression essential, while debate continues about what proportion of patients will actually be captured by routine testing — and how that denominator changes in patients who received FLAURA2-style doublet upfront therapy.

Discussed by: @M_Torasawa, @StephenVLiu, @HHorinouchi, @dplanchard, @BalazsHalmosMD, @peters_solange

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DESTINY-Lung04: first-line T-DXd beats chemotherapy plus pembrolizumab in HER2-mutant NSCLC

DESTINY-Lung04 is a phase III trial of 454 patients with HER2 exon 19/20 mutant NSCLC randomized to T-DXd 5.4 mg/kg versus chemotherapy plus pembrolizumab, with BICR-assessed PFS as the primary endpoint; first-line T-DXd significantly improved PFS, marking the first phase 3 trial in which a HER2-directed therapy outperformed the global standard of care in this setting. OS remains immature and full efficacy numbers are awaited at a forthcoming meeting. Clinicians noted that zongertinib already holds accelerated approval in the first-line setting, making DESTINY-Lung04 the first randomized data and positioning the field ahead of mature OS and CNS outcome results.

Discussed by: @DrSanjayPopat, @M_Torasawa, @StephenVLiu, @HHorinouchi, @dplanchard, @Dr_Oncologista

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RAS alterations emerge as a targetable escape route in oncogene-driven lung cancer, with KRAS G12D enriched after osimertinib

RAS alterations were found in 11.2% of patients progressing on first-line osimertinib, with KRAS G12D enriched and KRAS G12C notably rare; at lorlatinib resistance, RAS alterations were more frequent still, at 14.7%, and RAS alterations were detected in 7–16% of patients progressing on MET, ROS1, or RET inhibitors. In patient-derived osimertinib-resistant models, combining osimertinib with zoldonrasib or daraxonrasib showed marked synergy and overcame RAS-mediated resistance. The frequency across TKI classes led oncologists to debate whether RAS testing should become routine at progression on any oncogene-directed therapy, particularly given that the dominant post-osimertinib mutation is KRAS G12D rather than the more therapeutically accessible G12C.

Discussed by: @EladSharonMD, @HHorinouchi, @dplanchard, @Dr_ElvinaA

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Update: neoadjuvant chemoimmunotherapy in poorly selected stage III NSCLC draws a warning from radiation oncology

A JTO report describes harmful consequences of neoadjuvant chemoimmunotherapy in poorly selected patients with stage III NSCLC. In the ASTRES phase 2 study of atezolizumab in locally advanced unresectable stage III NSCLC, median OS was 38.8 months, median PFS was 16.7 months, the 12-month PFS rate was 54.9%, ORR was 44.9%, and grade 5 treatment-related adverse events occurred in 3.1% of patients. The combination of a positive signal in selected populations and documented harm in poorly selected ones has focused multidisciplinary discussion on how to determine which stage III patients proceed to surgery after chemoimmunotherapy rather than to definitive chemoradiation.

Discussed by: @EladSharonMD, @HHorinouchi

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Panku-Lung01: the EGFR-HER3 bispecific ADC iza-bren beats platinum chemotherapy after TKI failure

The phase III Panku-Lung01 study (BL-B01D1-301) of iza-bren, an EGFR-HER3 bispecific ADC, versus platinum doublet chemotherapy in EGFR-mutant NSCLC after TKI progression met its primary endpoint of PFS at interim analysis, with a favorable trend also observed in OS. This marks the fourth phase 3 trial for iza-bren to meet its primary endpoint, with more than 40 trials ongoing including in TNBC and urothelial cancer. The result prompted oncologists to debate whether an EGFR-HER3 bispecific ADC should now displace TROP2-directed ADCs and chemotherapy as the default strategy after osimertinib.

Discussed by: @StephenVLiu, @HHorinouchi, @DrJNaidoo, @dplanchard, @BalazsHalmosMD

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eVOLVE-Lung02 discontinued for futility: adding CTLA-4 blockade to PD-1 plus chemotherapy fails in PD-L1-low NSCLC

AstraZeneca's PD-1 × CTLA-4 bispecific volrustomig plus chemotherapy was stopped for futility in the first-line lung phase 3 setting; the IDMC determined the trial was unlikely to meet its dual primary endpoints of PFS or OS in metastatic NSCLC with PD-L1 <50%. Commentators framed the failure as a reminder that adding CTLA-4 to PD-1 plus chemotherapy was not sufficient to improve outcomes in this unselected population, and that better biomarkers are still needed to identify who benefits from CTLA-4 blockade. The result reopens the question of whether the problem is the target itself or the absence of a selection strategy.

Discussed by: @DrSanjayPopat, @HHorinouchi, @OncoAlert, @OncoAlert

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ABBV-706 in relapsed SCLC: the lower dose was chosen as RP2D with similar response and far less toxicity

ABBV-706, a SEZ6-targeting Top1 ADC, showed an ORR of 52% in relapsed/refractory SCLC overall; by dose level, ORR was 56% at 1.8 mg/kg versus 59% at 2.5 mg/kg, while grade ≥3 treatment-related adverse events were 54% versus 77%, with longer duration of response and numerically better PFS and OS at the lower dose, which was ultimately selected as the recommended phase 2 dose. Responses occurred across SEZ6 expression levels, suggesting ADC sensitivity extends beyond target expression alone, and the dose-selection data prompted specialists to ask how many other ADCs are being advanced above their optimal dose.

Discussed by: @JaniceTNBCmets, @LauraAlderMD

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Two B7-H3 ADCs report positive phase 3 results versus topotecan in relapsed SCLC

ARTEMIS-008, a phase 3 trial of risvutatug rezetecan in relapsed SCLC, met its primary endpoint of OS versus topotecan with a statistically significant and clinically meaningful benefit. TAISHAN-302, a randomized open-label phase 3 of the anti-B7-H3 ADC Tam-Peli versus topotecan in relapsed SCLC, is also scheduled for presentation at WCLC26, giving the meeting two randomized plenary presentations using B7-H3 ADCs in this setting. With two B7-H3 ADCs beating topotecan, specialists are debating whether the second-line SCLC decision now sits between a B7-H3 ADC and tarlatamab.

Discussed by: @HHorinouchi, @M_Torasawa, @DrRiyazShah, @HHorinouchi

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FDA approves zidesamtinib for previously treated ROS1-positive NSCLC as TKI-naive ARROS-1 data head to WCLC26

The FDA approved zidesamtinib (Jideytro) for adults with locally advanced or metastatic ROS1-positive NSCLC after prior ROS1 TKI therapy; in ARROS-1, the ORR was 44%, with many responses lasting at least 12 months. Efficacy and safety data for zidesamtinib in TKI-naive advanced or metastatic ROS1-positive NSCLC are scheduled for the WCLC26 plenary session. Clinicians noted that reimbursement in ROS1-positive disease is lagging, with crizotinib and entrectinib still the accessible options in the UK, raising the practical question of whether strong TKI-naive ARROS-1 data can support moving zidesamtinib to the first-line setting ahead of reimbursement catching up with the current label.

Discussed by: @HHorinouchi, @DrRiyazShah, @ClinOncNews

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🔥 Top Ranked Tweets

Hossein Borghaei, DO @HosseinBorghaei

RT @StephenVLiu: Nature publication today from Dr. Tina Cascone et al with tremendous detail on biomarkers from CheckMate 77T predicting benefit from perioperative nivolumab in patients with resectable NSCLC. Amazing amount of detailed data in this @Nature paper.

https://t.co/Sb0H4YOpxz

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