Datopotamab Deruxtecan (Dato-DXd) + Rilvegostomig (Rilve) in Patients (Pts) with Locally Advanced or Metastatic Urothelial Cancer (a/mUC): Results from the Phase II TROPION-PanTumor03 Study

Background

TROPION-PanTumor03 is a Phase 2 trial evaluating Dato-DXd (a TROP2-directed ADC) alone or with rilve, a bispecific anti–PD-1/TIGIT antibody, in multiple cancers. This report focuses on results in advanced/metastatic urothelial carcinoma (a/mUC). 

Aim

To assess the safety and antitumor activity of Dato-DXd ± rilvegostomig in patients with advanced/metastatic urothelial carcinoma.

Methods

Patients with unresectable advanced/metastatic urothelial carcinoma (a/mUC) were enrolled into two groups:

1L: No prior systemic therapy, cisplatin-ineligible, with progression >12 months post neoadjuvant/adjuvant platinum.

2L: Previously treated with platinum-based chemotherapy or had disease progression.

Results

• 1L Population: 22 patients
• 2L Population: 18 patients
• Median Age: 71 (1L), 66 (2L)
• Follow-up Duration: 
  • 1L: 6.7 months (range 2.6–15.3)
  • 2L: 6.9 months (range 4.1–13.6)

Efficacy Outcomes

1L Population

• ORR: 68.2% (95% CI: 45.1–86.1)
• DCR: 95.5% (80% CI: 83.4–99.5) at 12 weeks
• Median DoR & PFS: Not reached

2L Population

• ORR: 33.3% (95% CI: 13.3–59.0)
• DCR: 83.3% (80% CI: 66.6–93.7) at 12 weeks
• Median DoR: Not reached
• Median PFS: 12.5 months (95% CI: 6.1–NR)

Incidence of AEs, n (%)	Dato-DXd + rilve
	1L (n=22)	2L (n=18)
TRAEs	21 (95.5)	17 (94.4)
Grade ≥3 TRAEs	4 (18.2)	7 (38.9)
Any TRAE leading to:
Dose reduction of any study treatment	12 (54.5)	4 (22.2)
Dose interruption of any study treatment	6 (27.3)	6 (33.3)
Discontinuation of any study treatment	2 (9.1)	2 (11.1)
Death	0	0
Most common TRAEs:
Stomatitis, all grades	9 (40.9)	10 (55.6)
Grade ≥3	0	1 (5.6)
Nausea, all grades	3 (13.6)	7 (38.9)
Grade ≥3	0	0
Ocular surface events related to any study treatment	1 (4.5)	1 (5.6)
Adjudicated drug-related interstitial lung disease	1 (4.5)*	1 (5.6)*

AEs, adverse events; TRAEs, treatment-related AEs (related to any study treatment).*Grade 2.

Conclusion

Dato-DXd in combination with rilve showed encouraging efficacy and a manageable safety profile in pts with a/mUC

Reference

Sun Young Rha, et al, Datopotamab deruxtecan (Dato-DXd) + rilvegostomig (rilve) in patients (pts) with locally advanced or metastatic urothelial cancer (a/mUC): Results from the phase II TROPION-PanTumor03 study. Annals of Oncology,3072MO, (2025).

Disitamab Vedotin plus Tislelizumab as Nephron-sparing Therapy for High-risk Upper Tract Urothelial Carcinoma: The Phase II DISTINCT-I Trial

Background

The Phase II DISTINCT-I trial explores a kidney-sparing approach for high-risk UTUC using Thulium laser ablation or ureteral resection combined with perioperative disitamab vedotin (HER2-targeted) and immune checkpoint inhibitors.

Aim

To evaluate the safety and feasibility of a kidney-sparing approach using laser ablation or segmental resection combined with disitamab vedotin and immune checkpoint inhibitors in high-risk upper tract urothelial carcinoma.

Methods

• Phase II study (NCT05912816) initiated in Sept 2023 at Renji and Tianjin Second Hospitals, enrolling high-risk UTUC patients with renal preservation needs.
• Endoscopic biopsy followed by 2–4 cycles of disitamab vedotin (2.0 mg/kg) + tislelizumab (200 mg) every 3 weeks, then kidney-sparing surgery.
• 1-year kidney-intact event-free survival (KI-EFS), tracking recurrence, metastasis, or death.
• Clinical complete response (cCR), renal function change (ΔeGFR), and safety (CTCAE v5.0).

Results

• Enrollment & Follow-up: 20 patients enrolled; 19 completed treatment with a median follow-up of 13 months.
• HER2 Status: Biopsy IHC results—3+ (n=6), 2+ (n=2), 1+ (n=7), 0 (n=4).
• Procedures Performed: Kidney-sparing—ureteral resection (n=5), endoscopic ablation (n=9); RNU performed in 5 patients; 1 recurrence post-ablation led to salvage RNU.
• Kidney-Intact Survival: 1-year KI-EFS was 68.4% (13/19 patients).
• Tumor Response & cCR: cCR at 3 months was 73.7%; overall responses—CR (n=4), PR (n=9), SD (n=4), PD (n=1).
• Safety & Treatment Completion: 16 patients completed 4 cycles; no grade ≥3 systemic toxicities observed.

Conclusion

The DV-ICI combination with kidney-sparing surgery demonstrates promising tumor downstaging (73.7% cCR) and nephron preservation (68.4% 1-year KI-EFS) in high-risk UTUC, with favorable safety. HER2 overexpression (3+/2+: 42.1%) may correlate with enhanced response, warranting biomarker validation. This paradigm challenges RNU dominance in selected patients.

Reference

Jiwei Huang, et al, Disitamab vedotin plus tislelizumab as nephron-sparing therapy for high-risk upper tract urothelial carcinoma: The phase II DISTINCT-I trial. Annals of Oncology, 3071MO, (2025).

Fruquintinib (FRUQ) Plus Sintilimab (SIN) versus Axitinib (AXI) or Everolimus (EVE) Monotherapy as 2L Treatment in Pts with Locally Advanced or Metastatic Renal Cell Carcinoma (RCC): Results from Phase III Part of a Randomized, Open-label, Active-controlled Phase II/III Study (FRUSICA-2) 

Background

FRUSICA-2 (NCT05522231) is a randomized Phase 2/3 trial comparing fruquintinib + sintilimab versus axitinib or everolimus monotherapy as second-line treatment in advanced/metastatic renal cell carcinoma (RCC).

Aim

The aim of the FRUSICA-2 study is to evaluate the efficacy and safety of fruquintinib plus sintilimab compared to axitinib or everolimus monotherapy as second-line treatment in patients with locally advanced or metastatic RCC who have progressed after first-line VEGFR-TKI therapy

Method

• Eligible pts who had received one prior VEGFR-TKI therapy were randomized 1:1 to receive FRUQ (5 mg, QD, 2 weeks on/1 week off) plus SIN (200 mg, IV, Q3W), or investigator-selected AXI (5 mg, BID)/EVE (10 mg, QD) in 21-day cycles. Randomization was stratified by ECOG PS and IMDC prognostic risk. 
• Primary endpoint was blinded independent review committee (BIRC)-assessed progression-free survival (PFS) per RECIST 1.1.

Results

• Between Oct 2022 and Dec 2023, 234 pts were randomly assigned to FRUQ+SIN or AXI/EVE groups (119 vs 115; 101 on AXI, but 1 untreated). 
• Baseline characteristics were well balanced between groups. At the PFS final analysis cutoff (Feb 17, 2025), with 16.56 months median follow up, FRUQ+SIN significantly prolonged the BIRC-assessed mPFS (22.21 vs 6.90 months, stratified HR 0.373)

ITT set (BIRC-assessed)	IMDC risk factor						Number of IMDC risk factor
	Favorable-risk		Intermediate-risk		Poor-risk		0-1 risk factors
	FRUQ+SIN N=33	AXI/EVE N=32	FRUQ+SIN N=73	AXI/EVE N=72	FRUQ+SIN N=13	AXI/EVE N=11	FRUQ+SIN N=76	AXI/EVE N=73
mPFS, months	NR	8.31	22.21	6.97	9.69	4.21	24.87	8.31
Unstratified HR (95% CI)	0.270 (0.117, 0.620)	0.352 (0.221, 0.562)	0.591 (0.203, 1.721)	0.278 (0.168, 0.461)
Unstratified log-rank p*	0.0009		0.3267
ORR (%)	63.6	25.0	61.6	23.6	46.2	27.3	63.2	26.0
Odds ratio (95% CI)	5.250 (1.608, 17.712)	5.200 (2.394, 11.435)	2.286 (0.315, 19.098)	4.872 (2.292, 10.456)
p*	0.0019		0.3514

 

Conclusion

FRUQ+SIN demonstrated superior mPFS and manageable safety compared to AXI/EVE in pts with advanced or metastatic RCC post-VEGFR-TKI, offering a highly effective and tolerable option for pts with RCC.

Reference

Zhenhua Liu, et al, Fruquintinib (FRUQ) plus sintilimab (SIN) versus axitinib (AXI) or everolimus (EVE) monotherapy as 2L treatment in pts with locally advanced or metastatic renal cell carcinoma (RCC): Results from phase III part of a randomized, open-label, active-controlled phase II/III study (FRUSICA-2). Annals of Oncology, 2592MO, (2025).

NorthStar: A Phase II Randomized Study of Osimertinib (OSI) With or Without Local Consolidative Therapy (LCT) for Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

Background

Osimertinib is the standard of care for EGFR-mutant metastatic NSCLC. The NorthStar trial assessed whether the addition of LCT improves progression-free survival (PFS) in patients treated with osimertinib.

Aim

To determine whether adding local consolidative therapy (LCT) to osimertinib improves progression-free survival in patients with EGFR-mutant metastatic NSCLC.

Method

• Eligible patients had EGFR-mutant metastatic NSCLC and were either TKI-naïve or had acquired T790M without prior exposure to third-generation EGFR TKIs. 
• All patients received osimertinib 80 mg daily for 6–12 weeks, after which those without disease progression were randomized 1:1 to continue osimertinib alone or receive LCT in addition to osimertinib. 
• Stratification factors included line of therapy, number of metastases (≤3 vs >3), response to induction (PR vs SD), and CNS involvement. The primary endpoint was PFS.

Results

Here’s a 5-point summary of the NorthStar trial results:

• Median PFS was significantly longer with osimertinib + LCT (25.4 months) compared to osimertinib alone (17.0 months), with a 40% reduction in progression risk (HR 0.60; p=0.02).
• 119 patients were randomized—63 to osimertinib alone, 56 to osimertinib + LCT; most had polymetastatic disease (>3 lesions).
• Among those receiving LCT, 59% had radiation alone, 29% underwent surgery, and 12% received combined modalities.
• Adverse events occurred in over 96% of patients in both arms; grade ≥3 events were higher in the LCT arm (29% vs 16%), but no unexpected toxicities were reported.
• Skin disorders (~65%), anorexia (~18%), and dyspnea (17.5% vs 30.5%) were the most frequent, with manageable safety across both groups.

Conclusion

The addition of local consolidative therapy to osimertinib significantly extends progression-free survival in patients with EGFR-mutant metastatic NSCLC, even in the setting of polymetastatic disease. These results support the integration of LCT into the treatment paradigm for appropriately selected patients receiving EGFR-targeted therapy and may inform future standards of care.

Reference

Yasir Y. Elamin, et al, NorthStar: A Phase II Randomized Study of Osimertinib (OSI) With or Without Local Consolidative Therapy (LCT) for Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC). Annals of Oncology, LBA72, (2025).

Zongertinib as First-line Treatment in Patients with Advanced HER2-mutant NSCLC: Beamion LUNG 1

Background

Zongertinib, a HER2-selective irreversible TKI, showed promising first-line efficacy in treatment-naïve advanced HER2-mutant NSCLC patients in Cohort 2 of the Beamion LUNG-1 Phase Ib trial, offering a potential targeted alternative to chemotherapy ± immunotherapy, with durable responses and a manageable safety profile

Aim

The aim of Cohort 2 of the Beamion LUNG-1 study is to evaluate the safety and preliminary efficacy of zongertinib as a first-line treatment in patients with treatment-naïve advanced HER2-mutant NSCLC.

Method

• Cohort 2 included adult pts with treatment-naïve, advanced/metastatic, non-squamous, HER2-mutant NSCLC (TKD mutation), ≥1 measurable non-CNS lesion (RECIST v1.1), and ECOG PS of 0/1; pts received oral zongertinib 120 mg once daily.
• Pts with stable/asymptomatic brain metastases were eligible. 
• The primary endpoint was objective response (OR, RECIST v1.1). Secondary endpoints included duration of OR (DoR), disease control (DC), and progression-free survival (PFS). 
• All endpoints were assessed by blinded independent central review (BICR).

Results

• Confirmed ORR: 77% (CR: 8%, PR: 69%)
• Disease Control Rate (DCR): 96%
• 6-month DoR: 80%; 6-month PFS: 79%

• TRAEs in 91% of patients
• Grade 3 TRAEs in 18%; no grade 4/5 events

Conclusion

First-line zongertinib elicited strong and clinically meaningful efficacy with a manageable safety profile in treatment-naïve pts with advanced HER2-mutant NSCLC, underpinning its ongoing evaluation in the randomized phase III Beamion LUNG-2 study

Reference

Sanjay Popat, et al, Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG 1. Annals of Oncology, LBA74, (2025).

FLAURA2: Exploratory Overall Survival (OS) Analysis in Patients (pts) with Poorer Prognostic Factors Treated with Osimertinib (osi) ± Platinum-pemetrexed Chemotherapy (CTx) as First-line (1L) Treatment (tx) for EGFR-mutated (EGFRm) Advanced NSCLC

Background

FLAURA2 (NCT04035486) is a Phase III trial evaluating first-line osimertinib plus chemotherapy versus osimertinib alone in EGFR-mutant advanced NSCLC. Final OS analysis showed a significant survival benefit with the combination, consistent across subgroups with poor prognostic factors like CNS metastases, L858R mutation, plasma EGFRm detection, and TP53 alterations.

Aim

To evaluate whether adding chemotherapy to first-line osimertinib improves overall survival in patients with EGFR-mutant advanced NSCLC.

Method

• The study design was presented previously (Planchard, et al. N Engl J Med 2023;389:1935–48). Baseline CNS scans (CT/MRI) were required. 
• Tissue EGFRm type was tested via central or locally approved assays. Plasma EGFRm status was assessed via droplet digital PCR (Biodesix). Tissue TP53 was assessed via FoundationOne CDx test (Foundation Medicine). 
• Subgroup OS was analysed via an unstratified Cox proportional hazards model.

Results

• 557 patients were randomized—279 to osimertinib + chemotherapy (CTx), 278 to osimertinib monotherapy.
• Osimertinib + CTx significantly improved OS compared to monotherapy (HR: 0.77; 95% CI: 0.61–0.96; p=0.02).
• OS benefit was consistent across all predefined prognostic subgroups, including those with CNS metastases, L858R mutation, detectable plasma EGFR mutation, and TP53 alterations.
• Median OS: Not reached in several subgroups, but longer with combination therapy in patients with poor baseline prognostic factors.

	Osi + CTx		Osi mono		HR (95% CI)
	Events/pts, n	mOS, mo (95% CI)	Events/pts, n	mOS, mo (95% CI)
Baseline CNS mets
Yes	71/116	40.9 (35.2, 46.6)	79/110	29.7 (25.6, 35.8)	0.72 (0.52, 0.99)
No	73/163	NR (45.0, NC)	92/168	43.9 (37.8, 53.3)	0.77 (0.57, 1.05)
EGFRm
L858R	66/106	38.1 (33.4, 42.0)	74/107	32.4 (28.0, 37.6)	0.76 (0.55, 1.07)
Ex19del	78/172	NR (47.2, NC)	95/169	43.0 (35.7, 51.9)	0.76 (0.56, 1.02)
Plasma EGFRm
Det	88/148	38.4 (33.2, 46.6)	114/161	32.5 (28.8, 35.8)	0.79 (0.60, 1.03)
Undet	24/65	NR (50.8, NC)	21/48	NR (46.0, NC)	0.79 (0.44, 1.44)
Tissue TP53
Altered	22/46	51.1 (35.0, NC)	25/40	43.1 (34.0, 50.1)	0.71 (0.40, 1.27)
Wild type	11/33	NR (46.6, NC)	14/34	NR (41.3, NC)	0.70 (0.32, 1.54)

 

Conclusion

A survival benefit favouring osi + CTx vs osi mono was consistently observed across each prognostic subgroup evaluated, reinforcing osi + CTx as a 1L standard of care in this setting.

Reference

Pasi A. Jänne, et al, FLAURA2: exploratory overall survival (OS) analysis in patients (pts) with poorer prognostic factors treated with osimertinib (osi) ± platinum-pemetrexed chemotherapy (CTx) as first-line (1L) treatment (tx) for EGFR-mutated (EGFRm) advanced NSCLC. Annals of Oncology, LBA77, (2025).

Final Overall Survival (OS) and Safety Analysis of the Phase 3 ALEX Study of Alectinib vs Crizotinib in Patients with Previously Untreated, Advanced ALK-positive (ALK+) Non-small Cell Lung Cancer (NSCLC)

Background

The Phase 3 ALEX trial (NCT02075840) established first-line alectinib as the global standard for advanced ALK-positive NSCLC, showing superior PFS over crizotinib. This report presents final overall survival, duration of response, and updated safety outcomes.

Aim

To compare the overall survival, duration of response, and safety of first-line alectinib versus crizotinib in patients with advanced ALK-positive NSCLC

Method

• Eligible patients ≥18 years old with previously untreated, advanced ALK+ NSCLC were randomised 1:1 to receive alectinib (600 mg; BID) or crizotinib (250 mg; BID) until disease progression (PD), toxicity, withdrawal or death; no crossover was permitted before PD. 
• Stratification factors: ECOG performance status (0/1 vs 2); race (Asian vs non-Asian); baseline CNS mets (yes vs no).
• Key secondary endpoints: OS; DoR; safety.

Results

• 303 patients enrolled—152 received alectinib, 151 received crizotinib; median follow-up was 53.5 months (alectinib) vs 23.3 months (crizotinib).
• Median OS: 81.1 months (alectinib) vs 54.2 months (crizotinib)
• OS benefit observed across all CNS metastasis subgroups
• CNS Metastases Subgroup:
• With prior radiation: 92.0 vs 39.5 months
• Without prior radiation: 46.9 vs 23.7 months
• No CNS mets: 94.0 vs 69.8 months
• Median DoR was 42.3 months with alectinib vs 11.1 months with crizotinib.
• No new or unexpected safety signals reported, confirming long-term tolerability of alectinib.

Conclusion

Final data from ALEX show 1L alectinib induced a clinically meaningful OS benefit (regardless of baseline CNS mets status) and DoR compared with crizotinib in pts with previously untreated, advanced ALK+ NSCLC. Safety data were in line with the known safety profile of alectinib. These data continue to support 1L alectinib as a standard of care in pts with advanced ALK+ NSCLC.

Reference

Tony S.K. Mok, et al, Final overall survival (OS) and safety analysis of the Phase 3 ALEX study of alectinib vs crizotinib in patients with previously untreated, advanced ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Annals of Oncology, LBA73, (2025).

Low Dose Pembrolizumab in Addition to Neoadjuvant Anthracycline and Taxane in Triple Negative Breast Cancer: A Randomized Controlled Trial

Background

Low-dose immune checkpoint inhibitors have shown promise in various cancers. This study investigates whether adding low-dose pembrolizumab (LDPm) to neoadjuvant chemotherapy (NACT) enhances pathological complete response (pCR) in triple-negative breast cancer (TNBC).

Aim

To evaluate the impact of low-dose pembrolizumab combined with NACT on pCR rates in patients with stage II–III TNBC.

Method

• Phase II, open-label, randomized controlled trial in New Delhi, India
• Patients: Stage II–III TNBC, no access to standard-dose pembrolizumab
• Experimental: NACT + 50 mg LDPm every 6 weeks × 3 cycles
• Control: NACT alone
• NACT regimen: 4 cycles doxorubicin + cyclophosphamide → 4 cycles paclitaxel
• Primary endpoint: Pathological complete response (pCR)

Results

• 157 patients randomized; 152 underwent surgery
• pCR (Intention-to-treat):
• Experimental: 53.8%
• Control: 40.5%
• Absolute difference: 13.3% (p=0.047)
• pCR (Surgical population):
• Experimental: 56.7%
• Control: 41.0%
• Absolute difference: 15.7% (p=0.031)
• Grade ≥3 AEs: 50% (experimental) vs 59.5% (control)
• One treatment-related death due to toxic epidermal necrolysis (LDPm)

	NACT with low-dose pembrolizumab∗ (n=78)	NACT (n=79)
Baseline characteristics
Age, Median (Interquartile range)	45 (38-53)	45 (38-52)
Primary tumor stageT1-2T3-4	35 (44.9%)43 (55.1%)	39 (49.4%)40 (50.6%)
Nodal status Negative Positive	15 (19.2%)63 (80.8%)	18 (22.8%)61 (77.2%)
Menopausal status Premenopausal Postmenopausal	42 (53.8%)36 (46.2%)	44 (55.7%)35 (44.3%)
Pathological complete response
Modified intention-to-treat(P=0.047)	42/78 (53.8%)	32/79 (40.5%)
Surgery performed(P=0.031)	42/74 (56.7%)	32/78 (41.0%)

 

Conclusion

The absolute benefit with LDPm appears numerically comparable to that observed with SDPm in the KN522 trial. Therefore, in resource-constrained settings where SDPm is inaccessible, a low-dose alternative strategy may provide a viable treatment option in patients with TNBC.

Reference

Atul Batra, et al, Low Dose Pembrolizumab in Addition to Neoadjuvant Anthracycline and Taxane in Triple Negative Breast Cancer: A Randomized Controlled Trial. Annals of Oncology, LBA15, (2025).

Lenvatinib plus Pembrolizumab and Chemotherapy vs Pembrolizumab and Chemotherapy in Untreated Metastatic Esophageal Squamous Cell Carcinoma: The Randomized Phase 3 LEAP-014 Study.

Background

LEAP-014 (NCT04949256) is a randomized, open-label, phase 3 study of first-line lenvatinib (len) + pembrolizumab (pembro) + chemotherapy (chemo) vs pembro + chemo in metastatic esophageal squamous cell carcinoma (mESCC). We report the results of the second interim analysis.

Aim

To evaluate whether adding lenvatinib to pembrolizumab and chemotherapy improves outcomes compared to pembrolizumab plus chemotherapy alone in first-line treatment of metastatic esophageal squamous cell carcinoma.

Method

• Eligible participants (pts) had untreated mESCC, measurable disease, and ECOG PS 0-1. 
• All pts were randomized 1:1 to induction with len 8 mg PO QD + pembro 400 mg IV (Q6W x2) + chemo (FP [Q3W x4] or mFOLFOX6 [Q2W x6] or TP [Q3W x4 in East Asia, excluding Japan]) for 12 weeks followed by consolidation with len 20 mg PO QD (if initial len 8 mg PO QD dose was tolerated) + pembro 400 mg IV Q6W for up to 16 doses (arm 1) or to pembro + chemo (FP, mFOLFOX6, or TP [arm 2]). 
• Randomization was stratified by PD-L1 status, region, and chemo choice. The primary endpoint was OS. Secondary endpoints included PFS, ORR, and DOR (RECIST v1.1, BICR), and safety. Data cut-off was May 8, 2025.

Results

Here are 5 key points from the second interim analysis of the LEAP-014 Phase 3 trial:

• 850 patients with metastatic esophageal squamous cell carcinoma were randomized; 94% had PD-L1 CPS ≥1 and 65% had CPS ≥10.
• Median OS was 17.6 months with lenvatinib + pembrolizumab + chemotherapy vs 15.5 months with pembrolizumab + chemotherapy; the difference was not statistically significant (HR 0.92; p=0.1852).

• Median PFS: 7.2 vs 6.9 months (HR 0.89; p=0.0753)
• ORR: 62% vs 55%
• Median Duration of Response (DoR): 8.1 vs 6.8 months
• PFS and ORR were not formally tested due to non-significant OS

Conclusion

Lenvatinib + pembrolizumab + chemo vs pembrolizumab + chemo did not result in significant improvement in OS as first-line therapy in pts with mESCC. No new safety signals were observed.

Reference

Jong-Mu Sun, et al, Lenvatinib plus Pembrolizumab and Chemotherapy vs Pembrolizumab and Chemotherapy in Untreated Metastatic Esophageal Squamous Cell Carcinoma: The Randomized Phase 3 LEAP-014 Study. Annals of Oncology, LBA79, (2025).

A Randomised Trial of Continuing or De-escalating Bone Modifying Agents (BMA) After More than 2 Years of Treatment in Patients with Bone Metastases from Breast or Castration-resistant Prostate Cancer: REaCT-Hold BMA

Background

Guidelines recommend bone-modifying agents (BMAs) every 4 (Q4W) or 12 weeks (Q12W) to reduce symptomatic skeletal events (SSEs) in patients with bone metastases from breast or prostate cancer. However, the optimal dosing frequency beyond two years remains unclear.

Aim

To determine the optimal long-term dosing frequency of bone-modifying agents beyond two years in patients with bone metastases from breast or prostate cancer.

Methods

• Study Design: Multicenter, open-label, phase II non-inferiority trial comparing standard BMA dosing (Q4W or Q12W) versus de-escalated dosing (Q24W) in patients with bone metastases from breast cancer or CRPC who had received ≥2 years of prior BMA therapy.
• Randomization & Stratification: Patients were randomized 1:1 and stratified by cancer type (breast vs. prostate), prior BMA schedule, and history of symptomatic skeletal events (SSEs), with subgroup analysis based on prior BMA duration (2–3 years vs >3 years).
• Co-Primary Endpoints:  
  1. Physical Functioning (PF) via EORTC-QLQ-C30  
  2. Functional Interference (FI) via EORTC-QLQ-BM22  
  3. Assessed at week 48; higher scores indicate better function  
  4. Non-inferiority margins: −4.3 (PF) and −6.1 (FI)
• Secondary Endpoints: Included SSE incidence, time to first SSE, SSE-free survival, skeletal morbidity rate, health-related quality of life (HR-QoL), and BMA-related toxicity (e.g., osteonecrosis of the jaw).

Results

• 240 patients enrolled (218 with breast cancer, 22 with prostate cancer); randomized to standard (Q4W/Q12W) vs de-escalated (Q24W) BMA dosing; median follow-up was 23.9 months.
• At week 48, mean PF scores were 71 (standard) vs 73 (de-escalated); ANOVA difference of 3.2 (95% CI: −2.5 to 9.0), meeting non-inferiority criteria.
• Mean FI scores were 67 (standard) vs 73 (de-escalated); ANOVA difference of 4.4 (95% CI: −1.2 to 9.9), also meeting non-inferiority criteria.
• Rates of symptomatic skeletal events (SSEs), time to first SSE, and SSE-free survival were comparable between both dosing groups.
• Overall health-related quality of life (HR-QoL) outcomes were similar across arms, supporting the feasibility of de-escalated BMA dosing beyond two years.

Conclusions

In patients receiving long-term BMAs, de-escalation (Q24W) preserved physical function without increasing functional interference, and maintained SSE outcomes

Reference

Terry L. Ng et al, A randomised trial of continuing or de-escalating bone modifying agents (BMA) after more than 2 years of treatment in patients with bone metastases from breast or castration-resistant prostate cancer: REaCT-Hold BMA. Annals of Oncology, 2800O, (2025).

Anti-PD-1-antibody (Tislelizumab) Combined with Chidamide, Lenalidomide and Etoposide for the Treatment of Refractory/Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r-ENKTL): Preliminary Results from a Prospective, Multicenter, Single-arm, Phase II Trial

Background

Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is a highly aggressive non-Hodgkin lymphoma, with higher incidence in Asia. Patients with r/r-ENKTL have a poor prognosis and lack effective treatment.

Aim

To evaluate the efficacy and safety of novel therapies in patients with relapsed or refractory extranodal NK/T-cell lymphoma, addressing the urgent need for effective treatment options.

Methods

• This was a prospective, single-arm, multi-center, phase II clinical trial recruiting patients with r/r-ENKTL who had failed at least one prior treatment. 
• Patients received 6 cycles of Tislelizumab (200mg, Day 1), Chidamide (20mg, biw), Lenalidomide (25mg, Days 1-10) and Etoposide (100mg/m2, Days 1-3) every 21 days, followed by 10 cycles of Tislelizumab maintenance (200mg, Day1) every 21 days. 
• The primary endpoints were objective response rate (ORR) and progression-free survival (PFS).

Results

• 33 eligible patients enrolled across 5 centers between June 2020 and March 2024; median follow-up was 20 months as of July 2024.
• Efficacy Outcomes:
  1. Overall response rate: 81.8%
  2. Complete response rate: 66.7%
  3. Median PFS and OS not reached
  4. 3-year PFS: 51.8%; 3-year OS: 72.7%
• Survival Rates:
  1. 1-year PFS: 68.9%; 2-year PFS: 58.3%
  2. 1-year OS: 80.9%; 2-year OS: 72.7%
• Safety Profile:
  1. Most common TRAEs: anemia (81.8%), leukopenia (78.8%), neutropenia (75.7%), thrombocytopenia (60.6%)
  2. Grade ≥3 TRAEs: neutropenia (54.3%) most frequent
• Immune-Related AEs & Mortality:
  1. Grade ≥3 immune-related AEs: one case each of hypothyroidism and hyperglycemia
  2. 8 deaths occurred due to disease progression

Characteristic	No. of patients percent%
Sex
Male	25	75.8%
Female	8	24.2%
ECOG performance status
0-1	29	87.9%
2	4	12.1
CA stage
I-Ⅱ	3	9.1%
Ⅲ-Ⅳ	30	90.9%
PINK score
0-1	12	36.4%
2-4	21	63.6%
Previous treatment lines
1	19	57.6%
≥2	14	42.4%
Best response
ORR	27	81.8%
CR	22	66.7%

 

Conclusions

Tislelizumab combined with Chidamide, Lenalidomide and Etoposide shows a high response rate in r/r-ENKTL with acceptable safety. This regimen is promising and requires further study.

Reference

Hui Yu, et al, Anti-PD-1-antibody (tislelizumab) combined with chidamide, lenalidomide and etoposide for the treatment of refractory/relapsed extranodal natural killer/t cell lymphoma, nasal type (r/r-ENKTL): Preliminary results from a prospective, multicenter, single-arm, phase II trial. Annals of Oncology, 1241O, (2025).