Author: RR

ZEGFROVY® (Sunvozertinib)

RR

The FDA on July 2, 2025, granted accelerated approval to ZEGFROVY® for adult patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. ZEGFROVY® is a product of Dizal (Jiangsu) Pharmaceutical Co., Ltd.

LYNOZYFIC® (Linvoseltamab-gcpt)

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The FDA on July 2, 2025, granted accelerated approval to LYNOZYFIC®, a bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. LYNOZYFIC® is a product of Regeneron Pharmaceuticals, Inc.

KEYTRUDA® (Pembrolizumab)

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The FDA on June 12, 2025, approved KEYTRUDA® for adults with resectable locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with Radiotherapy (RT) with or without Cisplatin after surgery, and then as a single agent. KEYTRUDA® is a product of Merck.

Neoadjuvant Niraparib Plus Dostarlimab in BRCA or PALB2-Mutated Triple Negative Breast Cancer: Phase II TBCRC 056 Results

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer were diagnosed in 2025, and about 42,170 women died of the disease, largely due to metastatic recurrence.

Rationale for a Chemotherapy-Free Neoadjuvant Strategy

Patients with germline BRCA1/2 or PALB2–mutated breast cancer represent a biologically distinct population with heightened sensitivity to PARP inhibition. Beyond synthetic lethality, accumulating preclinical evidence suggests that PARP inhibitors activate the cGAS/STING pathway, increasing intratumoral inflammation, recruiting CD8+ T cells, and potentially priming tumors for immune checkpoint blockade.

While prior studies have not demonstrated a clear benefit for combining PARP inhibitors with immunotherapy in the advanced TNBC (Triple-Negative Breast Cancer) setting, investigators hypothesized that the early-stage, neoadjuvant context, characterized by less immune exhaustion and lower tumor burden, might offer a more permissive environment for synergy.

Study Design and Patient Population

TBCRC 056 is a randomized, Phase II study evaluating the PARP inhibitor Niraparib (ZEJULA®) in combination with the anti–PD-1 antibody Dostarlimab (JEMPERLI®) as neoadjuvant therapy for patients with HER2-negative breast cancer harboring germline BRCA1/2 or PALB2 mutations. The trial includes cohorts for both triple-negative and Estrogen Receptor (ER) positive disease. The current analysis focuses on TNBC cohorts (Arms A and B). Participants with ER positive breast cancer will be placed directly into Arm C. There is no randomization for these participants.

Eligible patients were ≥18 years old with Stage I–III TNBC, primary tumors ≥1.0 cm, HER2-negative disease, and confirmed germline BRCA1/2 or PALB2 mutations. Patients were randomized to:

  • Arm A: Niraparib 200 mg orally once daily plus Dostarlimab 500 mg IV every 3 weeks for 18 weeks
  • Arm B: Niraparib monotherapy for 3 weeks followed by Niraparib plus Dostarlimab for 15 weeks

Tumor biopsies were obtained at baseline and week 3 to assess immune modulation. Surgery followed 18 weeks of therapy, with optional additional neoadjuvant treatment at investigator discretion if residual disease was detected.

RCB (Residual Cancer Burden in the breast tissue and axillary lymph nodes) Categories:

  • RCB 0:No invasive cancer cells found (pCR).
  • RCB I (Minimal):Very small amount of residual disease.
  • RCB II (Moderate):Moderate amount of residual disease.
  • RCB III (Extensive):Significant amount of residual disease.

Endpoints and Statistical Considerations

The Primary endpoints were:

  • Pathologic Complete Response (pCR; RCB-0) rate in Arms A and B combined
  • Change in stromal Tumor-Infiltrating Lymphocytes (sTILs) from baseline to week 3

The study was powered to detect a pCR rate of ≥50%, allowing rejection of a null hypothesis pCR rate <30%.

Baseline Characteristics

A total of 46 patients with TNBC were enrolled across Arms A and B. The median age was 39.3 years, reflecting the young demographic typical of germline BRCA-associated disease. Most patients were White (84.8%), with representation from Black, Asian, and Hispanic populations. Clinically, 37.0% had Stage I disease, 45.7% Stage II, and 17.4% Stage III. The majority had node-negative and high-grade (grade 3) tumors. BRCA1 mutations predominated (82.6%), with the remainder harboring BRCA2 mutations. No PALB2-mutated TNBC patients were enrolled in this cohort.

Efficacy Outcomes: pCR and Residual Disease

Neoadjuvant Niraparib plus Dostarlimab achieved a pCR rate of 50.0% (90% CI, 37.1%–62.9%) among evaluable patients, meeting and exceeding the study’s predefined efficacy threshold.

Notably:

  • pCR rates were identical in both treatment strategies, at 50% in Arm A (concurrent therapy) and Arm B (niraparib lead-in)
  • The combined RCB-0/I rate was 60.0%, suggesting meaningful tumor eradication or minimal residual disease in a majority of patients
  • Approximately 24% of patients crossed over to additional preoperative therapy, reflecting real-world decision-making when residual disease is identified

These findings support the robustness of the regimen regardless of initial PARP inhibitor lead-in.

Immune Modulation and Biomarker Insights

A key translational objective of TBCRC 056 was to characterize early immune changes within the tumor microenvironment.

Both treatment arms demonstrated statistically significant increases in sTILs from baseline to week 3:

  • Arm A: Mean sTILs increased from 16% to 27.4%
  • Arm B: Mean sTILs increased from 19.5% to 42.1%, suggesting a pronounced immune activation following PARP inhibitor exposure

Importantly, patients who achieved pCR had higher baseline sTIL levels than those who did not, underscoring the prognostic relevance of preexisting immune infiltration. Baseline sTILs were also associated with achieving RCB-0/I.

In contrast, baseline PD-L1 expression, estrogen receptor status (ER-0 vs ER-low), and short-term changes in sTILs were not independently associated with pCR, highlighting the complexity of immune–genomic interactions in BRCA-driven TNBC.

Safety and Tolerability

The safety profile of Niraparib plus Dostarlimab was consistent with known toxicities of PARP inhibition and immune checkpoint blockade.

  • Grade ≥2 treatment-related adverse events occurred in 82.6% of patients
  • Grade 3 events were reported in 26.1%, and grade 4 events were rare (2.2%)
  • The most common higher-grade toxicities included anemia, fatigue, hypertension, hypothyroidism, and neutropenia

Treatment discontinuation occurred in 13% of patients, with discontinuations split between Niraparib and Dostarlimab, suggesting manageable but clinically relevant toxicity in a neoadjuvant setting.

Key Takeaways for Oncology Practice

  • TBCRC 056 demonstrates that a chemotherapy-free neoadjuvant therapy with Niraparib combined with Dostarlimab achieved a 50% pathologic Complete Response (pCR) rate in patients with germline BRCA-mutated early-stage TNBC, exceeding the study’s predefined efficacy threshold.
  • pCR rates were identical whether Dostarlimab was administered concurrently with Niraparib or following a short PARP inhibitor lead-in, suggesting flexibility in treatment sequencing.
  • Treatment was associated with a significant increase in stromal Tumor-Infiltrating Lymphocytes (sTILs) within 3 weeks, supporting biologic synergy between PARP inhibition and PD-1 blockade in early-stage disease.
  • Higher baseline sTIL levels were associated with both pCR and minimal residual disease (RCB-0/I), whereas baseline PD-L1 expression and ER-low status were not predictive.
  • These findings support further investigation of biomarker-driven, non-chemotherapy neoadjuvant strategies in genetically defined TNBC populations.

TBCRC-056: A phase II study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts. Mayer EL, Graham N, Leon-Ferre RA, et al. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF5-02.

 

 

 

 

Late Breaking Abstract – ASH 2025: Teclistamab Plus Daratumumab Redefines Outcomes in Early Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI&reg;), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX&reg;), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med. Published December 9, 2025. DOI: 10.1056/NEJMoa2514663