Category: Hem/Onc Updates

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights

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SUMMARY: The American Cancer Society estimates that 46,950 new cases of rectal cancer will be diagnosed in the US in 2025. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer all SEER stages combined is 67%.

The American Society of Clinical Oncology (ASCO) in 2024 published a guideline on treatment of locally advanced rectal cancer following a systematic review of research from 2013 to 2023. The systematic review included data from 12 randomized controlled trials, 2 systematic reviews, and 1 nonrandomized study.

The ASCO recommendations encouraged patients with MicroSatellite Stable (MSS) or proficient MisMatch Repair (MMR) locally advanced rectal cancer who have undergone assessment with dedicated rectal sequence pelvic MRI to consider Total Neoadjuvant Therapy (TNT) as initial treatment, for tumors in the lower rectum. They also encouraged those who are at a higher risk of local or distant metastases (T4, extramural vascular invasion and/or tumor deposits, threatened mesorectal fascia or intersphinteric plane and/or not eligible for sphincter sparing surgery, to consider TNT. For patients receiving TNT, long course chemoradiation is preferred, followed by chemotherapy consolidation prior to surgery.

Patients who do not present with high-risk factors (upper and middle rectal cancer and more than 5 mm of extramural invasion) are eligible to receive neoadjuvant FOLFOX chemotherapy, with selective ChemoRadiation Therapy (CRT) when extent of tumor response to chemotherapy is deemed insufficient.

Nonoperative management may be offered instead of total mesorectal excision for patients who demonstrate a clinical Complete Response to neoadjuvant therapy.

Immunotherapy is the recommended treatment for patients with tumors presenting with MicroSatellite Instability-High (MSI-H) or MisMatch Repair (MMR)-deficient disease.

The additional information provided below by ASCO is meant to addresses some of the questions that clinicians may face as they implement the recommendations into clinical practice.

Which Patients Are Included in the ASCO Guideline for Locally Advanced Rectal Cancer?
The ASCO guideline for locally advanced rectal cancer includes patients with T3 or T4 and/or node-positive disease. While T3 tumors with MRI-assessed extramural invasion ≤5 mm generally have better outcomes, the guideline classifies all low T3 rectal tumors, regardless of depth of invasion, as higher risk and includes them due to their increased recurrence risk. Patients with favorable T3 features may be addressed in a future guideline for early-stage rectal cancer.

What Is the Extent of Tumor Response Required for Omission of Radiation, That Is, Delivery of FOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin) Chemotherapy Alone, for Patients with Locally Advanced Rectal Cancer?
This question applies to patients similar to those enrolled in the PROSPECT trial—specifically, individuals with T2 or T3 rectal tumors situated at least 3 mm from the circumferential resection margin, with no more than three involved pelvic lymph nodes, and eligible for sphincter-sparing surgery. In the trial, a tumor area reduction of at least 20% was considered an adequate response to potentially omit radiation therapy. However, it’s important to note that some lower-risk patients from the study fall outside the scope of the current ASCO guidelines for locally advanced rectal cancer.

What Is the Balance of Benefits and Harms in the PROSPECT Trial of FOLFOX with Selective Chemoradiation Versus Chemoradiation Alone?
Neoadjuvant chemoradiation (CRT) for rectal cancer has historically been associated with long-term bowel, bladder, and sexual dysfunction in approximately 14% of patients. In light of this, the PROSPECT trial explored a de-escalation approach to potentially reduce toxicity by omitting routine pelvic radiation in select patients with mid-rectal tumors that do not involve the mesorectal fascia.

This phase III noninferiority trial demonstrated comparable Disease-Free Survival, Overall Survival, and local recurrence between patients treated with neoadjuvant FOLFOX (infusional 5-FU, leucovorin, and oxaliplatin) and those who received standard CRT with 5-FU. With efficacy outcomes being similar, patient safety and quality of life became central in guiding treatment choices.

Clinician-reported Adverse Events (AE) of Grade 3 or more were more common with FOLFOX (41.0%) compared to CRT (22.8%), with neutropenia, pain, and hypertension being the most frequent in the FOLFOX group. In the CRT group, common severe AEs included lymphopenia, diarrhea, and hypertension.

Regarding neuropathy, FOLFOX was associated with a higher rate pre-surgery (19% vs 5%) but showed comparable rates to CRT at 12 and 18 months postoperatively. Patient-reported outcomes revealed that while both groups experienced significant symptoms during treatment (e.g., fatigue, appetite loss, neuropathy, diarrhea), most severe symptoms resolved by 12 months post-surgery.

Sexual function, particularly among men and women in the CRT group, was more negatively impacted at 12 months, but differences between groups diminished by 24 months. Health-Related Quality of Life (HRQOL) was similar across both treatment arms throughout the follow-up period.

Treatment decisions may also be influenced by individual concerns: for example, younger women concerned about fertility might prefer chemotherapy alone, while those seeking to avoid long-term neuropathy might favor CRT. Surgical outcomes, including ostomy rates, also play a role. While data from the PROSPECT trial on surgical outcomes are forthcoming, similar trials (e.g., CONVERT) reported a lower rate of preventive ileostomy with neoadjuvant chemotherapy compared to CRT.

What Is the Timing of Assessment for Clinical Complete Response and Potential Nonoperative Management Following Total Neoadjuvant Therapy?
Although this topic was not formally evaluated in the ASCO guideline, the Expert Panel generally supported the assessment timeline used in the OPRA phase II trial, which evaluated clinical Complete Response approximately 8 weeks (±4 weeks) after completing total neoadjuvant therapy (TNT). Panelists noted that if radiation is given first in the TNT sequence, waiting an additional 8 weeks after chemotherapy might lead to an overly long treatment-free period. In such cases, an earlier response assessment may be appropriate. If the initial evaluation shows a near-Complete Response, reassessment within 8 weeks is advised to monitor for full clinical response and consider nonoperative management, as being studied in the ongoing JANUS trial comparing doublet and triplet consolidation chemotherapy.

What Tools Should Be Used in the Assessment of Patients Who Are Participating in NOM?
This guidance is based on the follow-up procedures used in the OPRA trial for NonOperative Management (NOM) of locally advanced rectal cancer. Patients underwent digital rectal exams and flexible sigmoidoscopy every 4 months during the first 2 years after initial response assessment, then every 6 months for the next 3 years. Rectal MRI was performed at least every 6 months for the first 2 years, with less frequent imaging afterward. If imaging or endoscopy showed signs of regrowth or a decline in response, patients exited the NOM protocol and were referred for surgery. Routine biopsies of the tumor site were not required. Annual CT scans of the chest, abdomen, and pelvis were conducted for all patients.

Does Circulating Tumor DNA Have A Role in the Assessment of Response for Patients Who Have Undergone Neoadjuvant Therapy for Locally Advanced Rectal Cancer?
Currently, there is not enough evidence to support the use of circulating tumor DNA (ctDNA) in predicting treatment response for patients with locally advanced rectal cancer. Ongoing research in this area will be reviewed for potential inclusion in future updates to the ASCO guideline.

Should Endorectal Ultrasonography And/or Computed Tomography Be Used to Assess Locally Advanced Rectal Cancer When MRI Is Not Available?
Traditionally, Endorectal UltraSound (EUS) and sometimes CT scans have been used to evaluate rectal cancer. However, high-resolution MRI provides a more accurate assessment of tumor invasion into the MesoRectal Fascia (MRF). While MRI might not be accessible in all settings, no validated alternative imaging method is currently recommended in this guideline. In cases where MRI is not feasible, EUS and CT may be used, though they do not offer complete tumor staging.

Management of Locally Advanced Rectal Cancer: ASCO Guideline Clinical Insights. Scott AJ, Kennedy EB, Berlin J, et al. JCO Oncol Pract. 2025 Mar;21:281-286.

Three-Year Overall Survival with OPDUALAG® in Advanced Melanoma

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SUMMARY: The American Cancer Society estimates that for 2025, about 104,960 new cases of melanoma of the skin will be diagnosed in the United States and 8430 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by immune checkpoints or gate keepers. With the recognition of immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

YERVOY® (Ipilimumab), a fully human immunoglobulin G1 monoclonal antibody that blocks immune checkpoint protein/receptor CTLA-4 was compared with PD-1 inhibitors, OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab) in patients with advanced melanoma, and both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), and with a better safety profile. In the CheckMate 067, which is a double-blind Phase III study, results from the 6.5 year analysis showed that a combination of OPDIVO® plus YERVOY® demonstrated significant improvement in OS and PFS, when compared to single agent OPDIVO® or single agent YERVOY®.

In an attempt to improve outcomes and enhance the risk-benefit profiles of immunotherapy combinations, alternate immune checkpoints are being explored. LAG-3 (Lymphocyte-Activation Gene 3 (LAG-3), is a cell-surface receptor expressed on immune cells including activated CD4+ T cells, and negatively regulates T-cell proliferation, inhibits T-cell activation and effector T-cell function. LAG-3 is upregulated in several tumor types, including malignant melanoma.

Relatlimab is a first-in-class human IgG4 LAG-3–blocking antibody that binds to LAG-3 and restores the effector function of exhausted T cells, resulting in T cell proliferation, activation and a therapeutic response. In preclinical studies, dual inhibition of LAG-3 and PD-1 showed synergistic antitumor activity, and in a Phase I/II trial, the combination of Relatlimab and OPDIVO®, demonstrated durable Objective Responses in patients with Relapsed/Refractory melanoma following treatment with PD-1 inhibitors.

RELATIVITY-047 is a Phase II/III, global, multicenter, double-blind, randomized trial in which a fixed-dose combination of Relatlimab and OPDIVO® (OPDUALAG®) was compared with OPDIVO® alone, in patients with previously untreated metastatic or unresectable melanoma. In this study, 714 patients were randomly assigned 1:1 to receive OPDUALAG®  (Relatlimab 160 mg and OPDIVO® 480 mg in a fixed-dose combination) (N=355) or single agent OPDIVO® 480 mg (N=359). Both regimens were administered as an IV infusion over 60 minutes every 4 weeks, and treatment was continued until disease progression, unacceptable toxicities, or withdrawal of consent. Both treatment groups were well balanced and patients were stratified according to LAG-3 expression (1% or more versus less than 1%), PD-L1 expression (1% or more versus less than 1%), BRAF V600 mutation status, and metastasis stage (M0 or M1 with normal LDH levels versus M1 with elevated LDH levels). More patients in the OPDUALAG® group had Stage M1c disease, and a larger proportion had three or more sites with at least one metastatic lesion. The Primary end point was Progression Free Survival (PFS) as assessed by blinded Independent Central Review. Secondary end points included Overall Survival and Objective Response Rate (ORR).

At a median follow up was 13.2 months there was a statistically significant improvement in progression-free survival (PFS), as well as a numerically higher objective response rate (ORR) with a fixed-dose combination of OPDUALAG®, compared with OPDIVO® alone. This led to the approval of this combination by the FDA in 2022.

The researchers herein reported updated descriptive efficacy and safety results from RELATIVITY-047 with a median follow-up of 33.8 months, which confirmed the sustained efficacy benefit of OPDUALAG®, compared with OPDIVO® alone.

The median PFS was 10.2 months with OPDUALAG® as compared with 4.6 months with OPDIVO® (HR=0.79; [95% CI, 0.66-0.95]).The 3-year PFS rates were 31.8% and 26.9% respectively. The median OS was 51.0 months and 34.1 months, respectively (HR, 0.80 [95% CI, 0.66 to 0.99]). The ORR was 43.7% (95% CI, 38.4 to 49.0) with OPDUALAG® versus 33.7% (95% CI, 28.8 to 38.9) with OPDIVO®.

The PFS benefit was more so with OPDUALAG® across key prespecified subgroups, compared to single agent OPDIVO®. Patients with poor prognosis characteristics, such as visceral metastases, high tumor burden, elevated levels of serum LDH, or mucosal or acral melanoma, had better outcomes with OPDUALAG®, than with single agent OPDIVO®. Further, a benefit with OPDUALAG® was also noted across BRAF mutant and wild-type subgroups, compared to single agent OPDIVO®. Expression of LAG-3 or PD-L1 was not useful in predicting a benefit of OPDUALAG® over single agent OPDIVO® and appears to NOT have a clear role in treatment selection.

Subsequent systemic therapy was received by 38% in the OPDUALAG® group and 39.3% in the OPDIVO® alone group. The median PFS2 was 29.6 months with OPDUALAG® and 20.3 months with OPDIVO® alone, further supporting the long-term benefits of OPDUALAG®.

Grade 3 or 4 toxicities occurred in 18.9% of patients in the OPDUALAG® group and in 9.7% of patients in the single agent OPDIVO® group. The Safety profile of OPDUALAG® appeared favorable, when compared with dual checkpoint inhibition with a CTLA-4 inhibitor and PD-1 inhibitor combination (YERVOY® plus OPDIVO®) in the CheckMate 067 trial, in which adverse events were noted in 59% of patients.

The researchers concluded that RELATIVITY-047 is the first study to show a statistically significant improvement in Progression Free Survival for an immunotherapy combination versus PD-1 monotherapy, in patients with previously untreated metastatic or unresectable melanoma. This is believed to be the first analysis demonstrating that a combination immunotherapy significantly improves Overall Survival compared to anti-PD-1 monotherapy (evidenced by an Overall Survival HR 95% CI upper bound now <1). The authors added that these results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma, and establishes LAG-3 as the third immune checkpoint pathway, thus providing more treatment options for patients with advanced melanoma.

Three-Year Overall Survival With Nivolumab Plus Relatlimab in Advanced Melanoma From RELATIVITY-047. Tawbi HA, Hodi FS, Lipson EJ, et al. J Clin Oncol 2024;43:1546-1552

BREAKWATER Trial Establishes Encorafenib Combination with Cetuximab Plus mFOLFOX6 as a First-Line Standard for BRAF V600E–Mutated mCRC

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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.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as Panitumumab (VECTIBIX®) and Cetuximab (ERBITUX®), as well as anti VEGF agent Bevacizumab (AVASTIN®), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

Encorafenib (BRAFTOVI®) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as Vemurafenib (ZELBORAF®) and Dabrafenib (TAFINLAR®), with a prolonged target dissociation half-life and higher potency. The FDA in 2020, approved Encorafenib in combination with Cetuximab for the treatment of adult patients with metastatic ColoRectal Cancer (mCRC) with a BRAF V600E mutation

Background and Unmet Need
BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Historically, patients with these mutations experienced shorter survival when treated with chemotherapy with or without biologics such as Bevacizumab, compared to their BRAF wild-type counterparts. While the BEACON CRC trial established the Encorafenib plus Cetuximab (EC) doublet as standard in the previously treated setting, the optimal first-line strategy remained undefined.

Design of the BREAKWATER Study
The Phase 3 BREAKWATER trial addressed this gap by evaluating first-line treatment with Encorafenib and Cetuximab, with or without chemotherapy, in patients with previously untreated BRAF V600E-mutated mCRC. Initially designed with three arms (1:1:1), EC: Encorafenib (300 mg PO QD) + Cetuximab (500 mg/m² IV q2w), EC + mFOLFOX6: As above + Oxaliplatin, Leucovorin, and 5-FU and Control/Standard of Care: mFOLFOX6, FOLFOXIRI, or CAPOX with or without Bevacizumab, the protocol was later amended to focus on the EC+mFOLFOX6 (N=236) versus Standard of Care comparison (N=243). The median age was 61 yrs and stratification was based on ECOG performance status and geographic region. Eligible patients had metastatic colorectal adenocarcinoma with measurable disease and a confirmed BRAF V600E mutation, but no prior systemic therapy for metastatic disease. The Primary endpoints included Progression-Free Survival (PFS) and Objective Response Rate (ORR). Secondary endpoints included Overall Survival (OS), Duration of Response (DoR) and Time to Response.

Efficacy Highlights
The results were compelling across both Primary endpoints (ORR and PFS), as well as key Secondary outcomes:

  • Objective Response Rate (ORR):
    EC+mFOLFOX6 achieved a confirmed ORR of 7%, compared with 37.4% in the Standard of Care arm (Odds Ratio, 2.44; P<0.001), with a median Time to Response of approximately 7 weeks. The median Duration of Response was 13.9 months and 10.8 months respectively
  • Progression-Free Survival (PFS):
    The median PFS was 8 months with EC+mFOLFOX6 versus 7.1 months with standard care (Hazard Ratio [HR] for progression or death, 0.53; P<0.001), representing a 47% reduction in risk.
  • Overall Survival (OS):
    Interim analysis demonstrated a median OS of 3 months with EC+mFOLFOX6, more than double the 15.1 months observed in the Standard of Care group (HR for death, 0.49; P<0.001). Twelve and 24 month survival rates favored the investigational arm (80.1% and 52.0%, respectively) over Standard of Care (66.0% and 29.0%).

Notably, survival outcomes with EC+mFOLFOX6 approached those historically seen in BRAF wild-type mCRC, underscoring the potential for targeted therapy to narrow the survival gap.

Subgroup and Secondary Analyses
Benefits of EC+mFOLFOX6 were consistent across prespecified subgroups, including patients with liver metastases or multi-organ involvement. Additionally, median second Progression-Free Survival was longer with EC+mFOLFOX6, reinforcing its value in delivering durable disease control.

Safety Profile
While the incidence of grade ≥3 adverse events was higher in the EC+mFOLFOX6 group (46.1%) compared to standard care (38.9%), toxicity was manageable, and treatment discontinuations remained relatively low. The safety profile was consistent with expectations for the individual agents, and chemotherapy dose reductions were not substantially increased.

Clinical Implications
These findings firmly establish EC+mFOLFOX6 as a new first-line standard for patients with BRAF V600E–mutated mCRC. The dual-targeted approach combined with chemotherapy offers significantly improved outcomes in a population long characterized by poor prognosis. The results also highlight the importance of early integration of targeted therapy, particularly encorafenib, into the treatment paradigm.

Next Steps in BRAF-Targeted Strategies
Although the EC doublet showed some activity, particularly in patients ineligible for chemotherapy, its efficacy was inferior to the triplet regimen. Enrollment into the EC-only arm was halted, and current exploration includes EC combined with FOLFIRI (ongoing in BREAKWATER cohort 3) and EC plus pembrolizumab in MSI-H/dMMR populations (SEAMARK trial).

Conclusion
The BREAKWATER trial demonstrated that first-line treatment with EC+mFOLFOX6 significantly improves Response Rates, Progression-Free Survival, and Overall Survival, compared to standard chemotherapy regimens, in BRAF V600E–mutated mCRC. This represents a transformative advance, closing the gap in outcomes between BRAF-mutated and wild-type mCRC, and setting a new benchmark in precision oncology.

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. Elez E,  Yoshino T,  Shen L, et al., for the BREAKWATER Trial Investigators. N Engl J Med 2025;392:2425-2437

FDA Approves Perioperative KEYTRUDA® for Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma

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SUMMARY: The FDA on June 12, 2025, approved Pembrolizumab (KEYTRUDA&reg;) for adults with resectable locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC) whose tumors express PD-L1 Combined Positive Score (CPS) of 1 or more, as determined by an FDA-approved test, as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with Radiotherapy (RT) with or without Cisplatin after surgery, and then as a single agent.This is the first approval for HNSCC in 6 years and the first overall perioperative approval for locally advanced HNSCC.

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 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.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-689, a landmark Phase 3 trial, has provided the most compelling evidence to date that perioperative immunotherapy, specifically Pembrolizumab, can significantly improve clinical outcomes for patients with resectable, locally advanced Head and Neck Squamous Cell Carcinoma (HNSCC). This international, randomized, placebo-controlled study enrolled 714 patients (N=714) with newly diagnosed, resectable, Stage III–IVA HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx.

Patients were randomized 1:1 to receive:

  • Investigational arm (N=356):
    • 2 cycles of neoadjuvant Pembrolizumab (200 mg IV Q3W) starting about 3 weeks before surgery.
    • Standard-of-care surgery.
    • Up to 3 doses of Pembrolizumab administered concurrently with adjuvant chemoradiotherapy, with Cisplatin (depending on pathologic risk- positive margins <1 mm or extranodal extension present at surgery was considered high risk).
    • 12 additional adjuvant doses of Pembrolizumab Q3W (total treatment duration: about 1 year).
  • Control arm (N=358):
    • Identical treatment structure, substituting placebo for Pembrolizumab.

PD-L1 expression was assessed via Combined Positive Score (CPS), and stratification included CPS ≥1 and CPS ≥10 subgroups, recognizing the prognostic and potentially predictive value of PD-L1 expression. The Primary endpoint was Event-Free Survival (EFS) by Blinded Independent Central Review, defined as time from randomization to disease progression, local/regional recurrence, distant metastasis, or death from any cause. Secondary endpoints included Overall Survival (OS) and Major Pathological Response.

The trial met its Primary endpoint of EFS. At median follow-up of 38.3 months, patients in the investigational arm had significantly improved EFS compared with the Standard of Care arm (median 51.8 months vs. 30.4 months; HR=0.73; P=0.0041). Patients who received Pembrolizumab who had a CPS score ≥10 derived the greatest benefit (median 59.7 months vs. 26.9 months; HR = 0.66; P=0.002) whereas the median EFS in the CPS ≥1 subgroup was 59.7 vs. 29.6 months (HR, 0.70; P = .0014).

Major pathological response defined as 90% or more tumor regression was also notably improved. Among all patients, the major pathological response rate was 9.4% with Pembrolizumab vs. 0% with Standard of Care (P < 0.00001). In the CPS ≥10 subgroup, the major pathological response rate reached 13.7%.

While the interim analysis did not demonstrate a statistically significant OS benefit, trends were favorable, particularly in the CPS ≥10 group (HR, 0.72; P =0.02). Further OS follow-up is ongoing.

Adverse events were consistent with known profiles of checkpoint inhibitors. Grade 3 or more Treatment-Related Adverse Events (TRAEs) occurred in 44.6% of the Pembrolizumab group and 42.9% in the Standard of Care group. Immune-mediated adverse events were observed in 43.2% of the Pembrolizumab arm, with hypothyroidism being the most common (24.7%). Mortality attributable to treatment was slightly higher with Pembrolizumab (1.1% vs. 0.3%).

The researchers concluded that perioperative Pembrolizumab is now emerging as a new standard of care in the treatment of resectable locally advanced HNSCC. The findings from this study underscore the importance of harnessing the immune system both before and after surgery. Neoadjuvant administration may prime the immune response when tumor antigen burden is highest, while adjuvant therapy may help eliminate residual microscopic disease.

Neoadjuvant and adjuvant pembrolizumab plus standard of care in resectable locally advanced head and neck squamous cell carcinoma: phase 3 KEYNOTE-689 study. Uppaluri R, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.

Late Breaking Abstract – ASCO 2025: Targeting ESR1 Mutations in Advanced Breast Cancer: Phase 3 VERITAC-2 Validates Vepdegestrant as a Promising Next-Generation Endocrine Therapy

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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 and Clinical Unmet Need
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, with up to 50% of patients acquiring ESR1 (Estrogen Receptor gene alpha) mutations after exposure to prior endocrine therapy in combination with CDK4/6 inhibitors. These mutations enable constitutive activation of the estrogen receptor, rendering tumors less responsive to traditional endocrine agents. Although Selective Estrogen Receptor Degraders (SERDs) such as Fulvestrant and Elacestrant are often used in this setting, their clinical activity is modest and limited by pharmacokinetic and mechanistic constraints, especially in heavily pretreated, endocrine-resistant disease.

A Novel Approach: Vepdegestrant and the PROTAC Platform
Vepdegestrant represents a first-in-class, oral PROteolysis TArgeting Chimera (PROTAC) designed to degrade the ER through direct engagement of the ubiquitin-proteasome system. Unlike traditional SERDs, which bind to and inactivate the ER before relying on indirect degradation pathways, Vepdegestrant forms a ternary complex between the ER and an E3 ubiquitin ligase. This results in efficient and targeted ubiquitination and subsequent degradation of the ER protein. Early-phase trials demonstrated that Vepdegestrant was well tolerated and exhibited promising antitumor activity in patients with heavily pretreated ER+/HER2-negative advanced breast cancer. This laid the foundation for VERITAC-2, the first Phase 3 study evaluating a PROTAC agent in oncology.

VERITAC-2: Study Design and Patient Population
Study Overview:
VERITAC-2 is a global, randomized Phase 3 trial comparing oral Vepdegestrant 200 mg once-daily continuously with Fulvestrant 500 mg intramuscularly days 1 and 15 of cycle 1 and day 1 of subsequent cycles, in postmenopausal women and men with ER+/HER2-negative advanced breast cancer, previously treated with a CDK4/6 inhibitor plus endocrine therapy. An additional line of endocrine therapy was permitted. However, patients previously exposed to SERDs or chemotherapy in the metastatic setting were excluded. A total of 624 patients (median age 60 years; 43% with ESR1mutation tumors) were randomized 1:1 to receive Vepdegestrant (N=313) or Fulvestrant (N=311). Approximately 80% were postmenopausal, and 20% had received two prior lines of therapy in the advanced setting. Patients were stratified by ESR1 mutation status and presence of visceral disease. The Primary endpoint was Progression-Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR), first in the ESR1mutations subgroup and then in the overall population contingent on statistical assumptions. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Clinical Benefit Rate (CBR), and Safety.

Key Efficacy Findings

In the ESR1-Mutant Population:

  • Median PFS: 5.0 months with Vepdegestrant vs 2.1 months with Fulvestrant
  • Hazard Ratio: 0.57 (95% CI, 0.42–0.77); P=0.0001
  • 6-Month PFS Rate: 45.2% with Vepdegestrant vs 22.7% with Fulvestrant
  • Objective Response Rate: 18.6% vs 4.0% (P=0.001)
  • Clinical Benefit Rate: 42.1% vs 20.2% (P<0.001)

There was a 43% relative reduction in the risk of disease progression or death with Vepdegestrant compared with Fulvestrant. These results represent a statistically significant and clinically meaningful improvement in PFS and response outcomes among ESR1mutated patients, reinforcing the hypothesis that targeted ER degradation via PROTAC technology can overcome a key mechanism of endocrine resistance.

In the Overall Population:

  • Median PFS: 3.7 months (Vepdegestrant) vs 3.6 months (Fulvestrant)
  • HR: 0.83 (95% CI, 0.68–1.02); P=0.07

Although trends favored Vepdegestrant, the PFS difference in the unselected population did not reach statistical significance, underscoring the critical role of ESR1 mutation status as a biomarker of response to this agent.

Safety and Tolerability
Vepdegestrant was generally well tolerated, with most Adverse Events (AEs) being Grade 1 or 2. Grade 3 or more Treatment-Emergent AEs occurred in 23.4% receiving Vepdegestrant versus 17.6% with Fulvestrant. The most toxicities with Vepdegestrant were fatigue, elevated ALT/AST, nausea, vomiting and diarrhea. Discontinuation due to AEs occurred in only 2.9% of patients receiving Vepdegestrant. Importantly, gastrointestinal side effects, often limiting with oral SERDs, were infrequent and generally low-grade, reflecting the favorable tolerability of this novel agent.

Clinical Implications and Future Directions
The VERITAC-2 trial offers a landmark clinical validation for PROTACs in oncology. For patients with ER+/HER2-negative advanced breast cancer harboring ESR1 mutations, Vepdegestrant offers a statistically significant and clinically relevant advantage in Progression-Free Survival over Fulvestrant. The favorable safety profile, oral dosing convenience, and mechanistic novelty support its development as a next-generation standard of care in this biomarker-defined subgroup.

Although benefit was not observed in the all-comer population, the compelling results in ESR1mutated disease position Vepdegestrant as a precision endocrine therapy option that could reshape the treatment landscape. Ongoing investigations will clarify its role in earlier lines of therapy and in combination strategies, including with targeted or immunotherapeutic agents.

Conclusion
Vepdegestrant has emerged as a promising, targeted therapy for patients with ESR1-mutated ER+/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy. As the first PROTAC to reach Phase 3, its success in VERITAC-2 signals the clinical viability of targeted protein degradation platforms in hormone receptor–driven malignancies.

Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. Hamilton H, De Laurentiis M, Jhaveri K, et al. J Clin Oncol 43, 2025 (suppl 17; abstr LBA1000)

 

Late Breaking Abstract – ASCO 2025: 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). 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

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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

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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

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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.

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

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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)