Category: Hem/Onc Updates

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

 

Landmark Analysis from PERSIST-2 Links Pacritinib Response to Survival Benefit in Myelofibrosis with Thrombocytopenia

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SUMMARY: Myelofibrosis (MF) is a progressive MyeloProliferative Neoplasm (MPN) characterized by bone marrow fibrosis, anemia, splenomegaly, and systemic symptoms. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact quality of life of an individual. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET).

The disease is frequently driven by mutations in JAK2, CALR, or MPL, with aberrant JAK-STAT signaling contributing to excessive inflammatory cytokine production, clonal proliferation, and cytopenias. Notably, thrombocytopenia (platelet count ≤100 × 10⁹/L) is a marker of high-risk disease, associated with poor prognosis and limited treatment options due to the hematologic toxicity of existing JAK inhibitors like Ruxolitinib and Fedratinib.

JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib (VONJO&reg;) is a JAK2/IRAK1/ACVR1 inhibitor with minimal JAK1 activity, allowing it to be administered at full dose in patients regardless of baseline platelet count. It is FDA-approved for the treatment of intermediate- or high-risk MF with platelet counts <50 × 10⁹/L.

PERSIST-2 Trial Design
PERSIST-2 was a randomized, controlled Phase 3 study evaluating Pacritinib in MF patients with baseline thrombocytopenia (platelets ≤100 × 10⁹/L), regardless of prior JAK inhibitor exposure. This study evaluated Pacritinib in MF patients with thrombocytopenia, a population typically underrepresented in prior JAK inhibitor trials.

Study Arms:

  • Pacritinib 200 mg twice daily (BID) – now FDA-approved dose
  • Pacritinib 400 mg once daily – discontinued due to unfavorable tolerability
  • Best Available Therapy (BAT) – including low-dose Ruxolitinib

Patient Population (N=311):

  • Median platelet count: ~54 × 10⁹/L
  • 46% had received prior Ruxolitinib
  • 63% were transfusion-dependent at baseline

Primary and Secondary Endpoints

  • Primary endpoint: Proportion of patients achieving ≥35% Spleen Volume Reduction (SVR35) at Week 24, measured by MRI or CT.
  • Key secondary endpoint: ≥50% reduction in Total Symptom Score (TSS50) based on the Myelofibrosis Symptom Assessment Form (MFSAF v2.0).

Primary Results:
Among patients receiving Pacritinib 200 mg BID (N=74) vs BAT (N=72):

  • SVR35 at Week 24: 22% vs 3% (P=0.001)
  • TSS50 at Week 24: 25% vs 14% (not statistically significant)
  • Red blood cell transfusion independence at Week 24: 37% vs 14% (P=0.04)
  • SVR was consistent across platelet subgroups, including <50 × 10⁹/L

Landmark OS Analysis (2024): Early Spleen Response Predicts Survival
A retrospective landmark analysis was conducted using a Week 12 timepoint to evaluate the association between early Spleen Volume Reduction and Overall Survival (OS) in PERSIST-2. Patients alive and on study at the 12-week assessment were included (N=173; Pacritinib N=89, BAT N=84).

  • SVR thresholds analyzed: ≥35%, ≥20%, ≥10% (SVR10), and >0% (SVR0).
  • Most prognostic threshold: SVR10 at Week 12 showed the strongest association with improved OS for Pacritinib (HR: 0.00; 95% CI: 0.00–0.14; P<0.01). No deaths occurred among SVR10 responders.
  • No OS benefit was observed with any SVR threshold in the BAT group, including among Ruxolitinib-treated patients.

These findings suggest that even modest Spleen Volume Reduction (≥10%) at Week 12 may serve as a prognostic marker for survival benefit in thrombocytopenic MF patients receiving Pacritinib, but not with BAT, including Ruxolitinib.

Clinical Implications and Conclusion:
This analysis is the first to demonstrate a survival advantage associated with spleen response in thrombocytopenic MF patients, a subgroup often ineligible for full-dose JAK2 inhibition. Given that SVR10 at Week 12 predicts better OS only in Pacritinib-treated patients, early spleen response may serve as a meaningful clinical benchmark for assessing benefit in this high-risk population. These findings reinforce the role of Pacritinib as a frontline option for Myelofibrosis patients with low platelet counts, and highlight the need for individualized treatment based on disease biology and cytopenia profile.

Pacritinib response is associated with overall survival in myelofibrosis: PERSIST-2 landmark analysis of survival. Ajufo H, Bewersdorf JP, Harrison C, et al. Eur J Haematol. 2025;114(2):238-247. doi:10.1111/ejh.14321

FDA Approves ZYNYZ® for Squamous Cell Carcinoma of the Anal Canal

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SUMMARY: The FDA on May 15, approved Retifanlimab-dlwr (ZYNYZ&reg;), a PD-1–blocking monoclonal antibody, with Carboplatin and Paclitaxel for the first-line treatment of adults with inoperable locally recurrent or metastatic Squamous Cell carcinoma of the Anal Canal (SCAC). The FDA also approved Retifanlimab as a single agent for adults with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy.

The American Cancer Society estimates that 10,930 new cases of Anus, anal canal, and anorectum cancers will be diagnosed in 2025, and 2030 individuals will die of the disease. Squamous Cell carcinoma of the Anal Canal (SCAC) is a rare but increasingly prevalent malignancy, closely associated with persistent infection by high-risk Human PapillomaVirus (HPV), particularly HPV-16 and HPV-18. HPV-driven oncogenesis plays a pivotal role in SCAC development by disrupting tumor suppressor proteins such as p53 and Rb via viral oncoproteins E6 and E7. These oncoproteins also generate a highly immunogenic Tumor MicroEnvironment (TME), recruiting Tumor-Infiltrating Lymphocytes (TILs) and expressing immune checkpoints like PD-L1, providing a compelling rationale for the use of Immune Checkpoint Inhibitors (ICIs) in this disease.

While early-stage SCAC is often curable with chemoradiation, outcomes in advanced or metastatic cases remain poor, with 5-year survival dropping to 30% in Stage IV disease. Platinum-based chemotherapy, particularly the combination of Carboplatin and Paclitaxel as established by the InterAAct trial, has been the frontline standard. However, outcomes have remained suboptimal, fueling efforts to explore combination regimens that leverage the immunogenicity of HPV-driven SCAC.

Rationale for Immunotherapy in SCAC

HPV-positive tumors are characterized by an “inflamed” TME, enriched with TILs and immune regulatory molecules such as PD-1 and PD-L1. This immune signature is associated with both favorable prognosis and responsiveness to immunotherapy. ICIs like Pembrolizumab and Nivolumab have demonstrated modest activity as monotherapy in pretreated SCAC, with Overall Response Rates (ORR) ranging from 13% to 30% and median Progression-Free Survival (PFS) of approximately 2-4 months. However, these agents alone have not transformed outcomes, prompting exploration of synergistic strategies.

Preclinical studies indicate that chemotherapy can enhance immunogenic cell death, promote antigen presentation, and reduce immunosuppressive myeloid populations, thus priming the TME for immune-based therapies. These insights provided the foundation for evaluating the anti–PD-1 antibody Retifanlimab in combination with Carboplatin and Paclitaxel.

Retifanlimab (ZYNYZ&reg;) is a humanized monoclonal antibody targeting PD-1, thereby restoring T-cell activity against tumor cells.

POD1UM-303 (InterAACT 2; NCT04472429) was a randomized, double-blind, multicenter Phase 3 trial that enrolled 308 patients across 81 centers with inoperable, locally recurrent, or metastatic SCAC who were chemotherapy-naive in the advanced setting. Participants received standard Carboplatin (AUC 5, IV day 1) and Paclitaxel (80 mg/m² IV, days 1, 8, and 15) for six cycles, and were randomized 1:1 to receive either:

  • Retifanlimab 500 mg IV every 4 weeks, or
  • Placebo IV every 4 weeks
    Treatment was continued for up to one year or until disease progression or unacceptable toxicity. Cross-over to single-agent Retifanlimab was allowed for patients in the placebo arm upon disease progression.

The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1 by Blinded Independent Central Review. Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), and Duration of Response (DoR).

Clinical Outcomes

  • Progression-Free Survival:
    • Retifanlimab arm: 9.3 months (95% CI, 7.5–11.3)
    • Placebo arm: 7.4 months (95% CI, 7.1–7.7)
    • Hazard ratio: 0.63 (95% CI, 0.47–0.84; P=0.0006)
  • Overall Survival (Interim Analysis):
    • Retifanlimab arm: 29.2 months (95% CI, 24.2–NE)
    • Placebo arm: 23.0 months (95% CI, 15.1–27.9)
    • HR: 0.70 (95% CI, 0.49–1.01), not yet statistically significant
  • Overall Response Rate:
    • Retifanlimab arm: 56% (95% CI, 48%–64%)
    • Placebo arm: 44% (95% CI, 36%–52%)
  • Disease Control Rate: 87% vs 80%, respectively
  • Crossover Allowed: 45% of patients in the placebo arm received Retifanlimab upon progression.

Safety and Tolerability

The combination of Retifanlimab and chemotherapy was generally well tolerated. Immune-related Adverse Events (AEs) increased, as expected with PD-1 blockade, but were manageable and did not significantly impact chemotherapy delivery or dose intensity.

Monotherapy Insights: POD1UM-202

Retifanlimab was also studied as a single agent in POD1UM-202 (NCT03597295), a Phase 2 trial of 94 patients with previously treated, platinum-refractory SCAC:

  • ORR: 14% (95% CI, 8%–23%)
  • Median DOR: 9.5 months
  • Notable Findings: Better responses observed in p16-positive and PD-L1–positive tumors; tumor inflammation signature scores correlated with improved survival.

Conclusion and Clinical Implications

The POD1UM-303 trial marks a major advancement in the treatment of advanced SCAC. Retifanlimab in combination with Carboplatin and Paclitaxel not only met its Primary endpoint but also demonstrated consistent improvements in response rates, survival outcomes, and disease control, without compromising safety.

As the first positive Phase 3 study in this setting, POD1UM-303 establishes a new standard of care for patients with advanced SCAC and solidifies the role of immunotherapy in HPV-associated malignancies. Continued exploration of predictive biomarkers and deeper understanding of the TME will be critical to refining treatment strategies in this rare but challenging cancer.

POD1UM-303/InterAACT 2: Phase 3 study of retifanlimab with carboplatin-paclitaxel (C-P) in patients (Pts) with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (Chemo). Rao S, et al. ESMO Congress 2024, LBA2

Pregnancy-Specific Glycoproteins Linked to Poorer Prognosis in Female Lung Adenocarcinoma Patients

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SUMMARY: Pregnancy-Specific Glycoproteins (PSGs), traditionally known for their role in fetal development and maternal immune tolerance, are emerging as unexpected contributors to oncologic processes. These placental proteins, members of the CarcinoEmbryonic Antigen Cell Adhesion Molecule (CEACAM) family and the broader immunoglobulin superfamily, are produced by trophoblasts and secreted into maternal circulation during pregnancy in high concentrations and act as immunomodulators, facilitating maternal-fetal tolerance and vascular remodeling. However, recent evidence suggests that these proteins may be aberrantly expressed in several malignancies, including lung cancer, with potentially detrimental effects, particularly among female patients.

Background and Rationale
While PSGs are primarily restricted to the placenta under normal physiological conditions, prior research has revealed their ectopic expression in various cancers such as breast, ovarian, uterine, and colon tumors. Their expression in these settings has been correlated with poorer overall survival. Yet the mechanisms and potential sex-specific effects remained unclear. Recognizing the immunological parallels between pregnancy and tumor immune evasion, researchers hypothesized that PSGs might confer a selective disadvantage in cancers by modulating the tumor microenvironment in a sex-dependent manner.

Study Design and Methodology
To explore this hypothesis, investigators conducted a sex-stratified analysis of PSG expression and survival outcomes using two independent transcriptomic datasets: The Cancer Genome Atlas (TCGA), encompassing 235 male and 271 female Lung Adenocarcinoma patients, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), including 70 male and 36 female patients. PSG mRNA expression profiles were integrated into machine learning models to assess their prognostic value. Key PSG family members, PSG3, PSG7, and PSG8 were specifically examined for their association with survival outcomes.

Key Findings
This analysis revealed a striking sex-specific prognostic disparity in Lung Adenocarcinoma. Female patients with elevated PSG expression exhibited significantly worse Overall Survival compared to their PSG-negative counterparts, a trend not observed in male patients. Notably, a combined expression signature of PSG3, PSG7, and PSG8 identified a high-risk subgroup encompassing approximately 30% of female patients. This signature was significantly associated with poor prognosis.

Pathway enrichment analysis further uncovered that PSG-expressing female Lung Adenocarcinoma tumors showed upregulation of the “KRAS Signaling Down” pathway, suggesting a potential mechanistic link. Incorporating KRAS pathway activity into the predictive model improved its prognostic performance in female patients, reinforcing the notion that PSGs may interface with oncogenic KRAS signaling in a sex-dependent fashion.

Clinical Implications
These findings underscore a previously unrecognized, sex-specific role for PSGs in modulating lung cancer outcomes. The ectopic expression of PSGs appears to mimic their immune-regulatory function during pregnancy, potentially allowing tumors to evade immune surveillance, particularly in female patients. As a result, PSG expression may serve as a prognostic biomarker and a novel therapeutic target in Lung Adenocarcinoma.

The research team is now investigating the development of antibody-based therapeutics aimed at inhibiting PSG expression, with the goal of improving outcomes in this vulnerable subgroup of female Lung Adenocarcinoma patients. Given that PSGs are typically silenced outside of pregnancy, targeting them may provide a tumor-specific strategy with minimal off-target effects.

Future Directions
Further investigations are planned to delineate the interplay between PSG expression, pregnancy history, and hormone-related gene activity. Such studies could elucidate whether reproductive history or endocrine factors influence the reactivation of PSG genes in female tumors, potentially refining risk stratification and therapeutic approaches.

Conclusion
This research highlights the adaptive reuse of fetal tolerance mechanisms by tumors and reveals PSGs as key contributors to sex-specific disparities in Lung Adenocarcinoma prognosis. By integrating transcriptomic profiling with clinical outcomes and pathway analysis, this study provides a compelling rationale for the clinical development of PSG-targeted therapies in female Lung Adenocarcinoma.

Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients. Oh JH, Rizzuto G, Elkin R, et al. Presented on April 28, 2025: AACR Annual Meeting 2025.

Rising Incidence of Pancreatic and Colorectal Adenocarcinoma among Younger Populations

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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%. Early detection is critical to expanding treatment possibilities and enhancing survival rates. 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. Even though the diagnosis of colorectal cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of colorectal cancer cases diagnosed in people under age 50, leading to revisions in screening guidelines.

Study Objective
To provide an updated analysis of Annual Percentage Changes (APCs) in the incidence of pancreatic and colorectal adenocarcinoma across different age groups, focusing on younger populations, using data from the SEER database (2000–2021).

Methods
Data Source

  • SEER (Surveillance, Epidemiology, and End Results) database (22 registries, ~47.9% of US population)
  • Data updated through April 17, 2024

Study Design

  • Retrospective cohort study
  • Inclusion: Pancreatic and colorectal adenocarcinoma only
  • Exclusion: Rare pancreatic cancer subtypes (e.g., neuroendocrine tumors, mucinous cystadenocarcinoma)
  • The Rutgers University IRB exempted the study, and informed consent was not needed owing to the deidentified nature of the data.

Analysis

  • Yearly incidence rates per 100,000 population
  • Annual Percentage Changes (APCs) and 95% confidence intervals calculated for three age groups:
    • 15–34 years
    • 35–54 years
    • 55+ years

Results
Pancreatic Adenocarcinoma

  • Total cases (2000–2021): 275,273
    • 51.8% male, 87.1% aged ≥55 years
  • APC in 15–34 years: 4.35% (95% CI, 2.03–6.73)
  • APC in 35–54 years: 1.54% (95% CI, 1.18–1.90)
  • APC in 55+ years: 1.74% (95% CI, 1.59–1.89)

The APC for pancreatic adenocarcinoma in the group aged 15 to 34 year was statistically significantly higher than the APCs of 1.74 (P =0.007) for the group aged 55 years and older and 1.54 (P =0.004) for the group aged 35 to 54 years. The authors commented that the dramatic increase in the APC in the younger population suggests that close attention should be paid to this trend.

Colorectal Adenocarcinoma

  • Total cases: 1,215,200
    • 52.8% male, 80.4% aged ≥55 years
  • APC in 15–34 years: 1.75% (95% CI, 1.08–2.42)
  • APC in 35–54 years: 0.78% (95% CI, 0.51–1.06)
  • APC in 55+ years: -3.31% (95% CI, -3.54 to -3.08)

The APC for colorectal adenocarcinoma for the group aged 55 years and older was statistically significantly lower than the APCs for the group aged 15 to 34 years (P =0.001) and for the group aged 35 to 54 years (P =0.002). Most declines in colorectal cancer incidence was attributed to increased screening in older adults. Screening age was lowered from 50 to 45 years and may likely reduce future incidence in those aged 35–54.

Interpretation & Implications

Pancreatic Cancer

  • Though rare, pancreatic adenocarcinoma in young adults (15–34 years) is rising at an alarming rate.
  • Potential contributors: Smoking, alcohol, environmental exposures, though definitive causes remain unclear.
  • Clinician awareness is critical when evaluating younger patients with:
    • Abdominal pain
    • Weight loss
    • Anemia
    • Family history of pancreatic cancer

Clinical Insight: Historically, the above findings are not investigated in a young individual. It is therefore important to make sure a serious condition is not missed.

Colorectal Cancer

  • Increasing in younger groups, despite an overall declining trend.
  • This supports recent screening age revisions and highlights the need for vigilance in symptomatic young patients.

Limitations

  • SEER data covers ~47.9% of the U.S. population.
  • However, SEER is designed for accurate trend analysis and has reliable coding for common cancers like pancreatic and colorectal adenocarcinoma.
  • Restricting to adenocarcinoma improves the homogeneity and accuracy of the study.

Conclusions

  • Pancreatic adenocarcinoma incidence is rising in all age groups, especially in the youngest cohort (15–34 years).
  • Colorectal adenocarcinoma is increasing among younger individuals, while declining among those 55 and older.
  • Clinicians must heighten awareness of these trends and consider appropriate workups in symptomatic younger patients.

Key Takeaways

  • Pancreatic adenocarcinoma incidence rose >4% annually in individuals aged 15–34 years.
  • Colorectal adenocarcinoma also increased among patients aged 15–34 years.
  • Consider early imaging and endoscopic evaluations in symptomatic young adults.
  • Continue to support early screening efforts, especially for high-risk individuals.

Incidence of Pancreas and Colorectal Adenocarcinoma in the US. Bussetty A, Shen J, Benias PC, et al. JAMA Netw Open. 2025;8(4):e254682. doi:10.1001/jamanetworkopen.2025.4682

 

 

 

 

 

Underutilization of Treatment Intensification in mCSPC: Persistent Gaps between Guidelines and Practice

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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. The American Cancer Society estimates 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.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX&reg; (Bicalutamide), NILANDRON&reg; (Nilutamide) and EULEXIN&reg; (Flutamide), or with second generation Androgen Receptor Pathway Inhibitors (ARPIs), which include ZYTIGA&reg; (Abiraterone), XTANDI&reg; (Enzalutamide), ERLEADA&reg; (Apalutamide) and NUBEQA&reg; (Darolutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.

Evidence from clinical trials indicates treatment intensification by combining ADT with ARPIs like Enzalutamide, Apalutamide, Abiraterone, or Darolutamide/chemotherapy, enhances survival in individuals with metastatic Castration-Sensitive Prostate Cancer (mCSPC). Despite clear, consensus-driven guidelines recommending treatment intensification (TI) for mCSPC, real-world data consistently show that many patients are not receiving evidence-based first-line combination therapy. This ongoing implementation gap could have significant consequences for patient survival and reflects a complex interplay of clinical, cognitive, and systemic factors.

Clinical Rationale for Treatment Intensification
Treatment Intensification, defined as the addition of an ARPI such as Abiraterone, Enzalutamide, Apalutamide, or Darolutamide, and/or Docetaxel chemotherapy to Androgen Deprivation Therapy (ADT), is supported by robust evidence from multiple Phase 3 clinical trials. These trials have demonstrated consistent Overall Survival (OS) benefits across broad patient populations with mCSPC. Median OS has improved from under three years in the pre-Treatment Intensification era to 50–60 months with modern combination approaches. As a result, major guidelines including NCCN, ASCO, and the American Urological Association now uniformly endorse Treatment Intensification as the standard of care for men with mCSPC who can tolerate it.

Real-World Underutilization of Treatment Intensification (TI)
Nevertheless, studies repeatedly show that Treatment Intensification remains underutilized in clinical practice. A recent analysis of 617 US patients with mCSPC, derived from the Adelphi Real World (ARW) of 107 US-based physicians, spanning July 2018 to January 2022, found that 69.7% of patients did not receive Treatment Intensification as initial therapy. Notably, this underuse persisted despite the availability of FDA-approved therapies and updates to treatment guidelines during this timeframe.

Similar trends have been observed in claims-based studies and physician-reported treatment patterns. A 2020 global survey revealed that 47% of patients worldwide and 36% in the U.S. did not receive Treatment Intensification. Concerningly, physician rationales often involved misinterpretations of the guidelines or concerns about treatment-related toxicity, even though trials have shown that Treatment Intensification maintains, and in some cases improves Quality of Life (QoL).

Key Findings from the ARW Survey
Physicians participating in the ARW study included medical oncologists (60.7%) and urologists (39.3%), mostly practicing in community settings. Of the 617 patients, 24.8% were African American, 8.1% were Hispanic or Latino, 58.0% were White or Caucasian, and 9.1% were of other race or ethnicity. Of note:

  • Tolerability and Guidelines were top-cited reasons for both prescribing and omitting Treatment Intensification (TI).
    • 64.7% of those prescribing TI cited favorable tolerability.
    • 58.6% of those avoiding TI cited tolerability concerns.
    • Similarly, guideline adherence was cited by 61.5% of TI users and 53.5% of non-TI users, revealing considerable guideline misinterpretation.
  • Disease burden influenced TI use. Patients with higher PSA levels, Gleason grade, and high-volume disease were more likely to receive TI. For instance:
    • PSA ≥75% reduction goals were associated with increased TI use (OR = 1.63).
    • High PSA levels were a driver for 39% of TI prescribers vs. 18.4% of non-TI prescribers (P < .001).
  • Guideline awareness was a significant predictor. Physicians who explicitly cited guidelines were more than three times as likely to prescribe TI (OR = 3.46; P = .01).
  • Misconceptions persist. Among patients who did not receive ARPIs, 31.4% of physicians cited a lack of perceived clinical trial evidence supporting survival benefits, despite level-one data to the contrary.
  • PSA targets may be misaligned. Many physicians aim for a 50% PSA reduction or PSA levels around 2.0 ng/mL, far above the <0.2 ng/mL level retrospectively linked to better outcomes. This disconnect may influence decision-making and undervalue the full benefits of TI.
  • Treatment access and Reimbursement. The physicians reported that only 4.9% of patients were not prescribed the treatment due to insurance coverage limitations. This suggests that access to the treatment, based on insurance, is not a major barrier to treatment.

Barriers beyond Clinical Characteristics
Contrary to initial hypotheses, access and reimbursement were infrequently cited as barriers. Only 4.9% of physicians indicated that insurance coverage prevented Treatment Intensification use. Furthermore, treatment decisions were rarely driven by patient preferences or behavior. Instead, the dominant theme is knowledge gaps in guideline familiarity, evidence interpretation, and understanding of Treatment Intensification’s impact on QoL and toxicity. Many physicians appear to base decisions on outdated assumptions or incomplete reading of the literature.

Toward Better Implementation: The Role of Education
Researchers argue that continued education for both clinicians and patients is essential. Oncologists often treat multiple malignancies and may struggle to stay current. Urologists, who balance surgical and medical roles, face similar constraints. Accessible continuing medical education (CME) programs and direct patient education may help address this disconnect.

Encouragingly, recent data from the Flatiron Health EHR database suggest progress. As of early 2025, 76.8% of patients treated in large academic and community oncology centers were receiving Treatment Intensification. However, questions remain about uptake in smaller or more rural practices.

Conclusion and Call to Action
This study reinforces the importance of bridging the gap between evidence and practice. Although Treatment Intensification in mCSPC is backed by compelling evidence and endorsed by all major guidelines, many patients continue to receive suboptimal therapy due to misconceptions and outdated practice patterns.

Key takeaways for clinicians:

  • Treatment Intensification is the standard of care in eligible patients with mCSPC, across disease volumes and PSA levels.
  • Clinical trials consistently show Treatment Intensification improves OS without compromising QoL.
  • Misinterpretation of guidelines and concerns over tolerability remain major barriers.
  • Improved education and dissemination of trial data are critical to closing the gap.

Addressing these issues is essential to ensure all patients with mCSPC receive life-prolonging therapies in line with current evidence and best practice.

Physician Reasons for or Against Treatment Intensification in Patients With Metastatic Prostate Cancer. Agarwal N, George DJ, Klaassen Z, et al. JAMA Netw Open. 2024;7(12):e2448707. doi:10.1001/jamanetworkopen.2024.48707