Author: RR

Elinzanetant Reduces Vasomotor Symptoms in Women Receiving Endocrine Therapy for HR-Positive Breast Cancer

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 will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 70% are Hormone Receptor (HR)–positive, and long-term endocrine therapy, typically 5 to 10 years of Tamoxifen or an Aromatase Inhibitor, with or without a GnRH analogue, substantially lowers recurrence and mortality. However, treatment-related Vasomotor Symptoms (VMS), such as hot flashes, are frequent and often more severe than those seen in natural menopause, particularly in younger women receiving GnRH suppression. These adverse effects diminish quality of life and contribute to nonadherence.

Because postmenopausal hormone therapy is contraindicated in this setting, current management options rely on lifestyle measures, behavioral strategies, or off-label medications (e.g., SSRIs, Gabapentin, Clonidine, Oxybutynin), each with limited evidence and tolerability concerns. Thus, effective nonhormonal therapies are a critical unmet need.

Elinzanetant and Mechanism of Action

Elinzanetant is a dual Neurokinin-1 (NK-1) and Neurokinin-3 (NK-3) receptor antagonist. It acts on hypothalamic KNDy (Kisspeptin–Neurokinin–Dynorphin) neurons, which regulate thermoregulation and are hyperactivated by estrogen withdrawal from natural menopause or endocrine therapy. This results in elevated expression of Neurokinin B and Substance P which are responsible for vasomotor symptoms. By modulating Neurokinin B and Substance P signaling, Elinzanetant reduces VMS and may improve sleep disturbances. Unlike other agents in this class, trials to date have not demonstrated hepatotoxicity.

Trial Design

The OASIS-4 trial is a Phase 3, randomized, double-blind, placebo-controlled study conducted at 90 sites across Europe, Canada, Israel, and Kazakhstan. This study included 474 women (aged 18–70) with HR-positive breast cancer or at high risk, receiving Tamoxifen or an Aromatase Inhibitor with or without GnRH analogue, and reporting 35 or more moderate-to-severe VMS episodes per week. Patients were randomized in a 2:1 to receive Elinzanetant 120 mg daily for 52 weeks (N=316) or Placebo once daily for 12 weeks followed by Elinzanetant 120 mg daily for 40 weeks (N=158). The Primary end points were the change in the mean daily frequency of moderate-to-severe vasomotor symptoms from baseline to week 4 and to week 12. While a general guideline is lacking for a “clinically meaningful” reduction in vasomotor symptoms (VMS) caused by endocrine therapy, the reduction of at least 50% from baseline is considered a significant individual benefit for women in natural menopause.

Results:

Elinzanetant significantly reduced moderate-to-severe vasomotor symptoms, improved sleep, and enhanced menopause-related quality of life compared to a placebo

  • Baseline mean daily VMS frequency: About 11 episodes/day in both arms
  • Week 4: Mean reduction of 6.5 daily episodes of moderate-to-severe VMS with Elinzanetant vs. reduction of 3.0 daily episodes with placebo (P <0.001)
  • Week 12: Mean reduction of 7.8 episodes of moderate-to-severe VMS with Elinzanetant vs. reduction of 4.2 daily episodes with placebo (P <0.001)
  • 50% or more reduction in VMS frequency at 12 weeks was achieved by >70% of Elinzanetant-treated participants
  • Benefits extended to improvements in sleep and menopause-related quality of life
  • Safety: most common adverse events were headache, fatigue, and somnolence; serious adverse events occurred in 2.5% vs. 0.6% with placebo
  • No hepatotoxicity signal was detected through 52 weeks
  • Treatment satisfaction: 91.6% of participants completing 52 weeks opted into a 2-year extension

Clinical Implications

Vasomotor symptoms and sleep disruption are among the most burdensome adverse effects of endocrine therapy and are key contributors to poor adherence, which directly impacts long-term breast cancer outcomes. Currently, management options are limited and inconsistently effective, particularly in this population where hormone therapy for menopausal symptoms is contraindicated.

Elinzanetant represents a novel, well-tolerated, nonhormonal strategy that demonstrated reproducible reductions in VMS across both naturally menopausal and endocrine therapy–induced settings. While OASIS-4 was not powered to evaluate breast cancer recurrence or survival, reducing symptom burden may indirectly enhance adherence to endocrine therapy and improve outcomes.

Limitations and Next Steps

The trial population was predominantly White, limiting generalizability. Long-term breast cancer outcomes were not assessed and Real-world tolerability and adherence remain to be defined. Ongoing extension studies and future trials will clarify durability of benefit, potential endocrine effects, and impact on long-term treatment adherence and survival.

Conclusion

In women receiving endocrine therapy for HR-positive breast cancer, Elinzanetant significantly reduced vasomotor symptoms (VMS), improved sleep, and enhanced quality of life with a favorable safety profile. These findings highlight its potential role as a much-needed nonhormonal therapeutic option to support adherence and improve patient-centered outcomes in breast cancer care.

Elinzanetant for Vasomotor Symptoms from Endocrine Therapy for Breast Cancer. Cardoso F, Parke S, Brennan DJ, et al. N Engl J Med 2025;393:753-763

FDA Grants Accelerated Approval to EMRELIS® for NSCLC with High c-Met Protein Overexpression

RR

SUMMARY: The FDA on May 14, 2025, granted accelerated approval to Telisotuzumab vedotin-tllv (EMRELIS®), a c-Met-directed antibody and microtubule inhibitor conjugate, for adults with locally advanced or metastatic, non-squamous Non-Small Cell Lung Cancer (NSCLC) with high c-Met protein overexpression [50% or more of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy. FDA also approved the VENTANA MET (SP44) RxDx Assay (Roche Diagnostics) as a companion diagnostic test to aid in detecting c-Met protein overexpression in patients with non-squamous NSCLC who may be eligible for treatment with Telisotuzumab vedotin .

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

Background

The MET proto-oncogene encodes the receptor tyrosine kinase c-Met, a key regulator of tumor cell proliferation, survival, invasion, and angiogenesis. Dysregulation of MET signaling can occur in NSCLC via gene amplification (about 5% of cases), exon 14 skipping mutations (about 2%-4%), or through c-Met protein overexpression, which is observed in approximately one-quarter to one-third of patients. Notably, c-Met protein overexpression represents a negative prognostic marker in both early and advanced NSCLC, particularly in nonsquamous, EGFR-wildtype disease, yet no therapies have been approved to directly address this biomarker.

Telisotuzumab vedotin (Teliso-V; EMRELIS®) is a first-in-class, c-Met–directed antibody-drug conjugate (ADC). It couples a c-Met–binding monoclonal antibody with the microtubule-disrupting agent MonoMethyl Auristatin E (MMAE) through a cleavable linker. Preclinical work showed that tumoricidal activity requires high levels of c-Met expression (>100,000 receptors per cell), which supports patient selection strategies for clinical use.

The LUMINOSITY Trial Design

LUMINOSITY study (NCT03539536) is an ongoing, nonrandomized, two-stage, Phase II, multicenter trial designed to identify and validate the NSCLC populations most likely to benefit from Teliso-V monotherapy in the second-line or third-line setting, and then to expand the groups to further evaluate efficacy in the selected populations.

  • Stage I: Patients were enrolled into three cohorts based on histology and EGFR mutation status: (1) nonsquamous EGFR-wildtype NSCLC, (2) nonsquamous EGFR-mutant NSCLC, and (3) squamous NSCLC.
  • Stage II: Only the nonsquamous EGFR-wildtype NSCLC cohort fulfilled expansion criteria and was carried forward for further evaluation.

Biomarker Definition:

  • Nonsquamous NSCLC: c-Met protein overexpression defined as 25% or more of tumor cells showing 3+ membrane staining intensity (with high expression 50% or more and intermediate expression 25-less than 50%).
  • Squamous NSCLC: a broader cutoff was applied (75% or more of tumor cells at any intensity) given generally lower c-Met expression levels.

Treatment regimen: Teliso-V was administered intravenously at 1.9 mg/kg every 2 weeks.

Endpoints: The Primary endpoint was Overall Response Rate (ORR) by Independent Central Review (ICR). Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety.

Key Efficacy Results in the Nonsquamous EGFR-wildtype NSCLC Cohort

As of February 21, 2024, 172 patients had received at least one dose of Teliso-V, with 168 patients (N=168) included in efficacy analyses (c-Met high, N=84, c-Met intermediate, N=84). The majority (97.6%) had previously received platinum-based chemotherapy, and nearly 80% had also received immune checkpoint inhibitors (ICIs).

  • Overall Response Rate (ORR):
    • Total c-Met overexpressing population: 29.2%
    • High expression: 34.5%
    • Intermediate expression: 23.8%
  • Median Duration of Response (DOR):
    • Overall: 7.2 months
    • High expression: 9.0 months
    • Intermediate expression: 7.2 months

Responses were consistent across patients pretreated with platinum alone or with both platinum and ICI, suggesting durability irrespective of prior therapy type.

Safety Profile

The safety of Teliso-V was generally manageable and consistent with its mechanism of action.

  • Most common treatment-related adverse events (any grade): peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%).
  • Most common grade 3 or more TRAE: peripheral sensory neuropathy (7%).

These findings align with the known toxicity profile of MMAE-based ADCs, highlighting neuropathy as the principal dose-limiting concern.

Limitations and Next Steps

While encouraging, the Phase II design lacked a comparator arm, limiting definitive conclusions about comparative efficacy. A randomized, Phase III trial, TeliMET NSCLC-01 (NCT04928846), is underway, directly comparing Teliso-V against Docetaxel in previously treated, c-Met–overexpressing, nonsquamous EGFR-wildtype NSCLC. Additionally, exploratory biomarker analyses may help refine patient selection, particularly given potential overlap between c-Met protein expression and other MET pathway genomic alterations.

Clinical Implications

LUMINOSITY demonstrates that Teliso-V can achieve durable clinical responses in a biomarker-selected subset of NSCLC patients who currently lack targeted treatment options. Response enrichment among patients with high c-Met protein expression reinforces the relevance of robust biomarker screening in clinical practice. Teliso-V represents the first therapy specifically directed against c-Met protein overexpression in NSCLC, addressing an important unmet need.

LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein–overexpressing non-squamous EGFR-wildtype advanced NSCLC: Efficacy outcomes by prior therapy. Goldman JW, Lu S, Bar J, et al. Journal of Clinical Oncology. Volume 43, Number 16_suppl. https://doi.org/10.1200/JCO.2025.43.16_suppl.8618

FDA Approves Zongertinib for NSCLC with HER2 TKD activating mutations

RR

SUMMARY: The FDA on August 8, 2025, granted accelerated approval to Zongertinib (HERNEXEOS®), a kinase inhibitor, for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy. FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to aid in detecting HER2 (ERBB2) TKD activating mutations in patients with non-squamous NSCLC who may be eligible for treatment with Zongertinib.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases.

The FDA in 2022 granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan), for adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) mutations. This is the first drug approved for HER2-mutant NSCLC. Trastuzumab deruxtecan, however, can be associated with toxicities including Interstitial Lung Disease (ILD). Similarly, Pan-HER TKIs such as Poziotinib and Pyrotinib have shown limited efficacy and are frequently associated with EGFR-related adverse events, underscoring the urgent need for more targeted, better-tolerated therapies.

Zongertinib is a novel, oral, irreversible Tyrosine Kinase Inhibitor designed to selectively target HER2 while sparing EGFR, thus minimizing common toxicities such as rash and diarrhea.

Beamion LUNG-1 is an ongoing Phase 1a/1b trial evaluating Zongertinib in previously treated patients with HER2-altered advanced or metastatic solid tumors (Phase 1a) and those with HER2-mutant advanced or metastatic NSCLC across multiple clinically relevant patient cohorts (Phase 1b). In the Phase 1a dose-escalation trial, Zongertinib showed encouraging preliminary activity at the recommended expansion doses of 120 mg and 240 mg once daily, with a low incidence of Grade 3 or higher adverse events.

The Phase 1b portion of the study evaluated Zongertinib in three key populations:

  • Cohort 1: Pretreated NSCLC patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
  • Cohort 5: NSCLC patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
  • Cohort 3: NSCLC patients whose tumor had HER2 mutations outside the TKD.

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance. The median age in Cohort 1 was 62 yrs. The Primary end point was an Objective Response Rate (ORR) assessed by Blinded Independent Central Review (Cohorts 1 and 5) or by Investigator Review (Cohort 3). Secondary end points included the Duration of Response and Progression-Free Survival (PFS).

Efficacy Outcomes
The median follow-up was 11.3 months at the data-cutoff date. Zongertinib demonstrated robust and durable activity, particularly in Cohort 1:

  • Cohort 1 (N=75 at 120 mg daily dose):
    • Objective response rate (ORR): 71% (P<0.001)
    • Median Duration of Response (DoR): 14.1 months
    • Median progression-free survival (PFS): 12.4 months

Importantly, responses were consistent across subgroups, including patients with brain metastases (ORR: 64%) and common TKD insertion subtypes such as A775_G776insYVMA (ORR: 81%).

  • Cohort 5 (N=31):
    • ORR: 48%, including patients previously treated with Trastuzumab deruxtecan (ORR: 42%)
    • Median Duration of Response: 27% had a DOR ≥ 6 months
  • Cohort 3 (N=20):
    • ORR: 30%
    • Activity observed across several non-TKD mutations (e.g., S310X, V659E)

These findings suggest that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

Safety and Tolerability
Zongertinib was well tolerated across all cohorts:

  • Grade ≥3 drug-related adverse events occurred in:
    • 17% of patients in Cohort 1
    • 3% in Cohort 5
    • 25% in Cohort 3
  • No cases of drug-related interstitial lung disease were observed
  • Most common adverse event was diarrhea (any grade: 56%; grade ≥3: 1%), followed by rash (all grade ≤2)

The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions
Compared with other HER2-targeted agents including Trastuzumab deruxtecan and investigational pan-HER TKIs, Zongertinib stands out for its high response rates, durability, and manageable toxicity. While cross-study comparisons have inherent limitations, these results support Zongertinib as a promising, HER2-selective oral agent for patients with HER2-mutant NSCLC. The ongoing Phase 3 Beamion LUNG-2 trial (NCT06151574) will further assess Zongertinib in the first-line setting, providing critical data on its role relative to current standard-of-care therapies.

Conclusion
Zongertinib has emerged as a strong candidate in the evolving landscape of HER2-mutant NSCLC. With high response rates, durable outcomes, and a favorable safety profile, it may soon offer oncologists a powerful new tool for treating this difficult-to-manage patient population.

Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer. Heymach JV, Ruiter G, Ahn M-J, et al. for the Beamion LUNG-1 Investigators. N Engl J Med 2025;392:2321-2333.

Tafasitamab Plus Lenalidomide and Rituximab Improves Outcomes in Relapsed/Refractory Follicular Lymphoma: Results from the Phase III inMIND Trial

RR

SUMMARY: The FDA on June 18, 2025, approved Tafasitamab-cxix (MONJUVI®) with Lenalidomide and Rituximab for adults with Relapsed or Refractory Follicular Lymphoma (FL).

The American Cancer Society estimates that in 2025, about 80,350 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,390 individuals will die of this disease. Indolent Non-Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

Follicular Lymphoma is the most indolent form and second most common form of all NHLs, and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas and the average age of diagnosis is 65 years. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance Rituximab (RITUXAN®). This can result in a median Progression Free Survival (PFS) of 6-8 yrs and a median Overall Survival (OS) of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years, with prognosis worsening after each subsequent relapse. Immunotherapy-based approaches are increasingly favored, yet durable disease control remains elusive, particularly among patients with high-risk features such as progression within 24 months of initial therapy (POD24) or resistance to anti-CD20 monoclonal antibodies.

Lenalidomide in combination with Rituximab (R²) is an established option after at least one prior line of therapy. Tafasitamab, a humanized anti-CD19 monoclonal antibody with both direct cytotoxic and immune-mediated mechanisms of action, has previously demonstrated efficacy in Diffuse Large B-Cell Lymphoma in combination with Lenalidomide (L-MIND trial). The Phase III inMIND study (NCT04680052) was designed to evaluate whether adding Tafasitamab to the R² backbone could improve outcomes in patients with Relapsed or Refractory (R/R) FL. This study was powered to assess PFS in patients with FL only.

Study Design and Methods
inMIND was a randomized, double-blind, placebo-controlled, global Phase III trial that enrolled 548 patients with Grade 1–3A FL or Marginal Zone Lymphoma. All patients had received at least one prior systemic therapy, including an anti-CD20 monoclonal antibody, and required treatment for Relapsed or Refractory disease. Key eligibility criteria included age 18 years or older, CD19+/CD20+ disease, and ECOG performance status 2 or less. Patients were stratified by POD24 status, refractoriness to prior therapy, and number of prior treatment lines (1 vs >1).

Participants were randomized 1:1 to:

  • Tafasitamab + Lenalidomide + Rituximab (Tafa arm)
  • Placebo + Lenalidomide + Rituximab (control arm)

A total of 548 patients were randomized (Tafa, n=273; Placebo, n=275). Baseline characteristics were balanced between arms:

  • Median age: 64 years
  • 79% with intermediate/high-risk FLIPI scores
  • 83% with high tumor burden (GELF criteria)
  • 32% with POD24
  • 43% refractory to prior anti-CD20 therapy

Tafasitamab (12 mg/kg IV) or placebo was administered on days 1, 8, 15, and 22 of cycles 1–3, and days 1 and 15 of cycles 4–12. All patients received standard dosing of Lenalidomide plus Rituximab for up to twelve 28-day cycles.

  • Primary endpoint: investigator-assessed Progression-Free Survival (PFS) in patients with FL.
  • Key secondary endpoints: Complete metabolic Response (PET-CR), Overall Response Rate (ORR), Duration of Response (DOR), Time To Next Treatment (TTNT), Overall Survival (OS), and safety.

At a median follow-up of 14.1 months:

  • Primary endpoint met: Tafasitamab significantly reduced the risk of progression, relapse, or death by 57%.
    • Median PFS: 22.4 months (Tafa) vs 13.9 months (placebo)
    • Hazard ratio (HR) 0.43; 95% CI 0.32–0.58; P < 0.0001
  • Independent Review Committee (IRC) confirmation: median PFS not reached with Tafasitamab vs 16.0 months with placebo (HR 0.41; P < 0.0001).
  • Response outcomes:
    • PET-CR rate: 49.4% vs 39.8% (P = 0.029)
    • ORR: 83.5% vs 72.4% (P = 0.0014)
    • DOR: 21.2 vs 13.6 months (HR 0.47; P < 0.0001)
    • TTNT: not reached vs 28.8 months (HR 0.45; P < 0.0001)
  • Overall Survival (immature): trend favoring Tafasitamab (HR 0.59; 95% CI 0.31–1.13).

Subgroup Analyses
PFS benefit with Tafasitamab was consistent across all prespecified groups, including POD24 patients, those refractory to prior anti-CD20 therapy and patients with ≥2 prior lines of therapy

Safety Profile
Adverse events were manageable and consistent with known profiles of the combination components.

  • Grade 3/4 adverse events occurred in 71% (Tafa) vs 69.5% (placebo).
  • Most common Grade 3/4 events: neutropenia (40% vs 38%), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%).
  • COVID-19 infections were slightly more frequent in the Tafasitamab arm (6% vs 2%).
  • Treatment discontinuation due to adverse events occurred in 11% (Tafa) vs 7% (placebo).
  • On-study deaths were less frequent in the Tafasitamab arm (5.5% vs 8.5%).

Importantly, Tafasitamab did not interfere with the administration of Lenalidomide or Rituximab and dose reductions and treatment interruptions were comparable across arms.

Clinical Implications
The inMIND trial is the first phase III study to validate a dual-antibody approach targeting both CD19 and CD20 in FL. The addition of Tafasitamab to R² not only extended PFS by nearly nine months but also improved depth of response and delayed the need for subsequent therapy, without introducing unexpected toxicities.

For high-risk patients, including those with POD24 or anti-CD20–refractory disease, these results are particularly impactful, addressing a long-standing gap in treatment outcomes.

As novel immunotherapies such as bispecific antibodies and CAR T-cell therapies are integrated earlier in the treatment paradigm, questions about sequencing and immune fitness will become increasingly relevant. Nonetheless, Tafasitamab plus R² emerges from inMIND as a practical, chemotherapy-free regimen that can be delivered in both community and academic settings, representing a potential new standard of care for patients with R/R FL.

Key Takeaways

  • inMIND met its primary endpoint, showing a 57% risk reduction in progression, relapse, or death with Tafasitamab + R² vs R² alone.
  • Benefits were consistent across high-risk subgroups, including POD24 and anti-CD20–refractory patients.
  • Secondary endpoints (ORR, CR, DOR, TTNT) also significantly favored Tafasitamab.
  • Safety profile was manageable and aligned with expectations.
  • Longer follow-up will clarify OS benefit, but current findings strongly support the role of Tafasitamab in improving outcomes for patients with Relapsed/Refractory Follicular Lymphoma.

Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND). Sehn LH, Luminari S, Scholz CW, et al. Blood (2024), Volume 144, Supplement 2: LBA-1. https://doi.org/10.1182/blood-2024-212970

Pirtobrutinib in Relapsed/Refractory CLL/SLL after Prior cBTKi: Phase III BRUIN CLL-321 Results

RR

SUMMARY: The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM).

The 3 covalent BTK inhibitors (cBTKi) presently approved by the FDA for CLL/SLL include Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®), and Zanubrutinib (BRUKINSA®). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.

Pirtobrutinib (JAYPIRCA®) is a next-generation, highly selective, reversible, non-covalent BTK inhibitor (BTKi), developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib is well tolerated and demonstrated encouraging efficacy and safety in early-phase studies, leading to FDA accelerated approval in December 2023 for patients with CLL/SLL who have received ≥2 prior lines of therapy, including both a BTKi and a BCL-2 inhibitor.

Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) in the post–covalent Bruton Tyrosine Kinase Inhibitor (cBTKi) setting remains a major therapeutic challenge. No prospective, randomized trials have previously evaluated treatment options in this population, and real-world data suggest poor outcomes, particularly after sequential covalent BTKi and BCL-2 inhibitor exposure.

Study Design
BRUIN CLL-321 is the first global, randomized, multicenter, Phase III trial conducted exclusively in patients with R/R CLL/SLL previously treated with a cBTKi.

  • Design: Open-label, 1:1 randomization to Pirtobrutinib 200 mg PO daily (N=119) vs. investigator’s choice (IC) of Idelalisib plus Rituximab (IdelaR-N=82) or Bendamustine plus Rituximab (BR-N=37).
  • Population: 238 patients; median 3 prior therapies; 50% had prior Venetoclax; high prevalence of high-risk genomic features (del[17p]/TP53 mutation ~54%, complex karyotype up to 72%).
  • Endpoints: Primary endpoint was Independent Review Committee (IRC)–assessed Progression-Free Survival (PFS). Secondary endpoints included Time to Next Treatment or death (TTNT), Overall Survival (OS), Overall Response Rate (ORR), and Safety.

Patients could cross over from IC to Pirtobrutinib upon confirmed progression, and treatment beyond IRC-defined progression was permitted if clinical benefit was maintained.

Efficacy Outcomes

  • PFS: Median 14.0 months with Pirtobrutinib vs. 8.7 months with IdelaR/BR (HR = 0.54; P =0.0002), representing a 46% reduction in the risk of progression or death.
  • TTNT: Median 24.0 months with Pirtobrutinib vs. 10.9 months with IC (HR = 0.37), reflecting sustained clinical benefit beyond protocol-defined progression in many patients.
  • OS: No statistically significant difference at final analysis (HR = 1.09), likely influenced by crossover (75.8% of eligible IC patients switched to Pirtobrutinib).
  • Subgroup Benefit: PFS improvement was consistent across key high-risk subgroups, including those with del(17p)/TP53 mutation, complex karyotype, and unmutated IGHV.

Safety Profile
Pirtobrutinib was generally well tolerated:

  • Grade ≥3 adverse events (AEs): 57.7% with Pirtobrutinib vs. 73.4% with IC.
  • Discontinuations due to AEs: 17.2% vs. 34.9%, respectively.
  • Class-related BTKi toxicities (atrial fibrillation, hypertension, major bleeding) were infrequent, with rates comparable to or lower than background incidence in CLL populations.
  • No cases of Richter transformation were reported in the Pirtobrutinib arm, versus three in the IC group.

Clinical Implications
The BRUIN CLL-321 trial establishes Pirtobrutinib as a new standard of care option for patients with CLL/SLL previously treated with cBTKi, offering:

  • Significant PFS improvement in a population with historically poor prognosis.
  • Prolonged TTNT, which may be more reflective of real-world benefit than PFS alone.
  • Favorable safety profile supporting long-term tolerability.

These findings also raise important considerations for sequencing strategies, including potential use of Pirtobrutinib prior to Venetoclax in certain patients, pending further prospective data (e.g., BRUIN-322 trial).

Takeaway for Practice:
For CLL/SLL patients progressing after cBTKi therapy, Pirtobrutinib offers a meaningful advancement, providing durable disease control with a manageable toxicity profile. BRUIN CLL-321 delivers the first randomized evidence supporting treatment in this setting, addressing a long-standing gap in the therapeutic landscape.

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321). Sharman JP, Munir T, Grosicki S, et al. J Clin Oncol. 2025;43:2538-2549

 

 

Tarlatamab Sets New Standard in Recurrent Small Cell Lung Cancer: Results from DeLLphi-304

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SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. Nearly all patients with SCLC experience disease recurrence during or after standard platinum-based chemotherapy, underscoring the need for novel treatment strategies Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-Like Protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab (IMDELLTRA®) is a first-in-class bispecific T-cell engager immunotherapy that directs the patients T cells to cancer cells expressing Delta-Like Ligand 3 (DLL3), independent of Major Histocompatibility Complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

In May 2024, the U.S. FDA granted accelerated approval to Tarlatamab for adult patients with extensive-stage SCLC whose disease progressed after platinum-based chemotherapy. This decision was based largely on early clinical benefit observed in the Phase 2 DeLLphi-301 trial, where Tarlatamab demonstrated a 40% Overall Response Rate (ORR) in previously treated patients. Now, confirmatory results from the Phase 3 DeLLphi-304 trial further support the role of Tarlatamab in the treatment landscape, and mark a potential new standard of care for recurrent SCLC.

Phase 3 DeLLphi-304: Study Design and Population
DeLLphi-304 was a global, randomized, open-label trial comparing Tarlatamab, with standard-of-care chemotherapy which included Topotecan, Lurbinectedin, or Amrubicin, in patients with extensive-stage SCLC, whose disease progressed after platinum-based chemotherapy. A total of 509 patients were randomized 1:1 to receive either Tarlatamab (N=254) or chemotherapy (N=255). The median patient age was 65 yrs, Approximately 45% of randomized patients had current or previous brain metastases, 35% had liver metastases, 71% had received previous therapy with checkpoint inhibitors and 44% had platinum-resistant disease. Stratification factors included prior PD-L1 inhibitor treatment, chemotherapy-free interval, presence of brain metastases, and intended chemotherapy regimen. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Patient-Reported Outcomes (PROs), and Safety.

Tarlatamab Demonstrates Significant Survival Benefit
At a median follow-up of approximately 11 months, Tarlatamab demonstrated a statistically and clinically significant improvement in OS:

  • Median OS: 13.6 vs 8.3 months (HR 0.60; 95% CI: 0.47–0.77; P<0.001)
  • Median PFS: 4.2 vs 3.2 months (HR 0.72; 95% CI: 0.59–0.88; P<0.001)

This translated to a 40% reduction in the risk of death for patients receiving Tarlatamab. The survival benefit extended across all prespecified subgroups, including age, gender, race, and prior anti–PD-L1 therapy. The ORR was 35% in the Tarlatamab group and 20% in the chemotherapy group.

Improved Symptom Control and Quality of Life
Beyond survival, Tarlatamab provided clinically meaningful improvements in Patient-Reported Outcomes, including relief from hallmark symptoms of SCLC:

  • Dyspnea score improved at 18 weeks: –1.94 with Tarlatamab vs +7.20 with CTx (mean difference –9.14; P< 0.001)
  • Cough improvement: 16% vs 9% (Odds Ratio 2.04; P = 0.012)
  • Chest pain improvement: 9% vs 4% (Odds Ratio 1.84; P = 0.100) – not significant

These findings reflect an overall better patient experience and potential Quality-of-Life benefit with Tarlatamab therapy.

Safety Profile and Tolerability
Tarlatamab was associated with a more favorable safety profile compared to chemotherapy:

  • Grade 3 or more Treatment-Related Adverse Events (TRAEs): 27% (Tarlatamab) vs 62% (Chemotherapy)
  • Discontinuations due to TRAEs: 3% vs 6%
  • Most common Grade 3 or more TRAEs with Tarlatamab were neutropenia (4%) and lymphopenia (4%)
  • Cytokine Release Syndrome (CRS) occurred in 56% of patients (mostly grade 1-2) and was manageable in clinical settings

These safety results support Tarlatamab as a more tolerable alternative to conventional chemotherapy.

Looking Ahead: Optimizing Treatment Sequencing
While the DeLLphi-304 trial has established Tarlatamab as an effective option post-platinum therapy, questions remain regarding its integration into the broader SCLC treatment paradigm. PD-L1 inhibitors already form part of standard first-line and maintenance therapy. Early-phase studies have shown that Tarlatamab can be safely combined with anti–PD-L1 agents, and this is being further evaluated in the ongoing DeLLphi-305 trial, a Phase 3 study assessing Tarlatamab plus PD-L1 inhibition as first-line maintenance following chemotherapy. Additionally, biomarker-driven analyses from DeLLphi-304 are underway to help identify patients most likely to benefit from Tarlatamab and those who may achieve durable responses.

Conclusion
The DeLLphi-304 trial positions Tarlatamab as a practice-changing therapy for patients with SCLC that has progressed after platinum-based chemotherapy. With significant improvements in Overall and Progression-Free Survival, better symptom control, and a favorable safety profile, Tarlatamab redefines second-line treatment for a historically underserved patient population. These results not only represent a meaningful advance in SCLC therapy but also signal a broader shift toward targeted immunotherapy strategies in aggressive thoracic malignancies.

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. Mountzios G, Sun L, Cho BC, et al. for the DeLLphi-304 Investigators. N Engl J Med 2025;393:349-361

 

Adjuvant Atezolizumab in Resected NSCLC: Five-Year Outcomes from IMpower010

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SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Atezolizumab (TECENTRIQ®) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

IMpower 010 is a global, multicentre, open-label, randomized Phase III study evaluating the efficacy and safety of Atezolizumab compared with Best Supportive Care (BSC), in patients with stage IB-IIIA NSCLC, following surgical resection and up to 4 cycles of adjuvant Cisplatin-based chemotherapy. In this study, 1005 patients were randomized 1:1 to receive Atezolizumab 1200 mg IV every 3 weeks for 16 cycles, or BSC. Both study groups were well balanced and eligible patients had an ECOG PS of 0-1. The Primary endpoint was Disease Free Survival (DFS) in the PD-L1-positive (1% or more) stage II-IIIA patients, all randomized stage II-IIIA patients and Intent to Treat (ITT) stage IB-IIIA populations. Key Secondary endpoints included Overall Survival (OS) in the overall study population and ITT stage IB-IIIA NSCLC patients.

Initial DFS Results at a Median Follow-Up of 32.2 Months
Adjuvant Atezolizumab demonstrated a clinically meaningful DFS advantage:

  • Stage II–IIIA, PD-L1 1% or more: 34% reduction in risk of recurrence or death vs. BSC (HR 0.66; P=0.0039); median DFS not reached vs. 35.3 months for BSC
  • Stage II–IIIA, PD-L1 50% or more: 57% risk reduction (HR 0.43)
  • All stage II–IIIA: HR 0.79 (P=0.02), median DFS gain of 7 months
  • No statistically significant DFS improvement in the ITT population
  • OS data immature at this stage

These findings led to regulatory approval of adjuvant Atezolizumab in resected stage II–IIIA PD-L1–positive NSCLC following chemotherapy.

Updated 5-Year Outcomes
Final DFS analysis and second OS interim analysis were reported with an additional 36 and 21 months of follow-up, respectively (clinical cutoff: January 26, 2024).

Disease-Free Survival:

  • Stage II–IIIA, PD-L1 ≥1% (N=476): HR 0.70 (95% CI, 0.55–0.91) – More than 30-month median DFS difference between arms
  • Stage II–IIIA, PD-L1 ≥50% (N=229): HR 0.48 (95% CI, 0.32–0.72)
  • All stage II–IIIA (N=882): HR 0.83 (95% CI, 0.69–1.00)
  • ITT (N=1005): HR 0.85 (95% CI, 0.71–1.01; P=0.07) – numerical improvement, not statistically significant
  • All randomized Stage II–IIIA (N=882): HR 0.83 (95% CI, 0.69–1.00)
  • PD-L1 ≥50% without EGFR/ALK alterations (N=209): HR 0.49 (95% CI, 0.32–0.75)

Overall Survival:

  • ITT: HR 0.97 (95% CI, 0.78–1.22)
  • Stage II–IIIA: HR 0.94 (95% CI, 0.75–1.19)
  • PD-L1 ≥1%: HR 0.77 (95% CI, 0.56–1.06)
  • PD-L1 ≥50%: HR 0.47 (95% CI, 0.28–0.77)

Since DFS in the ITT population did not cross the statistical significance boundary, formal OS testing was not conducted. OS data remain immature given a low event-to-patient ratio (~31%).

Clinical Perspective
IMpower010 remains the only Phase III trial with more than 5-year follow-up evaluating a checkpoint inhibitor as adjuvant therapy in resectable stage II–IIIA NSCLC. The most pronounced and durable benefits continue to be seen in PD-L1–selected populations, particularly those with PD-L1 50% or more and without EGFR/ALK alterations. These findings reinforce PD-L1 testing as a critical step in the adjuvant treatment algorithm for NSCLC, and they differentiate Atezolizumab from other checkpoint inhibitors evaluated in similar settings, where results have varied (e.g., KEYNOTE-091, BR.31)

Key Takeaways for Oncology Practice

  • Patient selection matters – Benefit is greatest in PD-L1–positive, especially PD-L1 50% or more
  • Durable effect – DFS benefit persists beyond 5 years in high PD-L1 subgroups
  • Ongoing OS follow-up – OS data are still maturing; future analyses may clarify survival impact
  • Safety reassurance – No new safety concerns after extended follow-up

Five-Year Survival Outcomes With Atezolizumab After Chemotherapy in Resected Stage IB-IIIA Non–Small Cell Lung Cancer (IMpower010): An Open-Label, Randomized, Phase III Trial. Felip E, Altorki N, Zhou C, et al. J Clin Oncol. 2025;43:2343-2349. 

Innovating Multiple Myeloma Care: IRAKLIA Confirms On-Body Injector for Subcutaneous Isatuximab as a Safe, Effective Alternative to IV Delivery

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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.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails.

With prevalence of multiple myeloma expected to climb further, disparities in care delivery remain a concern, often linked to treatment access, infusion-center capacity, and patient convenience. Advances in drug delivery technology, particularly subcutaneous (SC) administration, offer an opportunity to bridge these gaps. Compared with intravenous (IV) therapy, SC approaches can shorten administration time, improve comfort, and reduce healthcare resource demands.

However, conventional SC delivery of large-volume biologics can be challenging, often requiring high manual pressure over several minutes and the use of larger needles, both of which may cause discomfort and anxiety for patients and increase the physical burden for nurses. The IRAKLIA trial is the first Phase III study in multiple myeloma to evaluate an On-Body Injector (OBI) for delivering SC Isatuximab (Isa) in combination with Pomalidomide and Dexamethasone (Pd) in Relapsed/Refractory MM (RRMM).

Study Design
IRAKLIA was a global, open-label, randomized, noninferiority Phase III trial enrolling adults with 1 or more prior lines of therapy, including Lenalidomide and a Proteasome Inhibitor. A total of 531 patients were randomized (OBI, N=263; IV, N=268). Participants were assigned 1:1 to receive either:

  • Isa OBI: 1,400 mg SC via an OBI device (Enable Injections, Inc.)
  • Isa IV: 10 mg/kg IV infusion once weekly during cycle 1, then on days 1 and 15 of subsequent cycles.

Both arms received Pomalidomide 4 mg orally, days 1–21 and Dexamethasone 40 mg orally weekly and 20 mg if 75 years or older. Baseline characteristics were generally balanced, although the OBI group had slightly more patients ≥75 years, with higher rates of advanced disease features (soft-tissue plasmacytomas, ISS stage III, reduced renal function, and Lenalidomide-refractory status).

Key coPrimary endpoints were Overall Response Rate (ORR) and steady-state trough concentration (Ctrough) at cycle 6 day 1. The trial also assessed ≥Very Good Partial Response (≥VGPR) rate, pharmacokinetics at week 4, incidence of Infusion-related Reactions (IRs), and patient-reported satisfaction.

Efficacy after 12 Month Median Follow-Up

  • ORR: 71.1% (OBI) vs 70.5% (IV); noninferiority demonstrated (RR 1.008; 95% CI, 0.903–1.126).
  • Ctrough: Higher with OBI (geometric mean ratio 1.532; 90% CI, 1.316–1.784), meeting noninferiority criteria.
  • ≥VGPR rate: Comparable-46.4% (OBI) vs 45.9% (IV).
  • Results were consistent across most subgroups, with a lower response in patients ≥75 years in the OBI arm, likely due to baseline disease imbalances.

Safety

  • Grade ≥3 treatment-emergent adverse events occurred in 81.7% (OBI) vs 76.1% (IV).
  • Infusion-related Reactions were dramatically reduced with OBI (1.5%) compared with IV (25%).
  • Injection site reactions with OBI were rare (0.4%, all grade 1–2).
  • No unexpected safety signals emerged; the profile aligned with prior Isa studies.

Patient Experience

  • Satisfaction rates were higher with OBI (70.0%) than IV (53.4%).
  • Nearly all OBI doses (99.9%) were completed without interruption.

Clinical Implications

Reduced Infusion Reactions and Improved Workflow
The marked drop in Infusion-related Reactions incidence with OBI is likely related to slower systemic absorption from interstitial tissue compared with rapid IV exposure. This improvement not only enhances patient comfort but also reduces infusion chair time and the need for monitoring, potentially enabling at-home administration by healthcare professionals in select patients.

Efficiency for Nursing Staff
OBI eliminates the sustained manual pressure required for large-volume SC pushes and replaces large-bore needles with a smaller, hidden 30-gauge needle. This reduces nurse fatigue, frees up clinical resources, and may lower patient anxiety during injections.

Potential for Home Administration and Broader Access
Given the convenience and safety profile, OBI administration could be extended beyond the infusion center. This aligns with ongoing efforts to decentralize cancer care, expand access to anti-CD38 therapy, and improve treatment adherence in multiple myeloma.

Future Directions
Isa OBI is being further evaluated in other multiple myeloma settings, including:

  • IZALCO: Isa-Kd in RRMM (NCT05704049)
  • IsaSoCut: Isa-VRd in transplant-ineligible NDMM (NCT05889221)
  • GMMG-HD8: Isa-VRd in NDMM (NCT05804032)

Upcoming analyses from IRAKLIA will also explore the feasibility of at-home dosing.

Conclusion
The Phase III IRAKLIA trial demonstrates that Isa SC delivered via OBI is noninferior to IV administration in RRMM, with equivalent efficacy, favorable pharmacokinetics, and a significantly lower Infusion-related reaction rate. This hands-free delivery method offers a practical, patient-preferred, and resource-efficient alternative to standard IV infusion, potentially transforming anti-CD38 therapy administration in multiple myeloma.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. Ailawadhi S,  Špička I, Spencer A, et al. J Clin Oncol. 2025;43:2527-2537.

 

 

Endocrine Therapy Omission in ER-Low Early Stage Breast Cancer Linked to Worse Survival Outcomes

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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 will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Background
Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. Adjuvant Endocrine Therapy (ET) is a cornerstone in managing Estrogen Receptor (ER)–positive early-stage breast cancer, contributing significantly to reduced recurrence and improved Overall Survival (OS). However, its role in patients with ER-low disease, defined as tumors with 1%-10% ER positivity by ImmunoHistoChemistry (IHC), remains unclear and controversial.

Study Objective
The present study was conducted to determine the association between ET omission and OS in high-risk, ER-low early-stage breast cancer patients who received chemotherapy, leveraging Real-World Data from the National Cancer Database (NCDB).

Methods
A retrospective cohort analysis was conducted using the 2021 NCDB Participant User File, focusing on female patients diagnosed with Stage I–III ER-positive breast cancer between 2018 and 2020. ER-low status was defined as 1%-10% ER expression per ASCO/CAP guidelines. Progesterone Receptor (PR)–positive disease was defined as 1% or more receptor expression. This study included patients who received neoadjuvant or adjuvant chemotherapy, reflecting a high-risk population with aggressive tumor features. The study excluded male patients, Stage IV disease, noninvasive cancers, and cases with incomplete treatment or outcome data. The final cohort comprised 7,018 ER-low patients who received chemotherapy.

Key Findings

  • Endocrine Therapy (ET) Usage Patterns:
    Among patients with ER-low breast cancer receiving chemotherapy, 42% did not initiate ET within 12 months post-surgery. ET omission was more prevalent in tumors that were:

    • Progesterone Receptor (PR)–negative
    • HER2–negative
    • High grade (2 or 3)
    • High proliferative index (Ki67 ≥20%)
    • Treated with NeoAdjuvant Chemotherapy (NAC)
  • Survival Impact:
    Over a median follow-up of 3 years, 586 deaths occurred. ET omission was associated with significantly poorer OS:

    • Overall HR: 1.23 (95% CI, 1.04–1.46; P =0.02)
    • ER 1%-5% subgroup: HR 1.15 (95% CI, 0.91–1.45; P =0.24)
    • ER 6%-10% subgroup: HR 1.42 (95% CI, 1.00–2.02; P =0.048)
  • Effect in Residual Disease (RD) After NAC:
    • For patients with RD, ET omission led to worse OS (HR, 1.26; 95% CI, 1.00–1.57; P =0.046)
    • No OS difference was observed in patients who achieved pathologic Complete Response (pCR) (HR, 1.06; P =0.84)
  • 3-Year OS Estimates:
    • With ET: 92.3% (95% CI, 91.3–93.3%)
    • Without ET: 89.1% (95% CI, 87.8–90.5%)

Clinical Implications
These findings suggest that omission of ET in ER-low breast cancer is associated with an increased risk of mortality, particularly in patients with:

  • Residual disease after neoadjuvant chemotherapy
  • Tumors with higher ER expression (6%-10%)

This supports the clinical value of ET even in ER-low disease subsets, which have historically been managed more like Triple-Negative Breast Cancer (TNBC) due to their aggressive features and ambiguous endocrine responsiveness.

Guideline and Research Context
The 2010 ASCO/CAP guidelines established 1% or more ER positivity as the threshold for ET eligibility. Yet, international variation remains. Swedish guidelines, for instance, never adopted the lower threshold, and recent European discourse suggests reverting to 10% or more. Compounding the uncertainty, clinical trials often exclude ER-low tumors or treat them as TNBC. Retrospective studies from Sweden and China have shown mixed results regarding ET’s benefit in ER-low disease, further emphasizing the need for prospective data.

Discussion
Despite the relatively small proportion of ER-low tumors (3% of ER-positive breast cancer), the findings could impact the care of tens of thousands of patients globally. The biologic heterogeneity of ER-low tumors, often resembling basal-like subtypes, complicates treatment decisions. Still, evidence from this large cohort supports offering ET, particularly in patients with residual disease post-neoadjuvant chemotherapy, or tumors on the higher end of the ER-low spectrum. Additionally, the data align with emerging strategies to escalate therapy in ER-low BC, including use of CDK4/6 inhibitors (e.g., Abemaciclib, Ribociclib), which have demonstrated benefit even in this subgroup.

Limitations

  • Lack of data on ET adherence, recurrence, or cause of death
  • Short follow-up (3 years)
  • Potential confounding due to observational design
  • Lack of molecular characterization to distinguish responders

Nevertheless, sensitivity analyses confirmed the robustness of findings.

Conclusion
Omission of endocrine therapy in ER-low, early-stage breast cancer, especially following chemotherapy, is linked to inferior Overall Survival. The strongest signal of benefit is in patients with residual disease post- neoadjuvant chemotherapy and those with ER expression closer to 10%. Until randomized trials clarify endocrine sensitivity in this population, clinicians should counsel patients on the potential survival benefit of ET, even in cases with limited ER expression.

Key Takeaway for Oncologists:
In the absence of prospective trial data, Real-World Evidence supports continued use of endocrine therapy in patients with ER-low early-stage breast cancer, particularly those with residual disease after neoadjuvant chemotherapy or higher ER expression within the 1%-10% range.

Endocrine Therapy Omission in Estrogen Receptor–Low (1%-10%) Early-Stage Breast Cancer. Choong GM, Hoskin TL, Boughey JC, et al. J Clin Oncol 2025;43:1875-1885.

Neoadjuvant PD-1 Blockade Promotes Organ Preservation in Early Stage Mismatch Repair–Deficient Solid Tumors

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma–HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Background
Checkpoint inhibitors have revolutionized the treatment landscape for MisMatch Repair–deficient (dMMR) metastatic solid tumors, offering durable responses across tumor types. This paradigm is now being explored in early-stage settings. Dostarlimab (JEMPERLI®) is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Building on prior success in dMMR rectal cancer, this Phase 2, multicenter study investigated the feasibility of using neoadjuvant PD-1 blockade with Dostarlimab to achieve organ preservation in early-stage, surgically resectable dMMR solid tumors, potentially shifting the standard of care away from surgery and cytotoxic therapies.

Study Design and Patient Population
Conducted at Memorial Sloan Kettering Cancer Center, Hartford HealthCare, and Baptist Health Miami Cancer Institute, the study enrolled patients with newly diagnosed Stage I–III dMMR solid tumors, defined by loss of MLH1, PMS2, MSH2, or MSH6 expression on immunohistochemistry, that were amenable to curative-intent surgery. Two cohorts were formed:

  • Cohort 1: Patients with locally advanced rectal cancer.
  • Cohort 2: Patients with nonrectal dMMR solid tumors (including esophagogastric, colon, hepatobiliary, genitourinary, and gynecologic cancers).

All patients received Dostarlimab 500 mg IV every 3 weeks for 6 months (nine cycles). Clinical response was assessed within 8 weeks of completing therapy via tumor-specific imaging, endoscopy, and biopsy where applicable. Patients with residual disease were offered standard neoadjuvant therapy and surgery, while those achieving a clinical Complete Response (cCR) could opt for nonoperative management.

Primary and Exploratory Endpoints

  • Cohort 1: Co-primary endpoints were Overall Response Rate and sustained cCR at 12 months post-treatment.
  • Cohort 2: Exploratory analyses evaluated cCR rates, Recurrence-Free Survival (RFS), safety, and molecular correlates of response, including circulating tumor DNA (ctDNA).

Results
A total of 117 patients were analyzed:

  • Cohort 1 (Rectal Cancer): All 49 patients who completed therapy achieved a cCR and declined surgery. At 12 months, 37 maintained a sustained cCR, meeting the efficacy threshold.
  • Cohort 2 (Nonrectal Tumors): Of 54 patients, 35 achieved a cCR, with 33 choosing nonoperative management.

Across both cohorts:

  • 103 patients completed Dostarlimab therapy.
  • 84 (82%) achieved cCR.
  • 82 patients (80%) avoided surgery.
  • Two-year RFS: 92% (95% CI, 86–99).
  • Median follow-up for recurrence: 20 months (range, 0–60.8).
  • Safety: Most adverse events were grade 1–2 (60%), with 35% reporting no treatment-related events. No patient lost the opportunity for curative surgery due to disease progression.

Genomic and ctDNA Findings

  • Germline dMMR variants were present in 44% of patients.
  • Tumor-informed ctDNA testing tracked up to 50 tumor-specific mutations using a highly sensitive and specific assay.
  • ctDNA clearance correlated strongly with cCR: all patients with a cCR showed complete ctDNA clearance by end of treatment.
  • Persistently detectable ctDNA was associated with residual disease or eventual recurrence, reinforcing its value as a real-time, noninvasive biomarker for treatment response and residual disease monitoring.

Discussion
The findings underscore the transformative potential of neoadjuvant PD-1 blockade for early-stage dMMR cancers. Key takeaways include:

  • Tumor-Agnostic Efficacy: Dostarlimab elicited robust responses across a variety of histologies, suggesting that dMMR status, rather than tumor origin, may drive sensitivity to immunotherapy.
  • Organ Preservation: Surgery, and its associated morbidities, was avoided in the majority of patients, including those with rectal cancers where standard treatment often compromises fertility, continence, or other organ functions. Three women with rectal cancer treated in this trial successfully conceived and delivered children.
  • Variable Responses by Histology: While responses were highest in rectal, colon, hepatobiliary, and urothelial cancers, lower cCR rates were observed in prostate and upper gastrointestinal tumors. This suggests underlying biological variability despite shared dMMR status.
  • Monitoring Strategy: Integration of imaging, endoscopy, and ctDNA is critical. Liquid biopsy offered a reliable surrogate for tumor biopsy, particularly in inaccessible tumors, but caution is warranted as ctDNA alone may miss certain cases.
  • Safety and Feasibility: The 6-month regimen was generally well tolerated, and no patient lost surgical eligibility due to disease progression. This supports the feasibility of prolonged neoadjuvant immunotherapy in appropriately selected patients.

Clinical Implications and Future Directions
This study lays the groundwork for a paradigm shift in the management of early-stage dMMR tumors. However, key questions remain:

  • Long-Term Durability: While initial outcomes are promising, especially in rectal cancer, longer follow-up and additional data are necessary to confirm sustained benefit across nonrectal histologies.
  • Histology-Specific Trials: Basket trials and single-arm studies may suffice for anatomically sensitive tumors (e.g., rectum, bladder), but randomized trials may still be appropriate in less morbidly resectable cancers (e.g., colon).
  • Treatment Optimization: Determining the minimal effective duration of immunotherapy could reduce adverse events and cost. Median times to biopsy negativity (1.5 months) and imaging response (6.1 months) suggest a window for shortening therapy in responders.
  • Shared Decision-Making: Given the potential for curative nonoperative management, multidisciplinary care teams must align on strategies and engage patients in informed decision-making, particularly where standard surgery entails long-term quality-of-life tradeoffs.

Conclusion
Neoadjuvant PD-1 blockade with Dostarlimab achieved clinical Complete Responses in a substantial majority of patients with early-stage dMMR tumors, offering a path to organ preservation without compromising curative potential. These results highlight the tumor-agnostic power of checkpoint inhibitors and present a compelling case for redefining the treatment of dMMR solid tumors. As follow-up data matures and histology-specific nuances are better understood, immunotherapy may become the new cornerstone of early-stage dMMR cancer management.

Nonoperative Management of Mismatch Repair–Deficient Tumors. Cercek A, Foote MB, Rousseau B, et al. N Engl J Med 2025;392:2297-2308.