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• Pluvicto^TM plus standard of care (ARPI + ADT) significantly reduced risk of progression or death by 28% (HR 0.72) versus SoC alone, with positive trend in OS (HR 0.84) in PSMA+ metastatic hormone-sensitive prostate cancer (mHSPC)¹
• Most patients with mHSPC progress to metastatic castration-resistant prostate cancer, underscoring urgent need for new therapies that can reduce risk of progression in earlier disease settings^2,3
• The safety profile and tolerability of Pluvicto in this third positive Phase III study were consistent with its established profile in PSMAfore and VISION trials^1,4,5
• Novartis plans to submit to regulatory authorities by end of year; potential approval would double the number of patients eligible for Pluvicto and further establish its efficacy in metastatic prostate cancer settings

Basel, October 19, 2025 – Novartis today presents new Pluvicto™ (lutetium (¹⁷⁷Lu) vipivotide tetraxetan) data from the Phase III PSMAddition trial in a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2025.

Pluvicto plus standard of care (SoC) (androgen receptor pathway inhibitor [ARPI] + androgen deprivation therapy [ADT]) demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS), reducing the risk of radiographic progression or death by 28% (HR 0.72; 95% CI: 0.58, 0.90) versus SoC alone in patients with prostate-specific membrane antigen (PSMA)+ metastatic hormone-sensitive prostate cancer (mHSPC)¹.

Results also show an early positive trend in overall survival (OS) in patients treated with Pluvicto plus SoC (HR 0.84; 95% CI: 0.63, 1.13); follow-up will continue until data are mature¹. More patients achieved a complete response versus SoC alone (57.1% vs. 42.3%) and the overall response rate (ORR) was numerically higher in the Pluvicto plus SoC arm (85.3% vs. 80.8%)¹. Pluvicto delayed time to progression to metastatic castration-resistant prostate cancer (mCRPC) (HR 0.70; 95% CI: 0.58, 0.84)¹. The rPFS benefit was consistent across pre-specified subgroups¹.

“In metastatic prostate cancer, choosing the most efficacious treatment early is crucial, even at initial diagnosis,” said Scott T. Tagawa, MD, a professor of medicine at Weill Cornell Medicine and a medical oncologist at NewYork-Presbyterian/Weill Cornell Medical Center. “These findings suggest that combining ¹⁷⁷Lu-PSMA-617 with standard of care hormonal therapy offers patients more time without disease progression, a safety profile with adverse events that are most often low grade and managed with supportive care, and an encouraging trend in overall survival.” 

“These results reinforce the potential for Pluvicto, a radioligand therapy that delivers treatment directly to target cells, to change how we treat metastatic prostate cancer,” said Shreeram Aradhye, President, Development and Chief Medical Officer, Novartis. “With significant benefit now shown across multiple disease stages, Pluvicto is redefining the standard of care. The strength of these results reflects our deep commitment to patients with prostate cancer and our leadership in radioligand therapy.”

The safety profile and tolerability of Pluvicto were consistent with its established profile in PSMAfore and VISION^1,4,5. Grade ≥3 adverse events (AEs) were reported in 50.7% of patients in the Pluvicto plus SoC arm, compared to 43% on SoC alone¹. The most common all-grade AEs were dry mouth, fatigue, nausea, hot flush and anemia¹.

PSMAddition marks the third positive Phase III trial with Pluvicto^1,4,5. Building on the significant benefit demonstrated in PSMAfore, which led to the US Food and Drug Administration (FDA) approval in pre-taxane mCRPC in March 2025, these new results strengthen the evidence base for Pluvicto and demonstrate its potential to improve outcomes in an even earlier stage of metastatic prostate cancer^1,4,6. Novartis plans to submit these data to regulatory authorities before end of year.

About unmet need in mHSPC
Approximately 172,000 men are diagnosed with mHSPC each year across the US, China, Japan, France, Germany, Italy, Spain and the United Kingdom¹. Most patients progress to mCRPC, typically within 20 months^2,3,7,8. Progression to mCRPC is associated with significantly worse outcomes, including increased patient burden, worse quality of life and life expectancy less than two years^9,10. More than 80% of patients with prostate cancer highly express the PSMA biomarker, making it a promising therapeutic target^11–15.

About PSMAddition
PSMAddition (NCT04720157) is a Phase III, open-label, prospective, 1:1 randomized study comparing the efficacy and safety of Pluvicto in combination with SoC (ARPI + ADT) vs. SoC alone in adult patients with PSMA+ mHSPC¹⁶. The primary endpoint is rPFS, defined as the time to radiographic progression by PCWG3-modified RECIST V1.1 (as assessed by BIRC) or death¹⁶. The key secondary endpoint of OS is defined as time to death due to any cause¹⁶. The study remains ongoing and a total of 1,144 patients with mHSPC across 20 countries have been randomized in the trial¹⁶.

About Pluvicto™ (lutetium (¹⁷⁷Lu) vipivotide tetraxetan)
Pluvicto is an intravenous RLT that combines a targeting compound (a ligand) with a therapeutic radionuclide (a radioactive particle, in this case lutetium-177)^5,17. After administration into the bloodstream, Pluvicto binds to PSMA-expressing target cells, including prostate cancer cells that express PSMA, a transmembrane protein^5,17. Once bound, energy emissions from the radioisotope damage the target cells and nearby cells, disrupting their ability to replicate and/or triggering cell death¹⁷.

Pluvicto is the only PSMA-targeted agent approved for PSMA+ mCRPC and is the first RLT to demonstrate a clinical benefit for patients with PSMA+ mHSPC in a Phase III trial¹. Novartis is investigating Pluvicto in oligometastatic prostate cancer, an earlier stage of disease, in the PSMA-DC trial (NCT05939414).

Novartis and radioligand therapy (RLT)
Novartis is reimagining cancer care with RLT for patients with advanced cancers. By harnessing the power of targeted radiation and applying it to advanced cancers, RLT is designed to deliver treatment directly to target cells, anywhere in the body^18,19. Novartis is investigating a broad portfolio of RLTs, exploring new isotopes, ligands and combination therapies to look beyond gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and prostate cancer and into breast, colon, lung and pancreatic cancer. Novartis has established global expertise, with specialized supply chain and manufacturing capabilities across its network of RLT production sites. To support growing demand for RLTs, we have active production capabilities in Millburn (NJ), Zaragoza (Spain), Ivrea (Italy) and a state-of-the-art facility in Indianapolis (IN). Expansions are ongoing in Carlsbad (CA), where Novartis is establishing its third US-based RLT manufacturing site to support expanded use of RLTs, and Sasayama (Japan) to create resiliency and optimize delivery of medicines to patients.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis 
Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach nearly 300 million people worldwide.

Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn, Facebook, X/Twitter and Instagram.

Disclosure: Dr. Tagawa is a paid consultant for Novartis.

References

1. Novartis. Data on file.
2. Hussain M, Fizazi K, Shore ND, et al. Metastatic hormone-sensitive prostate cancer and combination treatment outcomes. JAMA Oncol. 2024;10(6):807-820. 
3. Kulasegaran T, Oliveira N. Metastatic castration-resistant prostate cancer: advances in treatment and symptom management. Curr Treat Options Oncol. 2024;25(7):914-931.
4. Morris M, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024. doi:10.1016/S0140-6736(24)01653-2.
5. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322.
6. Pluvicto [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2025.
7. Verry C, Vincendeau S, Massetti M, et al. Pattern of clinical progression until metastatic castration-resistant prostate cancer: an epidemiological study from the European Prostate Cancer Registry. Target Oncol. 2022;17(4):441-451.
8. Wenzel M, Siech C, Hoeh B, et al. Contemporary treatment patterns and oncological outcomes of metastatic hormone-sensitive prostate cancer and first- to sixth- line metastatic castration-resistant prostate cancer patients. Eur Urol Open Sci. 2024;66:46-54.
9. Freedland SJ, Davis M, Epstein AJ, Arondekar B, Ivanova JI. Real-world treatment patterns and overall survival among men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis. 2024;27(2):327-333.
10. Holmstrom S, Naidoo S, Turnbull J, et al. Symptoms and impacts in metastatic castration-resistant prostate cancer: qualitative findings from patient and physician interviews. Patient. 2019;12(1):57-67.
11. Hope TA, Aggarwal R, Chee B, et al. Impact of 68Ga-PSMA-11 PET on management in patients with biochemically recurrent prostate cancer. J Nucl Med. 2017;58(12):1956-61.
12. Hupe MC, Philippi C, Roth D, et al. Expression of prostate-specific membrane antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. Front Oncol. 2018;8:623.
13. Bostwick DG, Pacelli A, Blute M, et al. Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 1998;82(11):2256-61.
14. Pomykala KL, Czernin J, Grogan TR, et al. Total-body 68Ga-PSMA-11 PET/CT for bone metastasis detection in prostate cancer patients: potential impact on bone scan guidelines. J Nucl Med. 2020;61(3):405-11.
15. Minner S, Wittmer C, Graefen M, et al. High level PSMA expression is associated with early PSA recurrence in surgically treated prostate cancer. Prostate. 2011;71(3):281-8.
16. Clinicaltrials.gov. NCT04720157. An International Prospective Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With SoC, Versus SoC Alone, in Adult Male Patients With mHSPC (PSMAddition). Accessed October 2025. https://clinicaltrials.gov/study/NCT04720157.
17. University of Chicago Medicine. Lutetium-177 PSMA Therapy for Prostate Cancer (Pluvicto). Accessed October 2025. https://www.uchicagomedicine.org/cancer/types-treatments/prostate-cancer/treatment/lutetium-177-psma-therapy-for-prostate-cancer.
18. Jadvar H. Targeted Radionuclide Therapy: An Evolution Toward Precision Cancer Treatment [published correction appears in AJR Am J Roentgenol. 2017 Oct;209(4):949. doi:10.2214/AJR.17.18875]. AJR Am J Roentgenol. 2017;209(2):277-288. doi:10.2214/AJR.17.18264.
19. Jurcic JG, Wong JYC, Knoc SJ, et al. Targeted radionuclide therapy. In: Tepper JE, Foote RE, Michalski JM, eds. Gunderson & Tepper’s Clinical Radiation Oncology. 5th ed. Elsevier, Inc. 2021;71(3):209-249.

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Abstracts presented during the CHEST annual meeting, held in Chicago, Illinois, October 19-22, 2025, showed the efficacy of brensocatib (Brinsupr; Insmed Incorporated Investor Relations) in reducing the activity of neutrophil serine proteases (NSPs) and reducing symptom burden in patients with non–cystic fibrosis bronchiectasis.

Brensocatib was approved by the FDA for use in bronchiectasis just this year based on the findings of the ASPEN trial (NCT04594369).¹ Although the approval was solely in adults, other studies found that brensocatib was effective in adolescents as well, presenting the first-ever method of treatment for those living with bronchiectasis.

An abstract reporting on the effect of brensocatib on sputum NSP concentrations compared with placebo through 52 weeks of treatment and 4 weeks of follow-up was presented during the conference.² All participants were adult patients from the ASPEN trial and were required to have at least 2 instances of pulmonary exacerbations in the 12 months prior to screening for the trial. Participants were split 1:1:1 for 10-mg brensocatib, 25-mg brensocatib, or a matching placebo. Sputum samples were collected at baseline and weeks 4, 16, 28, 40, 52, and 56, with the last sample being collected 4 weeks after treatment.

There were 105 participants in the 10-mg group, 108 in the 25-mg group, and 115 in the placebo group who were included in the analysis. Neutrophil elastase (NE), cathepsin G (CatG), and proteinase 3 (PR3) were the primary NSPs evaluated and varied between the 3 groups at baseline.

Both groups receiving brensocatib saw a decrease in activity of NE, CatG, and PR3 by the fourth week compared with the placebo group, which did not see any change. The median (range) percent change in the 10-mg and 25-mg groups was –33.7% (–58.8% to 0.0%) and –41.2% (–71.1% to –3.6%), respectively, compared with –4.6% in the placebo group for NE; similar results were found for median change in CatG (–39.7%, –48.1%, and 0.0%, respectively) and PR3 (–27.7%, –58.4%, and 0.0%, respectively). When participants stopped taking treatment, activity returned to baseline.

The authors concluded that active receipt of brensocatib resulted in the reduction of activity in NSP within the first 4 weeks of taking the treatment. The 25-mg dose also resulted in a higher reduction in activity compared with the 10-mg dose.

The second abstract focused on the effect of brensocatib on symptom burden for patients with bronchiectasis with or without pulmonary exacerbations.³ The ASPEN trial had previously found that both the 10-mg and 25-mg doses of brensocatib had reduced the rate of pulmonary exacerbations, the time to first exacerbation, and increased the odds of going without an exacerbation for 52 weeks. This analysis instead focused on how brensocatib affected symptoms of those with bronchiectasis with or without pulmonary exacerbations using the Bronchiectasis Exacerbation and Symptom Tool (BEST).

Participants were all from the ASPEN trial randomized 1:1:1 to 10 mg of brensocatib, 25 mg of brensocatib, or placebo for 52 weeks. Severe exacerbations were defined as those that required intravenous antibiotics or hospitalization. The BEST measurement assessed breathlessness, fatigue, sputum volume, cough, symptoms of the cold or flu, and sputum purulence. These measurements were taken each day until the end of the study. Lower scores indicated fewer symptoms.

There were 784 participants in the group without exacerbations, 879 in the group with any exacerbation, and 194 in the group with severe exacerbations included in the study. Symptom burden was greater in patients with exacerbations compared with those without any exacerbations. Those who used brensocatib had a baseline decrease in BEST score that was greater than those who did not take brensocatib across all subgroups.

Those who took brensocatib had reduced symptom burden 21 days before and after a severe exacerbation compared with placebo, with a mean (SD) peak score increase from baseline of 3.45 (4.1) in the 10-mg group and 3.43 (4.4) in the 25-mg group that was taken 5 to 7 days before the start date of the severe exacerbation. In comparison, the mean peak score increase was 4.07 (4.4) in those who used placebo.

The researchers concluded that symptom burden was reduced in those taking brensocatib of either dose regardless of the occurrence of exacerbations. Those without exacerbations and patients using the 25-mg dose saw the greatest reductions in symptom burden.

References

1. McCormick B. Brensocatib becomes first FDA-approved therapy for bronchiectasis. AJMC^®. August 12, 2025. Accessed October 15, 2025. https://www.ajmc.com/view/brensocatib-becomes-first-fda-approved-therapy-for-bronchiectasis

2. Metersky ML, De-Soyza A, Burgel PR, et al. Effects of brensocatib on neutrophil serine protease levels in patients with noncystic fibrosis bronchiectasis: an analysis of the ASPEN trial. Presented at: CHEST; October 19-22, 2025; Chicago, Illinois.

3. Flume PA, Metersky ML, Mauger D, et al. The effect of brensocatib vs placebo on symptom burden in patients with or without on-study pulmonary exacerbations: a posthoc analysis from the ASPEN trial. Presented at: CHEST; October 19-22, 2025; Chicago, Illinois.

At the ESMO Congress 2025 in Berlin, Dr. Jean-Baptiste Bachet (Paris, France) presented the final results of the phase II OPTIPRIME trial (Abstract 727MO), a multicentre French study evaluating a novel “stop-and-go” strategy combining FOLFOX and panitumumab (Pmab) in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC).

At OncoDaily GI, we spotlight the innovations reshaping colorectal cancer care — from adaptive treatment sequencing to intelligent use of targeted therapies to mitigate resistance and cumulative toxicity.

Background

Epidermal growth factor receptor (EGFR) blockade has long been a cornerstone of therapy in RAS/BRAF wild-type mCRC, delivering significant response rates and survival benefits. Yet, the cumulative toxicities associated with prolonged anti-EGFR exposure — particularly dermatologic and nail toxicities — often limit treatment duration. Furthermore, continuous EGFR inhibition can foster resistant subclones, potentially diminishing long-term efficacy.

The OPTIPRIME trial was designed to test whether an intermittent (“stop-and-go”) use of panitumumab, alongside oxaliplatin-based chemotherapy, could maintain efficacy while improving tolerability and extending the duration of disease control (DDC) — a metric capturing both the initial and subsequent treatment phases under EGFR-targeted therapy.

Study Design and Methods

Conducted across 36 French centers between April 2018 and May 2023, OPTIPRIME enrolled 118 patients (mITT: 115 after excluding 3 with RAS or BRAF mutations). Eligible patients had previously untreated, measurable, RAS/BRAF wild-type mCRC with ECOG performance status 0–1.

Treatment consisted of

• Induction phase: 6 cycles of FOLFOX plus panitumumab
• Maintenance phase: Fluoropyrimidine monotherapy (LV5FU2 or capecitabine) for patients achieving disease control
• Reintroduction phase: Upon progression, reintroduction of panitumumab ± oxaliplatin for 6 cycles, repeated as needed (“stop-and-go”)

The primary endpoint, DDC, was defined as the time from inclusion to radiological progression under EGFR therapy with chemotherapy or death. Patients undergoing R0/R1 metastasectomy were censored at surgery, and those switching therapy without progression were censored at the time of switch.

The study was powered to detect an improvement from a median DDC of 14 months (H0) to 20 months (H1), with a 1-sided α of 5% and 80% power. The predefined threshold for success (upper critical value) was 17.84 months.

Results

After a median follow-up of 47.9 months, OPTIPRIME achieved its primary endpoint with a median DDC of 24.9 months (90 % CI 19.3–28.3), surpassing the predefined efficacy boundary. The overall response rate reached 74.8 %, reflecting substantial activity of the FOLFOX + panitumumab regimen.

Most patients (83.5 %) entered at least one maintenance phase, and many underwent repeated reintroductions of panitumumab, illustrating the practical feasibility of this cyclic regimen. A subset (11 %) proceeded to metastasectomy with curative intent. At data cut-off, 69.6 % of patients had received subsequent second-line therapy.

The median overall survival was 36.1 months (95 % CI 27.5–39.9), among the best reported for first-line mCRC in this molecular subgroup. Median progression-free survival (PFS) during the induction and first maintenance phase was 9.9 months (95% CI 8.3–11.1), confirming durable early disease control. These findings confirm that intermittent EGFR inhibition can sustain long-term disease control while preserving patient quality of life and delaying resistance.

Interpretation

The OPTIPRIME trial successfully met its primary endpoint, validating a biologically rational and clinically practical strategy for optimizing EGFR-targeted therapy in mCRC. The median DDC of nearly 25 months underscores the durability achievable through treatment holidays, allowing patients to recover from toxicity while preserving future sensitivity to anti-EGFR agents.

This “stop-and-go” model represents an important step forward in adaptive treatment design, addressing one of the key dilemmas in metastatic colorectal cancer: how to balance intensity, tolerance, and long-term benefit. It aligns with growing evidence from molecular studies showing that resistant EGFR clones can decay during drug-free intervals, restoring sensitivity upon rechallenge.

Clinical Implications

The OPTIPRIME findings strengthen the case for flexible, individualized sequencing of anti-EGFR therapy in mCRC. By alternating active and maintenance phases, clinicians can maintain high disease control rates while minimizing cumulative toxicity and optimizing quality of life.

With median survival exceeding three years, the study underscores how thoughtful integration of targeted agents within an adaptive framework can meaningfully extend outcomes in metastatic colorectal cancer.

You can read the full abstract here.

Conclusion

The OPTIPRIME phase II trial (NCT03584711) validates the clinical value of a “stop-and-go” panitumumab strategy in RAS/BRAF wild-type mCRC. By integrating periods of EGFR inhibition and maintenance fluoropyrimidine therapy, investigators achieved both prolonged disease control and strong overall survival, with improved tolerability.

These results may inform future treatment paradigms emphasizing adaptive, toxicity-conscious sequencing of targeted agents — a principle likely to gain further traction as precision oncology continues to evolve.

You can read about PERISCOPE II Trial: Randomized study finds no OS advantage for gastrectomy plus CRS/HIPEC versus systemic therapy on OncoDaily.

Infinatamab deruxtecan (I-DXd) demonstrated intracranial efficacy with acceptable safety in patients with extensive-stage small cell lung cancer (ES-SCLC) and baseline brain metastases, according to data from the primary analysis of the phase 2 IDeate-Lung01 trial (NCT05280470) presented during the 2025 ESMO Congress.¹

In those with baseline brain metastases (n = 65), the intracranial confirmed objective response rate (cORR) was 46.2% (95% CI, 33.7%-59.0%). Specifically, 30.8% of patients achieved a complete response (CR) as their best overall response, 15.4% experienced a partial response (PR), and 44.6% had stable disease (SD); 1.5% of patients experienced progressive disease (PD), and 7.7% were not evaluable (NE). The confirmed disease control rate (cDCR) was 90.8% (95% CI, 81.0%-96.5%). The median duration of response (DOR) was 6.2 months (95% CI, 4.0-7.9), and the median time to response (TTR) was 1.4 months (range, 0.9-8.5).

Moreover, in patients who had not previously received brain radiotherapy for baseline brain metastases (n = 26), I-DXd elicited an intracranial cORR of 57.7% (95% CI, 36.9%-76.6%). In those with baseline brain target lesions (n = 29), the intracranial cORR with the agent was 65.5% (95% CI, 45.7%-82.1%), and the central nervous system (CNS) cDCR was 96.6% (95% CI, 82.2%-99.9%).

“Intracranial efficacy with I-DXd [at] 12 mg/kg was promising, with 30.8% of patients achieving an intracranial CR, contributing to an intracranial cORR of 46.2% and DCR of 90.8%,” Pedro Simoes da Rocha, MD, PhD, said in a presentation of the data. Rocha is a medical oncologist at Vall d’Hebron University Hospital in Barcelona, Spain, and an International Association for the Study of Lung Cancer (IASLC) SCLC committee member.

What Did IDeate-Lung01 Examine?

The multicenter, randomized, open-label, phase 2 study included patients with histologically or cytologically documented ES-SCLC who were at least 18 years of age, had an ECOG performance status no higher than 1, and had previously received at least 1 but no more than 3 lines of platinum-based chemotherapy.² Patients must have experienced radiologically documented disease progression on or after their most recent previous systemic treatment; they also needed to have at least 1 measurable lesion by RECIST 1.1 criteria. Those with asymptomatic brain metastases were allowed.

For part 1 of the study, the dose-optimization portion of the research, patients were randomly assigned 1:1 to receive I-DXd at 8 mg/kg every 3 weeks (n = 46; arm 1) or at 12 mg/kg every 3 weeks. For part 2, the extension portion, the agent was further examined at the 12-mg/kg dose.

The primary end point was ORR by blinded independent central review (BICR), and secondary end points included DOR, progression-free survival (PFS), DCR, and TTR by BICR and investigator assessment. Other end points comprised overall survival (OS), investigator-assessed ORR, safety, pharmacokinetics, and immunogenicity.

Prior data from the IDeate-Lung01 study shared during the IASLC 2025 World Conference on Lung Cancer indicated that when I-DXd was given at a dose of 12 mg/kg every 3 weeks (n = 137), it elicited a systemic cORR of 48.2% (95% CI, 39.6%-56.9%). The DCR was 87.6% (95% CI, 80.9%-92.6%). The median TTR was 1.4 months (range, 1.0-8.1), and the median DOR was 5.3 months (95% CI, 4.0-6.5). Moreover, the median PFS was 4.9 months (95% CI, 4.2-5.5), and the median OS was 10.3 months (95% CI, 9.1-13.3).

A subgroup analysis of patients with asymptomatic brain metastases identified by CNS BICR at study baseline was conducted and shared during the 2025 ESMO Congress.¹ Brain CT or MRI was done at baseline for all patients. Those determined to have brain metastases had brain CT/MRI every 6 weeks for 36 weeks and every 12 weeks thereafter.

What Did the Patient Population Look Like in IDeate-Lung01?

Of the 137 total patients who received I-DXd at a dose of 12 mg/kg, 65 had baseline brain metastases, and 72 did not. Of those who did, 39 received prior brain radiotherapy, and 26 did not. A total of 29 patients had brain target lesions at baseline with a median size of 17 mm (range, 10-68); 15 of these patients had prior brain radiotherapy and 14 did not.

The median patient age was 61.0 years (range, 39.0-76.0). Moreover, 80.0% of patients had an ECOG performance status of 1, and 20.0% had a status of 0. The median number of prior lines of systemic therapy received was 2 (range, 1-3).

What Was Learned About the Systemic and Intracranial Efficacy of I-DXd in ES-SCLC?

In those with baseline brain metastases, the agent led to a systemic cORR of 46.2% (95% CI, 33.7%-59.0%). Best overall responses included CR (1.5%), PR (44.6%), and SD (43.1%); 7.7% of patients had PD, and 3.1% were NE. The systemic cDCR was 89.2% (95% CI, 79.1%-95.6%), the median DOR was 4.3 months (95% CI, 3.0-5.8), the median TTR was 1.4 months (range, 1.0-8.1), the median PFS was 4.5 months (95% CI, 4.0-5.4) and the median OS was 10.4 months (range, 7.9-15.3).

In those without baseline brain metastases (n = 72), the cORR with the agent was 50.0% (95% CI, 38.0%-62.0%) with best overall responses of CR in 2.8% of patients, PR in 47.2% of patients, and SD in 36.1% of patients; 6.9% of patients had PD, and 6.9% were NE. The cDCR in this group was 86.1% (95% CI, 75.9%-93.1%), the median DOR was 5.9 months (95% CI, 4.0-8.3), the median TTR was 1.4 months (range, 1.2-4.0), the median PFS was 5.4 months (95% CI, 4.2-6.7), and the median OS was 10.1 months (95% CI, 8.4-13.3).

Concordance between systemic and CNS objective response was 75.4%, Rocha said, adding that the concordance between systemic and CNS disease control was 86.2%. “OS and PFS were similar for patients with and without baseline brain metastases,” he said.

I-DXd showed intracranial efficacy irrespective of previous treatment for brain metastases at baseline. In those with prior radiotherapy (n = 39), the cORR was 38.5% (95% CI, 23.4%-55.4%); in those who received prior radiotherapy within 6 months prior to the study (n = 28), the cORR was 39.3% (95% CI, 21.5%-59.4%) and in those who received it 6 months or longer before study (n = 11), the cORR was 36.4% (95% CI, 10.9%-69.2%).

“Progression in the brain was uncommon, suggesting that I-DXd may prevent brain metastases,” Rocha added. Among the 65 patients with baseline brain metastases, 35.4% experienced progression in the brain; in those who had not received prior radiotherapy (n = 26), this rate was 23.1%, and in those who had (n =39), this rate was 43.6%. In those without baseline brain metastases (n = 72), 12.5% experienced progression in the brain.

The agent also elicited responses in those with brain target lesions at baseline (n = 29), he added. The CNS cORR in those without prior radiotherapy (n = 14) was 71.4% (95% CI, 41.9%-91.6%); in those with prior radiotherapy (n = 15), the CNS cORR was 60.0% (95% CI, 32.3%-83.7%). Concordance between systemic and CNS objective response was 69.0%, according to Rocha. The CNS DOR was 5.7 months (95% CI, 4.1-7.1) and the CNS TTR was 1.3 months (range, 0.9-3.0).

What Is the Safety Profile of I-DXd in ES-SCLC and Baseline Brain Metastases?

Any-grade treatment-related adverse effects (TRAEs) were experienced by 87.7% of patients with brain metastases at baseline (n = 65) and 91.7% of those without baseline brain metastases (n = 72); these effects were grade 3 or higher for 30.8% and 41.7% of patients, respectively. They were serious in 10.8% and 25.0% of cases. In those with baseline brain metastases, TRAEs led to dose delay, reduction, or treatment discontinuation for 23.1%, 15.4%, and 7.7% of patients; in those without baseline brain metastases, these rates were 27.8%, 15.3%, and 11.1%. TRAEs proved fatal for 1.5% and 6.9% of patients, respectively.

The most common TRAEs experienced by at least 10% of patients with baseline brain metastases were nausea (any grade, 49.2%; grade ≥3, 1.5%), decreased appetite (32.3%; 1.5%), neutropenia (30.8%; 6.2%), anemia (27.7%; 7.7%), asthenia (23.1%; 1.5%), fatigue (20.0%; 3.1%), lymphopenia (20.0%; 12.3%), diarrhea (16.9%; 0%), leukopenia (15.4%; 0%), thrombocytopenia (13.8%; 6.2%), increased aspartate aminotransferase level (10.8%; 1.5%), constipation (10.8%; 0%), and pneumonitis (10.8%; 0%).

What Is Next for I-DXd?

The phase 3 IDeate-Lung02 study (NCT06203210) will be evaluating the intracranial activity of I-DXd vs physician’s choice of treatment in the form of topotecan, amrubicin, or lurbinectedin (Zepzelca) in patients with relapsed SCLC.³

References

1. Simoes da Rocha PF, Kim YJ, Han J-Y, et al. Intracranial activity of ifinatamab deruxtecan (I-DXd) in patients (pts) with extensive-stage (ES) small cell lung cancer (SCLC) and baseline (BL) brain metastases (BM): Primary analysis of IDeate-Lung01. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2760MO.
2. Ahn M-J, Johnson ML, Paz-Ares L, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer: Primary analysis of the phase 2 IDeate-Lung 01 study. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA06.03.
3. A study of Ifinatamab deruxtecan versus treatment of physician’s choice in subjects with relapsed small cell lung cancer (IDeate-Lung02). Clinical Trials.gov. Updated August 7, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT06203210