Author: RR

Late Breaking Abstract – ASCO 2025: Tarlatamab Sets New Standard in Recurrent Small Cell Lung Cancer: Results from DeLLphi-304

RR

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). 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)

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 versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): Primary analysis of Ph3 DeLLphi-304. Rudin C, Mountzios G, Sun L, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA8008)

Late Breaking Abstract – ASCO 2025: AMPLITUDE Trial: Defining a New Treatment Paradigm in HRR-Altered mCSPC

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is a heterogeneous disease. Despite therapeutic advances, outcomes vary significantly based on underlying tumor biology. Approximately 25% of patients with mCSPC harbor Homologous Recombination Repair (HRR) gene mutations, including BRCA1, BRCA2, CHEK2, CDK12, PALB2, and others. Among these, BRCA1/2 mutations account for nearly half of HRR alterations and are particularly associated with aggressive disease biology, resistance to Androgen Receptor Pathway Inhibitors (ARPIs), and shortened Progression-Free and Overall Survival. The integration of AR-pathway inhibitors such as Abiraterone Acetate plus Prednisone into first-line treatment has meaningfully improved outcomes in the general mCSPC population. However, patients with HRR mutations, especially those with BRCA1/2, derive significantly less benefit from these agents alone, highlighting a substantial unmet clinical need.

Rationale for PARP Inhibition in HRR-Altered Prostate Cancer
Cancer cells with HRR deficiencies are vulnerable to PARP (Poly ADP-Ribose Polymerase) inhibition, which blocks DNA repair pathways and induces synthetic lethality. Prior landmark trials, MAGNITUDE (Niraparib with Abiraterone Acetate plus Prednisone) and TALAPRO-2 (Talazoparib  plus Enzalutamide), demonstrated the value of combining PARP inhibitors with ARPIs in Castration-Resistant Prostate Cancer (mCRPC) with HRR mutations. However, whether such a combination could offer meaningful benefit earlier in the disease course, in the castration-sensitive setting, remained unknown, until now.

AMPLITUDE Trial Design and Methods

Study Overview
The AMPLITUDE trial (NCT04497844) is a global, Phase 3, randomized, double-blind, placebo-controlled trial designed to evaluate whether combining the PARP inhibitor Niraparib with Abiraterone Acetate plus Prednisone improves clinical outcomes in patients with mCSPC (metastatic Castration-Sensitive Prostate Cancer) and HRR gene alterations.

Patient Population

  • Total enrolled: 696 men with mCSPC and at least one HRR gene mutation (germline or somatic)
  • Mutation profile: BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B, RAD54L
  • BRCA1/2 prevalence: 55.6% of enrolled patients
  • Metastatic disease burden: 78% were high-volume M1disease, 87% had de novo M1disease and 16% had prior therapy with Docetaxel.
  • Prior therapies allowed:
    • 6 months or less of Androgen Deprivation Therapy (ADT)
    • 6 cycles or less of Docetaxel
    • 45 days or less of prior Abiraterone and Prednisone

Randomization and Treatment Arms

Patients were randomized 1:1 to:

  • Experimental arm: Niraparib 200 mg once daily plus Abiraterone acetate 1000 mg daily and Prednisone 5 mg daily (N=348)
  • Control arm: Placebo plus Abiraterone acetate 1000 mg along with Prednisone 5 mg daily (N=348)
    All patients continued on ADT.

Endpoints

  • Primary: Radiographic Progression-Free Survival (rPFS), assessed by investigator
  • Secondary: Time to Symptomatic Progression (TSP), Overall Survival (OS), Safety/tolerability

Key Results and Interpretation

Efficacy Outcomes

Radiographic Progression-Free Survival (Primary Endpoint)

  • Median rPFS:
    • Niraparib plus Abiraterone and Prednisone: Not reached
    • Abiraterone and Prednisone alone: 5 months (95% CI, 25.8–NR)
  • Hazard ratio: 0.63 (P=0.0001)
  • BRCA1/2 subgroup: HR =0.52 (P<0.0001)

This translates into a 37% relative risk reduction in progression or death in the overall population, and a 48% reduction in the BRCA1/2 subgroup, indicating a clear therapeutic effect in genetically defined populations.

Time to Symptomatic Progression

  • HR (overall): 0.50 (P<0.0001)
  • BRCA1/2 subgroup: HR 0.44 (P=0.0001)

This is clinically meaningful, and delaying symptom onset can preserve quality of life and extend time before additional therapies are needed.

Overall Survival (Interim Analysis)

  • HR (overall): 0.79 (95% CI, 0.59–1.04; P=0.10)
  • BRCA1/2 subgroup: HR 0.75 (95% CI, 0.51–1.11; P=0.15)

Although OS data are not yet mature, the trend suggests a potential survival benefit with longer follow-up.

Safety Profile
The safety of Niraparib plus Abiraterone and Prednisone was consistent with known profiles of both agents. Grade 3-4 AEs in the Niraparib plus Abiraterone and Prednisone was 75.2% versus 58.9% with Abiraterone and Prednisone alone, with the most common higher Grade 3-4 AEs  noted in the Niraparib plus Abiraterone and Prednisone group (Anemia: 29.1% vs 4.6% and Hypertension: 26.5% vs 18.4%). The discontinuation rates due to AEs in the Niraparib plus Abiraterone and Prednisone group was 11.0% vs 6.9% in the Abiraterone and Prednisone group. These AEs were manageable with appropriate monitoring. No new safety signals were identified.

Conclusion
The AMPLITUDE trial marks a milestone and provides robust evidence to support Niraparib plus Abiraterone and Prednisone as a new first-line option in mCSPC patients with BRCA1/2 or other HRR gene mutations. By demonstrating that Niraparib plus Abiraterone and Prednisone improves Progression-Free outcomes in HRR-altered mCSPC, especially those with BRCA mutations, it paves the way for a more personalized, biology-driven approach to therapy in this setting. Ongoing follow-up will determine whether this translates into improved survival, but the current data already support Niraparib plus Abiraterone and Prednisone as a new treatment benchmark for this high-risk subgroup.

Phase 3 AMPLITUDE trial: Niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. Attard G, Agarwal N, Graff J, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5006)

 

Late Breaking Abstract – ASCO 2025: CASSANDRA Phase 3 Trial: Neoadjuvant PAXG Improves Event-Free Survival in Resectable and Borderline-Resectable PDAC

RR

SUMMARY: The American Cancer Society estimates that in 2025, about 67,440 people will be diagnosed with pancreatic cancer and 51,980 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies, ranking among the leading causes of cancer-related mortality globally. A significant challenge in improving PDAC outcomes is its frequent diagnosis at an advanced stage, when therapeutic options are limited and prognosis is poor, with a 5-year survival rate of approximately 10%.

For patients with resectable or borderline-resectable Pancreatic Ductal AdenoCarcinoma (PDAC), the ideal perioperative treatment regimen remains an area of active investigation. Existing strategies vary in chemotherapy combinations, timing and duration of neoadjuvant therapy, and the use of radiation. Modified FOLFIRINOX (mFOLFIRINOX) has emerged as a standard neoadjuvant approach; however, whether more intensified or differently structured regimens can yield better outcomes is a crucial question.

The CASSANDRA trial (NCT04793932) was designed to evaluate this, comparing two chemotherapy regimens, PAXG and mFOLFIRINOX, as neoadjuvant treatment in patients with resectable or borderline-resectable PDAC.

Trial Design: A 2×2 Factorial Randomization
CASSANDRA is a multicenter, randomized, Phase 3 superiority trial enrolling 260 patients 75 years or younger with resectable/borderline resectable PDAC. Patients were stratified by site and CA19.9 level, then randomized in a 2-by-2 factorial design:

First Randomization:

    • Arm A (PAXG) N=132: Capecitabine 1250 mg/m2 PO, daily,  along with Cisplatin 30 mg/m2, nab-Paclitaxel 150 mg/m2, and Gemcitabine 800 mg/m2, given biweekly.
    • Arm B (mFOLFIRINOX) N=128: 5-Fluorouracil (5-FU) 2400 mg/m2, Irinotecan 150 mg/m2, Oxaliplatin 85 mg/m2, and Leucovorin 400 mg/m2 given biweekly.

Second Randomization:
After 4 months of therapy, patients without disease progression or unacceptable toxicity were re-randomized to receive 2 additional months of the same regimen either before or after surgery.

The median age was 64 yrs and both treatment groups were well balanced.

Study Endpoints

  • Primary Endpoint: Event-Free Survival (EFS), defined as the absence of disease progression, recurrence, two consecutive CA19.9 increases 20% or more (separated by 4 weeks or more), unresectability, intraoperative metastasis, or death.
  • Secondary Endpoints: Overall survival (OS), radiographic response, CA19.9 response, pathological response, resection rate, toxicity, and Quality of Life (QoL).

Key Findings: PAXG Demonstrates Significant EFS Benefit

  • At the data cutoff of March 1, 2025, with a median follow-up of 23.9 months, PAXG significantly improved EFS compared to mFOLFIRINOX
  • The 3-year EFS rate more than doubled with PAXG and was 31% compared to 13% with mFOLFIRINOX (HR=0.64; P=0.003), and the median EFS was 16 months and 10.2 months, respectively.
  • The Disease Control Rate was 98% with PAXG and 91% with mFOLFIRINOX (P=0.009)
  • PAXG yielded greater CA19.9 responses and pathologic downstaging compared to mFOLFIRINOX. CA19.9 reduction more than 50% was 88% versus 64% (P<0.001), resection rate was 75% versus 67% (P=0.165), and pathologic stage less than II 35% versus 23% (P=0.03), respectively.
  • Notably, trends in OS also favored PAXG, though data are immature (median OS ~37 vs 26 months; HR ~0.70; P≈0.07)

The overall, toxicity profiles were similar between the two treatment groups. Patients who received PAXG did have a higher rate of grade 3-4 neutropenia, at 42% versus 29%.

Conclusion:
Neoadjuvant treatment with PAXG significantly improved EFS compared to mFOLFIRINOX in patients with resectable/borderline resectable PDAC. While PAXG shows potential as a new neoadjuvant standard, its role must be confirmed through long-term OS analysis from CASSANDRA and results from ongoing trials such as PREOPANC-3 and Alliance A021806 trials. If confirmed, neoadjuvant PAXG could become a preferred regimen for resectable or borderline-resectable PDAC, especially in patients with elevated CA19.9 or more aggressive disease phenotypes. Oncology teams should remain attentive to the evolving perioperative landscape, as long-term data and trial results continue to inform best practices.

Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I-III pancreatic ductal adenocarcinoma. Reni M, Macchini M, Orsi G, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4004)

Late Breaking Abstract – ASCO 2025: Redefining the First-Line Standard: DESTINY-Breast09 Highlights T-DXd Plus Pertuzumab as a Potential New Benchmark in HER2+ Metastatic 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Trastuzumab (HERCEPTIN&reg;) is a humanized monoclonal antibody targeting HER2. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Pertuzumab (PERJETA&reg;) is a recombinant humanized monoclonal antibody that binds to the HER2 at a different epitope of the HER2 extracellular domain (subdomain II) compared to Trastuzumab, and prevents the dimerization of HER2 with HER3 receptor. Pertuzumab stimulates ADCC similar to Trastuzumab. By combining Trastuzumab and Pertuzumab, a more comprehensive blockade of HER2 signaling can be accomplished, as these two agents bind to different HER2 epitopes and may complement each other and improve efficacy.

Trastuzumab deruxtecan (T-DXd) (ENHERTU®) is a next-generation Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike  ado-Trastuzumab emtansine, another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

Background and Clinical Rationale
Trastuzumab deruxtecan (T-DXd) has demonstrated potent antitumor activity in HER2-positive breast cancer across multiple treatment lines. However, prior to the DESTINY-Breast09 study, all approved indications for T-DXd required patients to have received prior systemic therapy in either the metastatic or adjuvant setting. With the longstanding CLEOPATRA regimen, Docetaxel, Trastuzumab, and Pertuzumab (THP) established over a decade ago as the first-line standard of care, the oncology community has been eager to evaluate whether T-DXd could improve frontline outcomes.

Study Design and Patient Population
DESTINY-Breast09 (NCT04784715) is a randomized, global Phase 3 study designed to evaluate the efficacy and safety of first-line T-DXd with or without Pertuzumab, versus Taxane plusTrastuzumab plus Pertuzumab (THP), in patients with HER2-positive advanced/metastatic breast cancer. A total of 1,157 patients were enrolled across 283 sites worldwide. Eligible patients had centrally confirmed HER2-positive disease (IHC 3+ or ISH+), no prior chemotherapy or HER2-targeted therapy in the metastatic setting, and ≤1 prior line of endocrine therapy. Patients were stratified by Hormone Receptor (HR) status, PIK3CA mutation status, and de novo vs recurrent disease, and randomized 1:1:1 to:

  • T-DXd + placebo – N=387
  • T-DXd + pertuzumab (T-DXd + P) – N=383
  • THP (control arm) – N=387

The interim analysis presented at ASCO 2025 focused on the comparison between T-DXd + P and THP. The T-DXd monotherapy arm remains blinded until the final PFS analysis.

The Primary endpoint was Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in the intent-to-treat population. Secondary endpoints included Overall Survival (OS), PFS by investigator (INV), Objective Response Rate (ORR), Duration of Response (DOR), and Safety

Efficacy Outcomes: Progression-Free Survival and Response
At a median follow-up of 29 months, T-DXd + P demonstrated a statistically significant and clinically meaningful improvement in PFS compared to THP:

  • Median PFS by BICR:
    • T-DXd + P: 40.7 months
    • THP: 26.9 months
    • HR: 0.56; P <0.00001
  • PFS by Investigator Assessment:
    • Median: 40.7 months vs 20.7 months
    • HR: 0.49 (95% CI: 0.39–0.61)
  • Overall Response Rate (ORR):
    • T-DXd + P: 85.1%
    • THP: 78.6%
  • Complete Response Rate:
    • T-DXd + P: 15.1%
    • THP: 8.5%
  • Median Duration of Response:
    • T-DXd + P: 39.2 months
    • THP: 26.4 months

The PFS benefit was consistent across all patient subgroups, including HR status and PIK3CA mutation.

Safety Profile and Adverse Events
The safety profile of T-DXd + P in the frontline setting was consistent with known toxicities of T-DXd, with no new safety signals. Adjudicated drug-related Interstitial Lung Disease/pneumonitis occurred in 12.1% of patients receiving T-DXd + P (mostly grade 1 and 2) in contrast to only 1.0% among patients receiving THP. Other treatment-related toxicities such as nausea, vomiting, and constipation were more common with T-DXd + P, possibly due to longer median treatment exposure (~3.5 years).

Clinical Implications and Emerging Questions
The marked 13.8-month PFS improvement positions T-DXd + P as a strong candidate to replace THP as the first-line standard for HER2-positive advanced metastatic breast cancer. These results mirror the transformative impact of T-DXd seen in the second-line DESTINY-Breast03 trial comparing T-DXd with ado-Trastuzumab emtansine, where it yielded a median PFS of 28.8 months.

However, while efficacy is unquestionable, questions remain around treatment sequencing, duration, and long-term quality of life:

  • Could T-DXd be reserved for second-line therapy in select patients with less aggressive disease?
  • Might a strategy of T-DXd + P induction followed by de-escalation to maintenance Trastuzumab/Pertuzumab reduce toxicity?
  • Can biomarker-driven personalization refine who should receive first-line T-DXd?

The researchers of this study emphasized that these results represent a paradigm shift in first-line treatment of advanced HER2-positive breast cancer.

Conclusion
DESTINY-Breast09 demonstrates that T-DXd + Pertuzumab significantly improves PFS compared to THP, with durable responses and manageable toxicity. The findings suggest a potential new first-line standard for HER2-positive metastatic breast cancer. While overall survival and long-term safety data are still maturing, the study sets a new benchmark in the frontline treatment landscape and invites critical dialogue on optimizing sequencing, duration, and patient-centered outcomes.

Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): Interim results from DESTINY-Breast09. Tolaney S, Jiang Z, Zhang Q, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1008)

Late Breaking Abstract – ASCO 2025: Rusfertide in Polycythemia Vera: Phase 3 VERIFY Trial Highlights a Practice-Changing Approach to Managing Hematocrit and Phlebotomy Burden

RR

SUMMARY: Polycythemia vera (PV) is a clonal myeloproliferative neoplasm characterized by excessive Red Blood Cell (RBC) production, most often driven by JAK2 mutations. A hallmark of PV is sustained erythrocytosis, which contributes to increased blood viscosity and significantly elevates the risk of thrombotic events. Standard management strategies include phlebotomy, low-dose Aspirin, and cytoreductive agents such as Hydroxyurea, Interferons, and Ruxolitinib. While phlebotomy remains a key tool for hematocrit (Hct) control, frequent procedures are burdensome for many patients, can worsen iron deficiency, and often fail to alleviate constitutional symptoms like fatigue. In this context, Rusfertide, a novel, self-injectable hepcidin mimetic, has emerged as a promising therapeutic strategy targeting iron metabolism to modulate erythropoiesis more precisely.

A Hepcidin-Based Therapeutic Approach
Hepcidin is a hormone produced by the liver that regulates iron absorption in the intestine and iron release from storage sites like macrophages and the liver. It does this by binding to ferroportin, an iron transport protein responsible for transporting iron out of intestinal cells and from storage sites (like macrophages) into the bloodstream. Following its binding to ferroportin, hepcidin causes its degradation, which in turn reduces iron export from cells and lowers iron levels in the blood. Hepcidin levels are generally low in iron deficiency anemia facilitating increased intestinal iron absorption and release of iron from storage sites and promoting iron availability for erythropoiesis. Hepcidin therefore is the master regulator that controls iron homeostasis in the bone marrow for RBC production.

Rusfertide is a first-in-class synthetic peptide the mimics hepcidin and reduces iron availability for erythropoiesis in the bone marrow, thereby mitigating RBC overproduction, characteristic of PV, potentially reducing or eliminating the need for phlebotomies. The unique, subcutaneously administered formulation of Rusfertide allows for convenient weekly self-injection, potentially decreasing reliance on phlebotomy and improving patient quality of life.

VERIFY Trial Design and Objectives
The VERIFY study (NCT05210790) is an ongoing, multinational, randomized, double-blind, placebo-controlled Phase 3 trial, designed to assess the safety and efficacy of Rusfertide in patients with phlebotomy-dependent PV receiving standard-of-care therapy. Enrolled patients were required to have frequent phlebotomies to maintain hematocrit control, with or without concurrent cytoreductive therapy. In Part 1a of the study (Weeks 0–32), patients (N=293) were randomized 1:1 to receive once-weekly Rusfertide (N=147) or placebo (N=146) and patients were stratified by concurrent cytoreductive therapy. The median patient age was 57 years. The Primary endpoint was the proportion of patients achieving clinical response, defined as the absence of phlebotomy eligibility, and no phlebotomies between weeks 20–32. Key Secondary endpoints included number of phlebotomies, proportion of patients with Hct <45%, and changes in patient-reported outcomes (PROMIS Fatigue Short Form-8a and MFSAF Total Symptom Score). Following the 32-week blinded phase (Part 1a), patients could enter an open-label extension (Part 1b, weeks 32–52), with a planned long-term follow-up (Part 2) for up to 3 years.

Clinical Outcomes: Efficacy Highlights
The trial met its Primary endpoint, demonstrating that 76.9% of patients treated with Rusfertide achieved a clinical response compared with 32.9% in the placebo group (P< 0.0001).

Key efficacy findings included:

  • Phlebotomy reduction: Mean number of phlebotomies from weeks 0–32 was o.5 with Rusfertide versus 1.8 with placebo (P< 0.0001).
  • Hematocrit control: 62.6% of Rusfertide-treated patients maintained Hct <45%, compared with 14.4% in the placebo group (P< 0.0001).
  • Symptom improvement: Statistically significant improvements were seen in fatigue (PROMIS Fatigue SF-8a) and PV-related symptom burden (MFSAF TSS), highlighting a benefit on patient quality of life (P<0.03).

Patients at baseline averaged over four phlebotomies in the preceding 28 weeks, yet the majority receiving Rusfertide required none during the first 32 weeks of the study. Notably, 72.8% of patients on Rusfertide required no phlebotomy at all during this period, compared to 21.9% on placebo.

Safety Profile and Tolerability
Rusfertide was generally well tolerated and injection site reactions were the most common adverse event (55.9% in Rusfertide vs. 32.9% in placebo). Anemia was more frequent with Rusfertide (15.9% vs. 4.1%), reflecting its mechanism of reducing iron availability. Interestingly, fewer new malignancies were reported in the Rusfertide arm (N=1) versus placebo (N=7), though the significance of this observation requires longer follow-up.

Implications for Practice
The VERIFY trial supports Rusfertide as a potential paradigm shift in the management of PV, particularly for patients who are phlebotomy-dependent. By addressing erythrocytosis through iron restriction rather than marrow suppression, Rusfertide introduces a novel mechanism that complements existing therapies.

If approved, rusfertide would:

  • Offer an effective alternative to repeated phlebotomies.
  • Provide symptom relief, particularly in domains like fatigue and cognitive impairment, which are often unaddressed by standard treatments.
  • Be suitable as an adjunct to cytoreductive therapy or as a standalone intervention for those who decline or are ineligible for such agents.
  • Improve patient autonomy and quality of life through self-administration and reduced healthcare interactions.

Ongoing Evaluation and Regulatory Outlook
VERIFY continues in its open-label and long-term follow-up phases to evaluate the durability of response, long-term safety, and thrombotic outcomes over 3 years. Regulatory submissions are in preparation across the U.S., Europe, and Japan. Should Rusfertide gain regulatory approval, it is anticipated to become a valuable component of the standard treatment landscape for PV—potentially freeing patients from the physical, logistical, and emotional burdens of recurrent phlebotomy.

Results from VERIFY, a phase 3, double-blind, placebo (PBO)-controlled study of rusfertide for treatment of polycythemia vera (PV). Kuykendall A, Pemmaraju N, Pettit K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA3)

Late Breaking Abstract – ASCO 2025: SERENA-6: A ctDNA-Guided Switch to Camizestrant Improves PFS in HR-Positive/HER2-Negative Advanced Breast Cancer

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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.

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including the development of ESR1 (Estrogen Receptor gene alpha) mutations.

Background
The SERENA-6 trial is the first global registrational Phase 3 study to evaluate a ctDNA-guided approach for the early detection and treatment of ESR1 mutations in HR+, HER2-negative advanced breast cancer. ESR1 mutations, which promote ligand independent Estrogen Receptor activation, are a common mechanism of acquired resistance to estrogen deprivation therapies such as Aromatase Inhibitors (AIs) plus CDK4/6 inhibitors (CDK4/6i). ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, has been associated with shorter Overall Survival. ESR1 mutations are typically absent at diagnosis but emerge during AI therapy. Detecting ESR1 mutations through circulating tumor DNA (ctDNA) provides a non-invasive method to identify molecular progression prior to radiographic evidence.

Camizestrant is an oral, next-generation Selective Estrogen Receptor Degrader (SERD) with antagonist activity against both wild-type and mutant estrogen receptors. SERENA-6 evaluated whether switching to Camizestrant plus continued CDK4/6i upon ctDNA detection of ESR1 mutations, but before radiographic progression, can improve outcomes, compared to continuing the standard AI-based regimen.

Study Design and Results
SERENA-6 is a randomized, double-blind, Phase 3 trial in which 3,256 patients with HR+/HER2-negative advanced breast cancer who had received 6 or more  months of first-line AI + CDK4/6 inhibitor (Palbociclib, Ribociclib, or Abemaciclib) were surveilled for ESR1 mutations using ctDNA performed every 2-3 months alongside routine imaging. Upon ESR1 mutations detection without clinical progression, 315 eligible patients (N=315) who were found to have an ESR1 mutation during ctDNA surveillance were randomized were randomized 1:1 to Switch to Camizestrant (75 mg daily) + continued CDK4/6i + placebo for AI (N=157) or continue AI + CDK4/6i + placebo for Camizestrant (N=158). Both treatment groups were well balanced. Stratification included visceral disease status, timing of ESR1 mutation detection, prior duration of therapy, and CDK4/6 inhibitor type. The Primary endpoint was Investigator-assessed Progression-Free Survival (PFS).

At the prespecified interim analysis, about 50% had ESR1mutations detected on the first ctDNA test. The median PFS was significantly longer with Camizestrant – 16.0 vs 9.2 months; HR=0.44, P<0.00001. This PFS benefit was consistent across all subgroups. The 12-month PFS rates were 60.7% in the Camizestrant group vs 33.4% in the control group. The 24-month PFS rates: 29.7% vs 5.4%. Overall survival (OS) data remains immature. Patients in the Camizestrant arm had a quality of life that was maintained longer than the AI group.

Treatment discontinuation due to adverse events were low at 1.3% for the Camizestrant, and 1.9% for the Aromatase Inhibitor group.

Clinical Implications
SERENA-6 demonstrated that early, ctDNA-guided switching from AI to Camizestrant in patients with emergent ESR1 mutations significantly prolonged PFS without added toxicity. This trial is the first to validate a molecular response–guided treatment strategy in HR+/HER2-negative advanced breast cancer, potentially redefining first-line management.

However, questions remain regarding long-term Overall Survival benefits and the cost-effectiveness and logistical feasibility of serial ctDNA monitoring. Additional follow-up and Real-World Data will be crucial to determine the broader clinical utility of this approach.

Conclusion
Camizestrant in combination with CDK4/6 inhibition, guided by ctDNA detected ESR1 mutations emergence, offers a promising new treatment paradigm for HR+/HER2-negative advanced breast cancer. SERENA-6 paves the way for incorporating precision molecular monitoring into routine first-line management.

Camizestrant + CDK4/6 inhibitor (CDK4/6i) for the treatment of emergent ESR1 mutations during first-line (1L) endocrine-based therapy (ET) and ahead of disease progression in patients (pts) with HR+/HER2– advanced breast cancer (ABC): Phase 3, double-blind ctDNA-guided SERENA-6 trial. Turner N, Mayer E, Park YH, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4).

Late Breaking Abstract – ASCO 2025: Durvalumab Plus FLOT Demonstrates Significant EFS Improvement in Resectable Gastric and GE Junction Cancers: Interim Results from the Phase 3 MATTERHORN Trial

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group. At 24 months, overall survival was 76% with Durvalumab versus 70% with placebo.

Pathologic and Disease-Free Outcomes
In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates, achieved in 19% of patients versus 7% in the placebo arm. This significant increase in pCR suggests more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

Disease-Free Survival (DFS) results mirrored those of EFS. The median DFS had not yet been reached in the Durvalumab arm and was 39.8 months in the placebo group (HR 0.70; P=0.012). At 24 months, DFS rates were 75% and 66%, respectively.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications
The interim findings from MATTERHORN, position Durvalumab plus FLOT as a potential new global standard of care for patients with resectable gastric and GEJ adenocarcinoma. The significant improvements in EFS and pCR, coupled with a manageable safety profile, support integration of immunotherapy into the perioperative management paradigm.

These results also underscore the importance of addressing systemic disease early in the treatment course. As Overall Survival data continue to mature, this study highlights the promising role of immunotherapy in curative-intent settings and may shift practice patterns globally.

Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). Janjigian Y, Al-Batran S-E, Wainberg Z, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA5).

Late Breaking Abstract – ASCO 2025: Adjuvant Immunotherapy Improves Outcomes in Stage III dMMR Colon Cancer: Results from the ATOMIC Trial

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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 CRC in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of CRC 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. Approximately 10% to 15% of nonmetastatic CRCs exhibit deficient mismatch repair (dMMR), accounting for an estimated 330,000 cases annually worldwide. 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. These tumors respond poorly to Fluoropyrimidine-based chemotherapy alone, especially in the adjuvant setting. While immune checkpoint inhibitors are approved for dMMR colorectal cancer in the metastatic setting, their benefit in earlier stages, particularly post-resection, had not been previously established in a prospective trial.

Atezolizumab (TECENTRIQ&reg;) 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.

The Phase 3 ATOMIC trial (NCT02912559), sponsored by the National Cancer Institute and conducted across multiple centers including NCTN sites and the German AIO group investigated whether the addition of Atezolizumab, a PD-L1 checkpoint inhibitor, to standard adjuvant chemotherapy could improve Disease-Free Survival (DFS) in patients with resected Stage III dMMR colon adenocarcinoma.

Study Design and Population
The trial enrolled 712 patients with surgically resected Stage III colon cancer confirmed to have dMMR. Eligibility included patients aged 12 years and older (one pediatric patient was enrolled). MMR status was initially determined locally by immunohistochemistry and subsequently confirmed centrally. Participants were randomized 1:1 to receive:

  • Control arm: mFOLFOX6 (5-Fluorouracil, Leucovorin, and Oxaliplatin) for 6 months (N=357)
  • Experimental arm: mFOLFOX6 plus Atezolizumab (840 mg IV every 2 weeks) for 6 months, followed by maintenance Atezolizumab monotherapy for an additional 6 months (N=355)

Median patient age was 64 yr. 55.1% were female, 84% of tumors were proximal, 46% were clinical low risk (T1-3N1) and 54% were high risk (T4 and/or N2). Stratification was based on nodal status (N1/N1c vs N2), tumor depth (T1-T3 vs T4), and tumor location (proximal vs distal colon). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included Overall Survival (OS) and Adverse Event (AE) profile. At the second interim analysis, median patient follow-up was 37.2 months and 124 DFS events were observed.

Results and Efficacy
After a median follow-up of 37.2 months, the Primary endpoint of DFS was significantly improved in the Atezolizumab arm. The 3-year DFS was 86.4% in the combination arm vs 76.6% in the mFOLFOX6-only arm (Hazard Ratio (HR)=0.50; P< 0.0001, crossing the prespecified efficacy boundary. This represents a 50% relative reduction in the risk of recurrence or death with the addition of Atezolizumab. Importantly, the benefit was consistent across predefined subgroups, including patients over 70 years old and those with both low and high-risk disease (based on T and N-stage). Tumor location, patient sex, and race did not impact the observed treatment benefit.

Safety and Tolerability
Grade 3 or more treatment-related adverse events occurred in 71.7% of patients receiving Atezolizumab plus chemotherapy, compared to 62.1% in those receiving chemotherapy alone. Although the addition of Atezolizumab resulted in a modest increase in toxicity, the side effect profile was consistent with prior experience with checkpoint inhibitors and considered manageable.

Clinical Implications
The ATOMIC trial is the first large, prospective, randomized Phase 3 study to demonstrate a clear benefit from adding immunotherapy to adjuvant chemotherapy in Stage III dMMR colon cancer. As highlighted by the investigators, current adjuvant treatment recommendations for dMMR tumors have historically been extrapolated from studies in mismatch repair–proficient populations or based on retrospective analyses. The robust DFS improvement observed here provides definitive evidence supporting a new treatment paradigm for this molecularly defined subgroup.

Although Overall Survival (OS) data are not yet mature with a median OS follow-up of 42.5 months, early signs are promising. However, future OS analyses may be complicated by the use of subsequent checkpoint inhibitors in patients who recur. The researchers emphasized the clinical relevance of these findings, noting their applicability to both sporadic dMMR cancers and Lynch syndrome associated tumors.

Future Directions
The ATOMIC trial sets a new benchmark for adjuvant therapy in dMMR colon cancer. However, important questions remain. Chief among them is the optimal duration of immunotherapy in this setting. Atezolizumab was administered for nearly a year, including maintenance. Ongoing research should clarify whether such prolonged treatment is necessary or if shorter regimens could maintain efficacy while reducing toxicity.

Moreover, while this study confirms benefit in the postoperative setting, parallel efforts are warranted to evaluate checkpoint inhibition in the neoadjuvant context. Encouraging responses such as those seen in small studies of neoadjuvant immunotherapy in dMMR rectal cancer highlight the need to explore earlier immunotherapeutic intervention in colon cancer as well.

Conclusion
The ATOMIC trial provides compelling evidence that incorporating Atezolizumab into adjuvant therapy improves Disease-free survival in patients with Stage III dMMR colon cancer, marking a major advancement in the management of this biologically distinct subset. Given these results, the combination of Atezolizumab and mFOLFOX6 should be considered the new standard of care in this setting. This trial also exemplifies the power of cooperative group studies in driving progress for biomarker-defined subsets within common malignancies.

Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). Sinicrope F, Ou F-S, Arnold D, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1)

Late Breaking Abstract – ASCO 2025: A New Era for High-Risk Resected Head and Neck Cancer: Nivolumab Adds Disease-Free Survival Benefit in NIVOPOSTOP Trial

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SUMMARY: The American Cancer Society estimates that 59,660 new cases of cancer involving the oral cavity and pharynx will be diagnosed in the US in 2025 and 12,770 will die of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma (SCC) of the Head and Neck accounts for about 3-5% of all cancers in the United States. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Even though tobacco has long been associated with head and neck cancer development, cannabis has similar carcinogens.

The Standard of Care for patients with Stage III–IVA Head and Neck Squamous Cell Carcinoma (HNSCC) has remained largely static for nearly 2 decades: surgery followed by risk-adapted adjuvant radiotherapy, with or without concurrent Cisplatin based chemotherapy. Despite refinements in technique and supportive care, relapse rates remain high, particularly among patients with adverse pathological features such as extranodal extension and positive margins.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Phase 3 NIVOPOSTOP trial (GORTEC 2018-01) provides compelling evidence that integrating immunotherapy into the adjuvant setting may finally shift this long-standing treatment landscape. Nivolumab (OPDIVO&reg;) is a fully human, immunoglobulin G4 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.

Study Design and Patient Population
NIVOPOSTOP (NCT03576417) was an international, randomized, open-label Phase 3 study that enrolled 680 patients with completely resected LA-SCCHN (Locally Advanced Squamous Cell Carcinoma of the Head and Neck), which included the oral cavity, oropharynx, hypopharynx, and larynx. Eligible patients were less than 75 years old, with ECOG performance status 0-1, and exhibited high-risk features for recurrence, including extracapsular nodal extension, positive surgical margins, involvement of 4 or more lymph nodes, or extensive perineural invasion. PD-L1 expression was not required for study eligibility. Majority of patients had disease of the oral cavity (58%), about 50% were current smokers, most patients had Stage IVA or IVB disease (83%), and slightly more than one-half of patients (56%) had a PD-L1 Combined Positive Score less than 20. Patients were first stratified by HPV status and enrolling center before being randomly assigned to receive standard CRT or standard CRT plus nivolumab.

Patients were randomized 1:1 to receive:

  • Control Arm (SOC CRT): 66 Gy radiotherapy with three cycles of Cisplatin 100 mg/m² Q3W (N=334).
  • Experimental Arm (NIVO + CRT): One lead-in dose of Nivolumab 240 mg, followed by CRT plus Nivolumab 360 mg Q3W for three cycles, followed by six cycles of Nivolumab 480 mg Q4W for maintenance (N=332).

Both treatment groups were well balanced. The Primary endpoint was Disease Free Survival (DFS). Key Secondary endpoints include Overall Survival (OS) and Safety.

Primary Endpoint Met: Significant Improvement in Disease-Free Survival
At a median follow-up of 30.3 months, the trial met its Primary endpoint. Among the 666 patients included in the Disease-Free Survival (DFS) analysis (ITT population), the addition of adjuvant Nivolumab significantly reduced the risk of disease recurrence or death compared with CRT alone (HR 0.76; 95% CI, 0.60–0.98; P = 0.034).

Three-year DFS rates were 63.1% with NIVO + CRT (95% CI, 57.0–68.7) and 52.5% with CRT alone (95% CI, 46.2–58.4). This represents a 24% relative reduction in recurrence risk with Nivolumab. Importantly, this benefit was observed across all PD-L1 expression levels, supporting the use of this strategy in an unselected population.

Safety Profile: Manageable Toxicity with Increased Grade 3–4 Events
While the addition of Nivolumab was associated with an increase in grade 3-4 adverse events, particularly within the first 100 days post-CRT (13.1% vs. 5.6%), no increase in treatment-related mortality was seen (0.6% vs. 0.7%). Late grade ≥3 toxicities occurring beyond 9 months were rare in both groups and did not exceed grade 3. The overall safety profile was considered acceptable and consistent with known immune-related toxicities.

Locoregional Control Improved with Nivolumab
One of the most noteworthy findings was a significant reduction in locoregional recurrences. At 3 years, locoregional failure occurred in 13% of patients in the NIVO + CRT arm versus 20% in the CRT-only arm (HR 0.63; 95% CI, 0.42–0.94). Interestingly, unlike perioperative immunotherapy regimens such as KEYNOTE-689 that predominantly reduced distant failures, NIVOPOSTOP’s benefit was concentrated in locoregional disease control, suggesting a synergistic effect between radiotherapy and immune checkpoint inhibition.

Survival Data Pending but Trending Favorably
Although Overall Survival (OS) data remain immature, early trends favor the Nivolumab arm. At the time of reporting, 74% of patients receiving NIVO + CRT remained alive at 3 years, compared to 68% in the CRT-alone group. The final OS analysis is planned upon reaching 283 events (currently at 158).

Clinical Context and Expert Perspectives
The NIVOPOSTOP findings stand in sharp contrast to prior trials like KEYNOTE-412 and JAVELIN Head and Neck 100, which failed to show benefit from concurrent immune checkpoint inhibitor with CRT in unselected populations. Notably, the timing and sequencing of immunotherapy in NIVOPOSTOP, administered in the postoperative setting and continued as maintenance may have circumvented the immunosuppressive milieu of CRT and allowed more robust immune priming. The researchers emphasized the clinical need among the ~40–45% of LA-SCCHN patients who relapse after surgery and CRT.

Conclusion
NIVOPOSTOP represents the first successful Phase 3 trial to demonstrate a Disease-Free Survival advantage with the addition of immunotherapy to adjuvant CRT in high-risk, resected LA-SCCHN. With a favorable balance of efficacy and manageable toxicity, this regimen is poised to reshape clinical practice, marking a long-overdue advancement in the postoperative management of head and neck cancer.

NIVOPOSTOP (GORTEC 2018-01): A phase III randomized trial of adjuvant nivolumab added to radio-chemotherapy in patients with resected head and neck squamous cell carcinoma at high risk of relapse. Bourhis J, Auperin A, Borel C, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA2).

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

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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% 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 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.

The MET proto-oncogene encodes c-Met, a receptor tyrosine kinase also known as the Hepatocyte Growth Factor (HGF) receptor, that plays a central role in regulating cellular processes such as proliferation, survival, and angiogenesis. Aberrations in the MET pathway, including gene amplification or exon 14 skipping mutations, are implicated in a subset of non–small cell lung cancer (NSCLC) cases. Approximately 5% of patients harbor MET amplification and 2-4% carry MET mutations, making this an increasingly relevant therapeutic target. While MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and are under investigation for amplification, no targeted therapies are currently available for MET protein overexpression, a phenomenon observed in roughly 25-39% of NSCLCs and associated with poor prognosis.

Telisotuzumab vedotin is a first-in-class Antibody-Drug Conjugate directed against c-Met. It combines a monoclonal antibody targeting c-Met with the cytotoxic agent MonoMethyl Auristatin E (MMAE). Telisotuzumab uses c-Met protein overexpression as a biomarker to deliver its cytotoxic payload selectively to tumor cells, distinguishing it from therapies that rely on genomic alterations alone. In early-phase studies, it demonstrated encouraging antitumor activity and manageable toxicity in c-Met–overexpressing NSCLC.

LUMINOSITY Trial Design
The Phase II LUMINOSITY trial evaluated Telisotuzumab in patients with locally advanced or metastatic c-Met–overexpressing NSCLC who had received ≤2 prior lines of systemic therapy. Stage I of this study enrolled three cohorts based on tumor histology and EGFR status:

  1. Nonsquamous EGFR-wildtype
  2. Nonsquamous EGFR-mutant
  3. Squamous NSCLC

Stage II of this trial focused on the nonsquamous EGFR-wildtype cohort, which showed the most promise in Stage I part of the study. c-Met overexpression was determined by immunohistochemistry (IHC), with high expression defined as ≥50% of tumor cells showing 3+ membrane staining, and intermediate expression as ≥25% to <50%. Telisotuzumab was administered at a dose of 1.9 mg/kg IV every two weeks. The Primary endpoint was Overall Response Rate (ORR) as assessed by Independent Central Review using RECIST v1.1 criteria. Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).

Efficacy Outcomes
Among 172 patients with nonsquamous EGFR wild-type NSCLC treated at the 1.9 mg/kg dose, 161 were evaluable for efficacy. This group included 84 patients with high c-Met expression and 84 with intermediate expression. The ORR in the total c-Met overexpression group was 28.6% (95% CI, 21.7–36.2). When stratified, ORRs were higher in the c-Met high group at 34.6% (95% CI, 24.2–46.2) compared to 22.9% (95% CI, 14.4–33.4) in the intermediate group.

The median time to response was 1.41 months. Duration of response was also encouraging, with medians of 9.0 months in the high-expression group and 7.2 months in the intermediate group. Median PFS across all c-Met–overexpressing patients was 5.7 months, with similar figures for the high and intermediate groups. Median OS was 14.5 months overall and nearly identical across subgroups.

Safety Profile
Telisotuzumab was generally well tolerated. The most common treatment-related Adverse Events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade ≥3 AEs were infrequent, with peripheral sensory neuropathy being the most common (7%).

Conclusion
Telisotuzumab demonstrated durable antitumor activity and manageable toxicity in patients with c-Met protein–overexpressing, nonsquamous EGFR-wildtype NSCLC, especially those with high c-Met expression. Although the LUMINOSITY trial lacked a comparator arm, the results support further evaluation of Telisotuzumab in this population. A randomized phase III trial is ongoing and will compare Telisotuzumab monotherapy with Docetaxel in previously treated patients. Given the unmet need and lack of approved therapies targeting c-Met protein overexpression, Telisotuzumab represents a promising therapeutic advance in NSCLC.

 Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous EGFR-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial. Camidge DR, Bar J, Horinouchi H, et al.  J Clin Oncol 42:3000-3011, 2024