Osimertinib with/without Chemotherapy in Patients with Persistent ctDNA EGFR Mutant (EGFRm) NSCLC at 3 Weeks After 1L osimertinib: A Randomized Phase II Study (FLAME Study)

Presenter: Zhijie Wang

Background

Persistent plasma circulating tumor DNA (ctDNA) epidermal growth factor receptor mutations (EGFRm) detected at 3 weeks following first-line osimertinib are associated with poor clinical outcomes in advanced EGFR-mutated non-small cell lung cancer (NSCLC). Although osimertinib combined with chemotherapy has demonstrated superior efficacy over monotherapy, its benefit in patients with persistent ctDNA EGFRm remains unclear. This study evaluates the efficacy and safety of osimertinib plus chemotherapy versus osimertinib alone in this high-risk subgroup.

Aim

To evaluate whether osimertinib plus chemotherapy improves progression-free survival (PFS) compared with continued osimertinib monotherapy in patients with persistent ctDNA EGFR mutations after 3 weeks of treatment.

Methods

• Multicenter, randomized, phase II FLAME study in advanced NSCLC with EGFR Ex19del or L858R mutations and persistent ctDNA EGFRm.
• Plasma ctDNA EGFRm assessed using Super ARMS-PCR.
• Patients randomized (1:1) to:
• Osimertinib + carboplatin–pemetrexed
• Osimertinib monotherapy
• Stratification: central nervous system metastases and EGFR mutation subtype.

Study Endpoints

• Primary endpoint: PFS (RECIST 1.1)
• Secondary endpoints: Overall survival (OS) rate at 18 months, overall response rate (ORR), disease control rate (DCR), duration of response (DoR), safety and resistance profile

Results

• Among 448 screened patients, 134 had persistent ctDNA EGFR mutations
• 80 patients were randomized (n=40 per arm).
• Baseline characteristics were comparable between treatment groups.

Efficacy Outcomes

• Osimertinib plus chemotherapy significantly improved PFS compared with monotherapy (hazard ratio [HR] 0.53; p=0.024).
• Median PFS was 23.1 months in the combination arm vs 12.7 months in the monotherapy arm.
• The ORR was higher in the combination arm (50%) compared with the monotherapy arm (35%).
• Median DoR was also prolonged (15.6 vs 10.5 months).

Table 1. Key Efficacy Outcomes

Parameter	Osimertinib + Chemotherapy	Osimertinib	Effect Estimate	p-value
Median PFS (months)	23.1	12.7	HR 0.53	0.024
ORR	50%	35%	—	—
DoR	15.6 months	10.5 months	—	—

Safety

• Grade ≥3 treatment-related adverse events (TRAEs) were higher with combination therapy (65%) compared with monotherapy (10%).
• Toxicities were manageable, with no new safety signals observed.

Conclusion

This randomized phase II study demonstrates that osimertinib combined with chemotherapy significantly prolongs PFS compared with osimertinib alone in patients with persistent ctDNA EGFR mutations. These findings support a strategy of biomarker-guided treatment intensification based on early molecular response assessment.

Low-dose Pembrolizumab with Chemotherapy in Advanced NSCLC: A Phase 3 Randomized Trial

Presenter: Nandini Menon

Background

Pembrolizumab with platinum chemotherapy is standard for advanced non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA), but high costs limit access to immune checkpoint inhibitors (ICI). Emerging evidence suggests lower doses may remain effective; however, randomized data supporting low-dose pembrolizumab in this setting are currently lacking.

Aim

To evaluate the efficacy and safety of low-dose pembrolizumab in combination with platinum doublet chemotherapy compared with chemotherapy alone in advanced NSCLC without AGAs.

Methods

• Phase III, open-label, randomized trial with a superiority design.
• Patients aged ≥18 years with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 were randomized (1:1) to:
• Arm A: Platinum doublet chemotherapy
• Arm B: Platinum doublet chemotherapy + low-dose pembrolizumab

Intervention
Chemotherapy included pemetrexed or paclitaxel with carboplatin or cisplatin for 4–6 cycles.

• Pembrolizumab 50 mg was administered every 3 weeks for 4 doses, followed by every 6 weeks until progression or unacceptable toxicity.

Study Endpoints

• Primary endpoint: Overall survival (OS)
• Secondary endpoints: Progression-free survival (PFS), safety, and quality of life (QoL)

Results

A total of 380 patients were randomized (Arm A: n=187; Arm B: n=193). The median follow-up was 13 months. Baseline characteristics were well balanced.

Efficacy Outcomes

• Median OS was significantly improved with combination therapy (13.46 vs 10.47 months; HR 0.72; p=0.020).
• 1-year OS rate was higher in Arm B (57.32%) compared to Arm A (44.4%).
• Median PFS was improved (6.73 vs 4.70 months; HR 0.70; p=0.003).
• 1-year PFS rate was 26.72% in Arm B versus 18.79% in Arm A.

Safety

• Grade ≥3 neutropenia was higher in the combination arm (28%) compared with chemotherapy alone (17.6%) (p=0.02).
• No significant differences were observed in grade ≥3 anemia or thrombocytopenia.
• Grade ≥3 immune-related pneumonitis occurred in 3.1% of patients receiving pembrolizumab.
• No new safety signals were identified.

Conclusion

The addition of low-dose pembrolizumab to platinum doublet chemotherapy significantly improved survival outcomes in advanced NSCLC without AGAs, with no new safety signals. This approach may enhance access to ICIs in resource-limited settings.

Durvalumab Monotherapy versus Active Monitoring for Resected Primary Renal Cell Carcinoma in RAMPART: An International, Phase 3, Randomized Controlled Trial

Presenter: James Larkin

Background

RAMPART evaluated one year of immune checkpoint inhibitor therapy versus active monitoring in renal cell carcinoma (RCC) at intermediate/high recurrence risk post-nephrectomy or (M1 no evidence of disease [M1NED]). Prior analyses showed improved disease-free survival (DFS) with durvalumab plus tremelimumab, particularly in higher-risk populations.

Aim

To compare the efficacy of durvalumab alone and durvalumab plus tremelimumab versus active monitoring in improving DFS in patients with resected RCC.

Methods

• Phase III randomized trial conducted across 80 sites.
• A total of 790 patients were randomized in a 3:2:2 ratio to:
• Arm A: Active monitoring
• Arm B: Durvalumab (1500 mg for 13 cycles)
• Arm C: Durvalumab + tremelimumab (75 mg for cycles 1–2)
• Primary endpoint: DFS
• Statistical power: 80% to detect hazard ratio (HR) of 0.60 (Arm B vs A) and 0.55 (Arm C vs A).

Results

A total of 790 patients were enrolled (Arm A: 340; Arm B: 225; Arm C: 225). Baseline characteristics were balanced. Median age was 60 years, 72% were male, and 84% had clear cell histology.

Efficacy Outcomes

• Durvalumab monotherapy (Arm B) showed a 26% relative reduction in recurrence or death compared with active monitoring (HR 0.74), but did not reach conventional statistical significance.
• 3-year DFS was 78% with durvalumab versus 72% with active monitoring.
• Durvalumab plus tremelimumab (Arm C) significantly improved DFS compared with active monitoring (HR 0.65).
• The benefit was more pronounced in higher-risk patients (HR 0.52).

Table 1. Primary DFS Outcomes

Population	Arm C vs A (HR)	Arm B vs A (HR)
All patients	0.65 (95% CI 0.45–0.93)	0.74 (95% CI 0.53–1.04)
Higher risk	0.52 (95% CI 0.34–0.80)	0.77 (95% CI 0.53–1.12)
Intermediate risk	1.19 (95% CI 0.61–2.32)	0.64 (95% CI 0.30–1.34)

Conclusion

Durvalumab plus tremelimumab significantly improved DFS compared with active monitoring in resected RCC, particularly in high-risk patients, whereas durvalumab monotherapy did not demonstrate a statistically significant benefit. These findings support combination immunotherapy as a potential adjuvant treatment strategy.

Efficacy and Safety of Asandeutertinib versus Osimertinib as First-Line Treatment in EGFR-Mutated NSCLC Patients with Brain Metastases: Interim Analysis of An Open-Label, Multicenter, Randomized, Pivotal Phase II Study (ESAONA)

Presenter: Yuankai Shi

Background

Asandeutertinib (TY-9591) is a novel EGFR-TKI that showed promising efficacy and tolerable safety in its early-phase I & II trials. The ESAONA study was conducted to compare iasandeutertinib with osimertinib in patients with EGFR-mutated NSCLC with brain metastases.

Aim

To evaluate the efficacy and safety of asandeutertinib versus osimertinib as first-line therapy in treatment-naïve EGFR-mutated NSCLC patients with stable brain metastases.

Methods

• Phase comparative study with treatment-naïve NSCLC patients having EGFR-sensitizing mutations and stable brain metastases

• Randomization 1:1:
• Asandeutertinib 160 mg once daily
• Osimertinib 80 mg once daily
• Stratified by:
• Number of brain lesions (>3 vs ≤3)
• EGFR mutation type (L858R vs exon 19 deletion)
• Primary endpoints
• Intracranial objective response rate (iORR)
• Intracranial progression-free survival (iPFS)
• Assessed by blinded independent central review (RECIST v1.1)

Results

• Total 224 patients randomized (111 asandeutertinib, 113 osimertinib).
• Median follow-up ~19 months; baseline characteristics balanced.
• Efficacy
• Significantly higher iORR with asandeutertinib (95.5%) vs osimertinib (79.6%) (p=0.0004).
• BICR-assessed and INV-assessed median iPFS not reached with asandeutertinib vs 17.5 months with osimertinib (HR 0.46, p=0.0020 and HR 0.56, p=0.0122 respectively)
• Consistent improvement across investigator and subgroup analyses.
• Overall systemic efficacy numerically favored asandeutertinib; overall survival data immature.
• Safety
• Treatment-related adverse events: 99.1% asandeutertinib vs 95.6% osimertinib arm
• Serious adverse events: 10.8% vs 7.1%, respectively

Conclusion

Asandeutertinib significantly improved intracranial response and PFS compared to osimertinib, with a manageable safety profile. It represents a promising new first-line treatment option for EGFR-mutated NSCLC patients with brain metastases.

Anbenitamab Plus Albumin-Bound Docetaxel (Nab-Docetaxel) ± Carboplatin (Cb) versus Trastuzumab and Pertuzumab Plus Docetaxel (THP) ± Cb As Neoadjuvant Therapy for HER2-Positive Early or Locally Advanced Breast Cancer (LABC): A Randomized, Open-Label, Multicenter, Phase 3 Trial

Presenter: Zhi-Ming Shao

Background

THP ± Cb is the current standard neoadjuvant therapy for HER2-positive breast cancer. Pathological complete response (tpCR) rates remain suboptimal (39.3–56.0%), and improving tpCR is important as it correlates with long-term survival. Anbenitamab (KN026) is a novel biparatopic HER2-targeting antibody designed to enhance efficacy.

Aim

To compare the efficacy and safety of an Anbenitamab-based regimen versus standard-of-care THP ± Cb as neoadjuvant therapy in HER2-positive early or LABC.

Methods

• Phase 3 randomized clinical trial
• Patients with HER2-positive early or LABC (n=521) randomised to receive either Anbenitamab + nab-docetaxel ± carboplatin or Trastuzumab + pertuzumab + docetaxel ± carboplatin (THP ± Cb); stratified by clinical stage, hormone receptor status, and planned carboplatin use
• Primary endpoint: Total pathological complete response (tpCR: ypT0/is, ypN0), assessed by blinded independent review committee (BIRC)

Results

Efficacy

Outcome	Anbenitamab arm	THP ± Cb arm	Significance
BIRC-assessed tpCR	62.4%	51.2%	Δ 11.4%, p=0.0036
Investigator-assessed tpCR	63.9%	51.2%	p=0.0011
Breast pCR	64.6%	55.0%	p=0.0099

• Consistent tpCR improvement across all subgroups (hormone receptor status, stage, carboplatin use).

Safety

Safety Outcome	Anbenitamab arm	THP ± Cb arm
Any TEAEs	98.5%	98.8%
Grade ≥3 TEAEs	29.3%	28.3%
Common Grade ≥3 TEAEs	Neutropenia (11.4%), leukopenia (7.6%)	Neutropenia (10.9%), leukopenia (8.5%)
Drug interruption	5.7%	7.4%
Discontinuation	4.9%	3.5%

• Toxicities were mainly hematologic and gastrointestinal.
• No new safety signals were identified.

Conclusion

Anbenitamab plus nab-docetaxel ± Cb significantly improved tpCR compared to standard THP ± Cb, with comparable and manageable safety. This regimen shows promise as a potential new standard neoadjuvant therapy for HER2-positive BC.

FrontMIND: Phase 3 Study of Tafasitamab (Tafa) Plus Lenalidomide (Len) and R-CHOP for Patients (pts) with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Presenter: Georg Lenz

Background

A substantial unmet need for more effective first-line (1L) regimens exists since almost 40% of  diffuse large B-cell lymphoma (DLBCL) patients are not cured with first-line (1L) R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate/oncovin, prednisone). Tafasitamab (anti-CD19 mAb) in combination with lenalidomide (Tafa-Len)-R-CHOP in the phase 1b First-MIND study demonstrated safety and efficacy in patients with newly diagnosed disease.

Aim

To compare Tafa-Len-R-CHOP with R-CHOP in patients with high-risk aggressive BCLs.

Methods

• frontMIND was a phase 3, randomized, double-blind, placebo-controlled study
• Patients: Aged 18–80y with newly diagnosed, high-intermediate/high-risk DLBCL or HGBL (IPI 3–5, aaIPI 2–3 if ≤60 y) and ECOG PS 0–2
• Randomized 1:1 to Tafa-Len-R-CHOP or R-CHOP
• Primary endpoint: investigator-assessed PFS
• Secondary endpoints: EFS, OS, CR, ORR, safety

Results

• Total 899 patients were randomized to Tafa-Len-R-CHOP (n=448) or R-CHOP (n=451)
• Median follow-up: 35.2 mo
• Efficacy
  • Tafa-Len-R-CHOP achieved significant improvement in PFS versus R-CHOP (HR 0.75; P=0.019) in the overall population as well as in patients with centrally confirmed lymphoma subtypes (n=773; HR 0.68)
  • The 24-mo PFS was higher as compared to R-CHOP: 72.7% vs 62.2%
  • Tafa-Len-R-CHOP improved PFS in both molecular COO subtypes, ABC and GCB
  • Tafa-Len-R-CHOP significantly improved EFS vs R-CHOP; CR and ORR were similar between arms and HR for OS was 0.85 (final OS planned at 5y)
• Safety
  • Any-grade TEAEs were similar in treatment arms (98.6% vs 97.1%)
  • Grade ≥3 TEAEs occurred often with Tafa-Len-R-CHOP vs R-CHOP (86.7% vs 76.1%).
  • Discontinuations due to TEAEs occurred in 25.7% vs 17.9% and deaths due to TEAEs in 5.9% vs 3.8% of patients for Tafa-Len-R-CHOP vs R-CHOP
  • Fewer deaths with Tafa-Len-R-CHOP vs R-CHOP (18.5% vs 21.7%)

Conclusions

• Tafa-Len-R-CHOP significantly reduced the risk of disease progression or death compared with R-CHOP by 25%, with an 8.2% difference in 24-month PFS rate in the overall population and 10.5% difference in patients with centrally confirmed lymphoma subtypes
• TEAEs were manageable and consistent with the expected safety profile
• Tafa-Len-R-CHOP represented a potential new 1L standard of care for patients with both COO subtypes of high-risk DLBCL or HGBL

Efficacy outcomes (investigator-assessed) by treatment arm

Variable	Tafa-Len-R-CHOP (n=448)	R-CHOP (n=451)	HR or OR	Pvalue
PFS, # events (%)†	121 (27.0)	155 (34.4)	0.75	0.019
PFS rate at 24 mo (%)	71.1	62.9	-	-
PFS rate at 36 mo (%)	67.3	60.7	-	-
EFS, # events (%)	154 (34.4)	191 (42.4)	0.79	0.026
OS, # events (%)	82 (18.3)	95 (21.1)	0.85	0.270

^†Progressive disease or death from any cause

TALAPRO-3: Talazoparib (TALA) + Enzalutamide (ENZA) Compared with Placebo (PBO) + ENZA for the Treatment of Patients (pts) with Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Harboring Homologous Recombination Repair (HRR) Gene Alterations.

Presenter: Neeraj Agarwal

Background

In the Phase 3 TALAPRO-2 trial, addition of poly (ADP-ribose) polymerase inhibitor TALA to the androgen-receptor pathway inhibitor (ARPI) ENZA significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC), with the HRR-deficient cohort experiencing the greatest benefit.

Aim

To evaluate the efficacy and safety of TALA + ENZA in men with mCSPC bearing HRR gene alterations.

Methods

• Phase 3, double-blind TALAPRO-3 trial

• Patients were randomized 1:1 to TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO plus ENZA 160 mg once daily, stratified by de novo vs relapsed mCSPC, high- vs low-volume disease, and BRCA vs non-BRCA mutational status
• Patient eligibility: ECOG PS 0 or 1, presence of HRR gene alteration(s) (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C) confirmed by tumor tissue and/or circulating tumor DNA testing, ongoing androgen deprivation therapy (ADT), no prior treatment with docetaxel, and ≤3 mo of ADT with or without an approved ARPI for mCSPC
• Primary endpoint: Investigator-assessed rPFS
• Secondary endpoint: OS

Results

• 599 patients were randomized to TALA + ENZA (n=300) and PBO + ENZA (n=299)
• Median follow-up: 37.6 mo (TALA + ENZA) and 37.7 mo (PBO + ENZA)
• Efficacy
  • TALA + ENZA significantly improved rPFS vs PBO + ENZA (HR, 0.481; P<0.0001; median rPFS not reached vs 45.8 mo)
  • The HR for rPFS was 0.368 in the BRCA-mutated subgroup (n=207; 34.6%) and 0.567 in the non-BRCA-mutated subgroup (n=392; 65.4%)
  • TALA + ENZA showed a trend to improve the OS in the interim analysis (HR, 0.767; not statistically significant)
• Safety
  • The most common all-grade TEAEs in the TALA + ENZA group were anemia (71.2%), fatigue (28.4%), neutrophil count decreased (27.1%), neutropenia (22.1%), asthenia (21.4%) and white blood cell count decreased (21.4%)
  • TEAEs were generally manageable with dose modifications; 56 (18.7%) patients discontinued TALA due to TEAEs

Conclusions

• TALA + ENZA significantly and clinically improved rPFS with a trend towards improved OS vs standard-of-care ENZA in patients with HRR-deficient mCSPC
• Safety profile was generally manageable and consistent with those for TALA and ENZA

Phase 3 Clinical Trial of the Combination of Erlotinib Plus Ramucirumab Compared with Osimertinib in Untreated Advanced or Recurrent Non-Small Cell Lung Cancer with EGFR L858R Mutation: The REVOL858R Trial (WJOG14420L).

Presenter: Naoki Haratake.

Background

L858R EGFR‑mutant NSCLC is less sensitive to EGFR‑TKIs and carries poorer prognosis than exon 19 deletion. REVOL858R is the first phase III trial conducted exclusively in patients with advanced/recurrent L858R‑mutant NSCLC.

Aim

To compare the impact of erlotinib plus ramucirumab (E + RAM) followed by osimertinib (OSI) upon T790M acquisition vs. first‑line OSI monotherapy.

Methods

• Eligible treatment‑naïve adults (≥20 years) with advanced/recurrent EGFR L858R‑positive NSCLC and ECOG PS 0–1 were randomized 1:1 in two groups
• Arm A: OSI 80 mg daily
• Arm B: E + RAM (E 150 mg daily + R 10 mg/kg biweekly)
• A rebiopsy/liquid biopsy was mandated in patients in Arm B; T790M‑positive patients subsequently received OSI.
• The study participants were followed for time to failure of strategy (TFS), defined as disease progression or death during OSI or during the primary treatment when OSI was not administered in Arm B.

Results

Enrollment: 232 patients with EGFR L858R‑mutant NSCLC enrolled (Arm A: n=116; Arm B: n=116).

Primary Outcome

Median TFS was 14.8 vs 16.6 months (HR 1.03; 95% CI 0.78–1.38; p=0.49)

Secondary outcomes as mentioned in the table.

Table: Incidence of the secondary outcomes in the study arms

Key secondary endpoint,median (months)	Arm A (OSI)	Arm B (E+RAM)	HR (95% CI)
OS	44.0 (31.1-NR)	38.4 (33.3-NR)	0.98 (0.66-1.45)
3-y OS (%)	56.1%	57.2%	–
ORR (%)	73.2%	66.3%	–
PFS1	14.8	14.9	1.08 (0.81-1.44)
PFS2	23.8	25.1	0.96 (0.70-1.33)
Time to treatment failure	12.6	11.2	1.34 (1.02-1.77)
Key prespecified TFS subgroups
<65 years / ≥65 years	18.4 / 14.8	21.2 / 16.0	0.90 (0.40-1.99) / 1.06 (0.78-1.45)
With / Without baseline BM	11.8 / 19.2	14.7 / 17.8	0.81 (0.49-1.34) / 1.11 (0.79-1.57)

Safety

• Common AEs: Diarrhea; 41% (Arm A), 54% (Arm B).
• Acneiform rash; 30% (Arm A), 71% (Arm B).
• Hypertension (39%) and proteinuria (18%) frequent in Arm B.
• Incidence of interstitial lung disease: 10% (Arm A) vs. 2% (Arm B).
• Discontinuation due to AEs 21% (Arm A), 36% (Arm B).

Conclusions

A planned E+RAM-to-OSI strategy did not improve TFS, as compared to upfront OSI in EGFR L858R–mutated NSCLC. Safety outcomes aligned with expected profiles, though tolerability issues led to higher treatment discontinuation in the sequential strategy arm.

Final Results from ZZFIRST: A Randomized Phase 2 Trial of Enzalutamide (EZ) and Talazoparib (TALA) in Metastatic Hormone-Naïve Prostate Cancer (mHNPC).

Presenter: Joaquin Mateo.

Background

Androgen deprivation therapy (ADT) plus androgen receptor (AR) pathway inhibition (ARPI) improves outcomes in metastatic hormone‑naïve prostate cancer (mHNPC), though responses vary. AR–PARP co-stargeting has demonstrated enhanced activity, but mechanisms remain unclear.

Aim

To evaluate the effect of enzalutamide (EZ) plus talazoparib (TALA) in mHNPC, incorporating on‑therapy biopsies to study tumor adaptation to ADT+ARPI.

Methods

• Study design: An open label, randomized academic phase 2 trial.
• Patient Population:Patients with high‑volume mHNPC and ECOG PS ≤1, PSA≥4 ng/mL, randomized (as stratified by DDR mutation status) 2:1 as follows:
• EZ+TALA 0.5 mg/day
• Continued EZ alone until progressive disease (PD), unacceptable toxicity, or withdrawal
• All patients received two 28-days cycle of standard ADT+EZ (160 mg/day) before randomization
• Primary endpoint: Confirmed PSA <0.2 response rate at 12 months for EZ+TALA (powered to detect ≥40% vs null 20%).
• Key secondary endpoints: rPFS, time to PSA-PD, time to castration resistance, and safety.

Results

Enrollment: 54 patients (37 EZ+TALA, 17 EZ), 7 patients harbored HRR alterations by tumor tissue NGS (13%; 5 EZ+TALA, 2 EZ). Visceral metastases present in 17 pts (32%); de novo M1 disease present in 51 pts (94%).

Median follow-up: 3.6 years

Efficacy

• 12-mo PSA < 0.2-RR for EZ+TALA: 73% (95%CI, 55.9%-86.2%, p < 0.001) and for EZ: 64.7%.
• Median rPFS: 45.3 mo (29.4-NR) for EZ+TALA vs 31.1 mo (13.5-NR) for EZ (HR = 0.62; 95%CI, 0.28-1.37).
• Median time to PSA-PD not reached (30.4-NR) for EZ+TALA vs 30.7 mo (6.6-NR) for EZ (HR = 0.47; 95%CI, 0.21-1.04).
• Median TTCR: 30.4 mo (23.0-NR) for EZ+TALA vs 22.8 mo (6.3-45.4) for EZ (HR = 0.62; 95%CI, 0.30-1.26).

  Safety

• Common TEAEs: TALA+EZ- fatigue (any grade: 83.8%; G≥3: 13.5%) and anemia (67.6%; G≥3: 40.5%).
• 14 (38%) pts required TALA dose reductions.
• Two patients on EZ+TALA developed acute myeloid leukemia (AML) 26.0 and 32.8 months after study entry.
• Transcriptomics analysis on C2D1 vs BL biopsies revealed induction of cell cycle arrest, with downregulation of AR and DDR signatures and upregulation of IFN-related and inflammatory response signatures upon ADT+EZ.

Conclusions

EZ+TALA showed promising antitumor activity in high‑volume mHNPC. The toxicity profile was consistent with prior AR+PARP trials, though two cases of AML occurred with prolonged TALA exposure. Paired biopsies revealed tumor adaptation mechanisms to ADT+EZ, supporting a biologically informed rationale for AR+PARP treatment intensification strategies in mHNPC.

Integrating BTK Inhibition into R-da-EPOCH for HIV-Related DLBCL

Presenter: Ida Wong-Sefidan.

Background

Human immunodeficiency virus (HIV)-related diffuse large B-cell lymphomas (DLBCL) are clinically & molecularly heterogeneous in nature. R-da-EPOCH is the standard of care in HIV+DLBCL. Classification of tumors based on immunophenotype & genomic features may facilitate personalized therapy to improve outcomes. Ibrutinib (Ibr), a Bruton’s tyrosine kinase (BTK) inhibitor inhibits inducible T cell kinase (ITK). HIV hijacks host ITK during replication, hence ibr may have additional clinical benefits in HIV+DLBCL.

Aim

To evaluate safety, feasibility & activity of adding Ibr to R-da-EPOCH in HIV+DLBCL patients. The impact on T cells & correlate lymphoma cell of origin (COO) with response were also analyzed.

Methods

• Study design: A multi-center study including a 3+3 dose de-escalation cohort followed by dose-expansion at recommended phase 2 dose (RP2D).
• Patient Population: Patients with stage II-IV HIV-DLBCL (age 18-64 years, 86% were stage III/IV, 40% non-GCB, & 88% had ECOG 0-1), CD4 <100 & asymptomatic leptomeningeal disease were allowed.
• Treatment as follows:
  • Either untreated or received 1 cycle R-da-EPOCH/CHOP off-study.
  • Ibr given as daily dose on days 1-21, R-da-EPOCH administered as pre-specified standards for 6 total cycles.

Results

• Patients evaluable for toxicity: 43, patients evaluable for response: 37
• Patients tolerating ≥2 cycles: 95% (41/43)
• Median cycles of study therapy (tx) received: 5
• Median age at baseline: 52 years
• Median CD4 count at baseline: 204; (CD4 <100 in 9 patients).
• Ibr RP2D daily dose: 560 mg daily.

  Efficacy

• Overall response rate: 100% [complete (CR): 57% & partial responses (PR): 43%]. Relapse/progression: 16% (1CR, 5PR) during a median follow-up of 4.2y (95%CI = 2.3 to 4.87)
• Median duration of response: 2.8y
• 3-yr EFS: 83% (GCB: 88%, non-GCB: 76%)
• OS: 81% r (GCB: 87% non-GCB: 63%)

  Safety

• Treatment-related adverse events (TRAE): 679; most frequent: (total, % grade (gr) 3+) anemia (105, 50%), thrombocytopenia (81, 41%), neutropenia (60, 88%) & lymphopenia (60, 68%).
• Non-hematologic AEs (total TRAE, # max gr): Diarrhea (22, 2 gr3), nausea (21, 1 g3), hypokalemia (20, 4 gr3), fatigue (17, 17 gr1), & sepsis (1 gr4).
• Reasons for treatment discontinuation: 1 progression, 4 withdrawal, 4 TRAE, 1 lost to follow up.

Conclusions

Incorporating Ibr 560 mg daily with R‑da‑EPOCH for HIV‑related DLBCL resulted in manageable toxicities consistent with R‑da‑EPOCH. Confirmed CR rates were lower, 3‑year EFS and OS were comparable or superior to prior HIV+DLBCL R‑da‑EPOCH studies. Ongoing analyses will assess T‑cell subsets and correlate outcomes with circulating tumor DNA, & lymphoma features (EBV, MYC, BCL2, BCL6, and COO genomic determinations of COO).

Reference: Annual Meeting of the American Society of Clinical Oncology (ASCO 2026), 29^th May – 6^th June 2026, Chicago, IL.