📬 Lung/Head and Neck/Thymoma Intelligence Digest — Week 2026-W31

FDA approved zidesamtinib for previously treated ROS1-positive NSCLC, MARIPOSA reported time to symptomatic progression of 43.6 vs 29.3 months, and the OPTIM trial showed nivolumab-ipilimumab is inferior to docetaxel after PD-1 progression in HNSCC.

⚡ TL;DR

📄 Publications

Interstitial lung disease in patients treated with antibody-drug conjugates: a review. — With T-DXd, pooled analyses report ILD incidence of approximately 10-15%, median onset 5-6 months, and a fatal-event rate of about 2.2%
Assessing time to symptomatic progression, a patient-relevant efficacy endpoint, in the MARIPOSA study in non-small cell lung cancer. — Median TTSP was 43.6 months with amivantamab and lazertinib versus 29.3 months with osimertinib (HR 0.69)

🐦 Twitter / 🦋 Bluesky

FDA approves zidesamtinib for previously treated ROS1-positive NSCLC — The FDA approved zidesamtinib for adults with locally advanced or metastatic ROS1-positive NSCLC previously treated with a ROS1 kinase inhibitor
MARIPOSA reports time to symptomatic progression with amivantamab-lazertinib versus osimertinib — Median time to symptomatic progression was 43.6 months with amivantamab plus lazertinib versus 29.3 months with osimertinib (HR 0.69)
SKYSCRAPER-05: neoadjuvant tiragolumab plus atezolizumab and chemotherapy in resectable NSCLC — Neoadjuvant tiragolumab plus atezolizumab plus chemotherapy gave RR 66%, MPR 51%, pCR 29% and a 2-year EFS rate of 60%, with 96% undergoing surgical resection (93% R0)
Update: CheckMate 227 vs 9LA real-world Japanese comparison of nivo-ipi with and without chemotherapy — In 181 patients, adding 2 cycles of chemotherapy gave higher RR (68% vs 34%) and DCR (83% vs 53%) but no significant difference in PFS or OS and higher grade 3+ TRAEs
TRACER/HERTras real-world cohort of T-DXd in HER2-mutant NSCLC — In 168 patients, ORR was 55%, median PFS 7.2 months and intracranial ORR 74%

Full details below ↓

📄 What's Being Published

Manuscripts:

Izalontamab Brengitecan (Iza-Bren), a First-in-Class EGFR-HER3 Bispecific Antibody-Drug Conjugate in Extensive-Stage Small Cell Lung Cancer: Results From a Phase Ib Study. — Zhao Yuanyuan et al., J Clin Oncol

In relapsed extensive-stage SCLC, iza-bren produced an ORR of 48.1% (95% CI, 34.0 to 62.4), with a median PFS of 4.1 months (95% CI, 3.0 to 5.5) and a median OS of 12.2 months (95% CI, 9.1 to 13.2). Among patients who received iza-bren as second-line treatment (n = 22), the ORR was 72.7% (95% CI, 49.8 to 89.3), median PFS 6.2 months (95% CI, 3.7 to 8.2), and median OS 15.0 months (95% CI, 8.7 to not reached).

Clinical bottom line: The EGFR-HER3 bispecific ADC iza-bren produces high response rates in relapsed extensive-stage SCLC, especially in the second-line setting, and is now being tested against topotecan in a phase III trial.

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Design-Outcome Concordance in Targeted-Therapy trials in Non-Small cell lung cancer: a Meta-Research study. — Mastrantoni Luca et al., J Natl Cancer Inst

Across 45 phase III RCTs, the median expected HR was 0.64 (IQR 0.61–0.67), while the pooled observed HR was 0.47 (95% CI 0.40–0.54); studies with higher standard errors were associated with larger treatment effects (P<.001). The proportional hazards assumption was violated in 8 trials (19%), and the pooled HR/RMST ratio was 1.40 (95% CI 1.29–1.52).

Clinical bottom line: Targeted-therapy trials in oncogene-driven NSCLC systematically exceed their design assumptions, and reporting retrodesign metrics plus restricted mean survival time would make their effect sizes easier to interpret.

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Interstitial lung disease in patients treated with antibody-drug conjugates: a review. — Petrelli Fausto et al., Lung Cancer

ILD with trastuzumab deruxtecan (T-DXd) has been most extensively characterized: pooled analyses report an incidence of approximately 10–15%, a median onset of 5–6 months, and a fatal-event rate of about 2.2%. Pharmacovigilance data from 1,277 cases showed that ILD, pneumonitis, and acute respiratory distress syndrome accounted for 40.6%, 27.9%, and 7.6% of pulmonary events, respectively, with acute respiratory distress syndrome carrying the earliest onset and highest case-fatality.

Clinical bottom line: ADC-related interstitial lung disease is a class effect extending well beyond HER2-directed agents and demands baseline risk assessment, serial HRCT, and prompt treatment interruption.

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Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study. — Niknafs Noushin et al., Clin Cancer Res

Targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) was conducted in 109 patients with metastatic NSCLC receiving anti-PD-(L)1 either as monotherapy or in combination. Patients in the landmark molecular response group had longer progression-free (p=1.6e-06) and overall survival (p=2.5e-05) than those with molecular progression.

Clinical bottom line: Undetectable ctDNA within 3–9 weeks of starting immunotherapy is an accurate early readout of survival benefit in metastatic NSCLC and should be prospectively tested as a trial endpoint.

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Utilizing machine learning to identify multimodal signatures for patients who would benefit from the addition of tremelimumab to durvalumab and chemotherapy (TRIDENT). — Skoulidis Ferdinandos et al., Clin Cancer Res

Using clinical and genomic data from the POSEIDON trial, a machine-learning model predicted treatment benefit from adding tremelimumab to first-line durvalumab and chemotherapy; the top-ranked 50% of patients with non-squamous tumors achieved an OS HR of 0.56 (95% CI: 0.33–0.97). EGFR wild-type, FGFR3 wild-type, CDKN2A wild-type, KRAS mutations, and STK11 mutations were the factors most associated with higher OS benefit.

Clinical bottom line: A machine-learning signature from POSEIDON points to KRAS- and STK11-mutant non-squamous NSCLC as the group that gains most from adding tremelimumab to durvalumab plus chemotherapy.

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Assessing time to symptomatic progression, a patient-relevant efficacy endpoint, in the MARIPOSA study in non-small cell lung cancer. — Nguyen Danny et al., Eur J Cancer

At the final protocol-specified OS analysis (median follow-up: 37.8 months), median time to symptomatic progression was 43.6 months with amivantamab and lazertinib versus 29.3 months with osimertinib (HR: 0.69; 95% CI: 0.57–0.83; p < 0.0001).

Clinical bottom line: Amivantamab plus lazertinib delays symptomatic progression by more than a year versus osimertinib, adding a patient-relevant dimension to the MARIPOSA benefit already seen on PFS and OS.

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Safety and efficacy of fecal microbiota transplantation in solid cancers resistant to immune checkpoint inhibitors: results of the MITRIC trial. — Ullern Andreas et al., J Immunother Cancer

No objective responses were observed in the MITRIC trial, while 5/12 patients recorded stable disease. Median PFS was 1.5 months and median OS was 10.1 months in this ICI-refractory solid tumour population.

Clinical bottom line: Fecal microbiota transplantation combined with checkpoint inhibitors was safe and feasible but produced no objective responses in ICI-refractory solid tumours including HNSCC.

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Development and validation of a risk-stratification model for individualized management of leptomeningeal metastases in EGFR-mutant NSCLC (LM-Index). — Wu Yingxi et al., Lung Cancer

The LM-Index risk score stratified patients into low-risk and high-risk groups with median OS of 22.6 months versus 9.9 months, respectively (p < 0.001). The model demonstrated good discrimination with a bias-corrected C-index of 0.73 in the derivation cohort and maintained consistent performance in external validation (C-index = 0.71).

Clinical bottom line: A five-factor index built on performance status, brain metastasis, meningeal enhancement, CSF cytology, and intracranial pressure gives clinicians a validated way to stratify survival in EGFR-mutant NSCLC with leptomeningeal disease.

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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).

FDA approves zidesamtinib for previously treated ROS1-positive NSCLC

The FDA approved zidesamtinib, a selective ROS1 inhibitor, for adults with locally advanced or metastatic ROS1-positive NSCLC previously treated with a ROS1 kinase inhibitor, based on the ARROS-1 trial showing an RR of 44% after prior TKI with a 1-year DOR rate of 69%. In heavily pretreated patients (1–4 prior ROS1 inhibitors), ORR was 44%, rising to 51% if repotrectinib-naive, with intracranial ORR of 50%. In cross-trial context, zidesamtinib's ORR of ~44% sits between taletrectinib (55%), repotrectinib (38%), and lorlatinib (35%), with an apparently better toxicity profile including less neurotoxicity. With five approved ROS1 TKIs, oncologists are debating which agent to use first line and how to sequence the others after progression.

Discussed by: @StephenVLiu, @RManochakian, @BalazsHalmosMD, @OncBrothers, @JessicaJLinMD, @mgonzalezvelMD, @LungCancerEu

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MARIPOSA reports time to symptomatic progression with amivantamab-lazertinib versus osimertinib

At the final protocol-specified OS analysis (median follow-up: 37.8 months), median time to symptomatic progression in MARIPOSA was 43.6 months with amivantamab plus lazertinib versus 29.3 months with osimertinib (HR 0.69; 95% CI: 0.57–0.83; p < 0.0001), with TTSP strongly correlated with PFS and OS. Clinicians weighing frontline EGFR strategy continue to debate whether combination therapy should be the default over monotherapy for patients with newly diagnosed EGFR del 19 metastatic NSCLC. The central question is whether a delay in symptomatic progression of this magnitude changes how patients are counselled when weighing amivantamab-lazertinib against osimertinib monotherapy.

Discussed by: @StephenVLiu, @lungoncdoc, @lungoncdoc, @maraantonoff

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SKYSCRAPER-05: neoadjuvant tiragolumab plus atezolizumab and chemotherapy in resectable NSCLC

In SKYSCRAPER-05, neoadjuvant tiragolumab (anti-TIGIT) plus atezolizumab plus chemotherapy produced an RR of 66%, MPR of 51%, and pCR of 29%, with a 2-year EFS rate of 60%; 96% of patients underwent surgical resection, of whom 93% achieved R0 resection. The broader question of neoadjuvant-only versus perioperative immunotherapy in resectable NSCLC is under concurrent review in the ASCO Educational Book. Whether anti-TIGIT combinations add meaningful benefit over chemo-immunotherapy alone in this setting — given the negative phase 3 TIGIT experience in advanced disease — remains an open debate among specialists.

Discussed by: @StephenVLiu, @dr_yakupergun, @drcoronacruz

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Update: CheckMate 227 vs 9LA real-world Japanese comparison of nivo-ipi with and without chemotherapy

In 181 patients, adding 2 cycles of chemotherapy to nivolumab-ipilimumab produced higher RR (68% vs 34%) and DCR (83% vs 53%) but no significant difference in PFS or OS, and was associated with higher grade 3+ TRAEs. The broader question of ICI monotherapy versus combination with chemotherapy is being addressed prospectively by the recently completed ECOG-SWOG phase 3 INSIGNA trial, which includes the PD-L1 1–49% group, with data analysis pending. The trade-off between improved response rates and increased toxicity — without a survival advantage — is the central point of debate for clinicians deciding which patients still warrant the added chemotherapy.

Discussed by: @StephenVLiu, @drgandara

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TRACER/HERTras real-world cohort of T-DXd in HER2-mutant NSCLC

In the multinational TRACER/HERTras real-world cohort (n=168), T-DXd achieved an ORR of 55%, median PFS of 7.2 months, and an intracranial ORR of 74%; ORR and OS were similar to the DESTINY trials at approximately 55% and approximately 18 months, with PFS slightly lower in this unselected population. ILD remains the dominant safety concern: pooled analyses of T-DXd report an incidence of approximately 10–15%, a median onset of 5–6 months, and a fatal-event rate of about 2.2%. The debate centres on whether the real-world intracranial activity seen here justifies using T-DXd before local therapy in HER2-mutant NSCLC with brain metastases, given that ILD risk.

Discussed by: @UOzkerim, @mgonzalezvelMD, @JTOonline

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Head-to-head comparison of ctDNA assays for MRD detection in resected NSCLC

A head-to-head comparison of ctDNA assays for MRD detection in resected NSCLC showed that the personalized assay achieved sensitivity of 40.9% and specificity of 100%, with MRD positivity predicting shorter DFS (HR 13.98) and a 7-month lead time over radiographic recurrence. A counterpoint raised by clinicians is that the comparison covers genomics-only assays, while emerging assays are multi-omic — incorporating not only genomics but also DNA fragmentomics and methylation — which may substantially enhance their application. Whether tumor-informed personalized panels should be the reference standard, or will be displaced by multi-omic platforms before broad adoption, is the central question.

Discussed by: @HHorinouchi, @drgandara

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OPTIM: nivolumab plus ipilimumab loses to docetaxel after PD-1 progression in head and neck cancer

In the OPTIM trial, nivolumab plus ipilimumab after PD-1 progression in recurrent/metastatic HNSCC produced an ORR of 0% versus 17.6% with docetaxel, with PFS of 1.97 versus 3.66 months (p=0.036) and OS of 3.97 versus 11.9 months (p=0.356), all favoring docetaxel. These results bring into question whether there is any remaining rationale for adding CTLA-4 blockade following anti-PD-1 failure in this setting, or whether chemotherapy should be the unambiguous standard.

Discussed by: @DaisukeKotani, @UOzkerim

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DART: durvalumab with radiotherapy alone in chemoradiation-ineligible stage III NSCLC

In the single-arm phase II DART study, patients with locally advanced unresectable NSCLC ineligible for concurrent chemoradiation received radiation without chemotherapy plus concurrent durvalumab followed by durvalumab consolidation, achieving a 2-year PFS of 39% versus a historical benchmark of 20%, and a 2-year OS of 54%; PD-L1 positivity and better performance status were associated with improved outcomes. The design met its primary endpoint, but specialists continue to debate whether concurrent durvalumab with radiation is necessary in this population or whether consolidation durvalumab alone would suffice.

Discussed by: @StephenVLiu, @HHorinouchi

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Iza-bren, an EGFR-HER3 bispecific ADC, in relapsed extensive-stage SCLC

In the phase Ib study, iza-bren produced an overall ORR of 48.1%, median PFS of 4.1 months, and median OS of 12.2 months, with results in the second-line setting showing ORR 72.7%, median PFS 6.2 months, and median OS 15.0 months; HER3 positivity may predict better response. A phase III randomized controlled trial of iza-bren compared with topotecan (NCT06500026) is ongoing. With tarlatamab currently the preferred second-line option and ADCs emerging as a class in SCLC, oncologists are debating whether a bispecific EGFR-HER3 ADC can displace topotecan and compete with DLL3-directed agents in the relapsed setting.

Discussed by: @HHorinouchi, @lungoncdoc

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🔥 Top Ranked Tweets

Kate Sears @MedwatchKate

RT @StephenVLiu: FINALLY! AstraZeneca reaches deal with Dizal to bring sunvozertinib to the US! Approved for EGFR exon 20 NSCLC over a year ago but only available in China (and at a different dose). This deal comes off phase 3 WU-KONG28 showing superiority over 1L chemo.

https://t.co/qNuZpeSNKn https://t.co/MUrUmSQNsM

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