Category: Precision Oncology

Reassessing the Role of Carboplatin in Neoadjuvant Therapy for HER2-Positive Breast Cancer: Insights from the neoCARHP Trial

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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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Human epidermal growth factor receptor 2–positive (HER2+) breast cancer accounts for approximately 15%–20% of all breast malignancies and historically has been associated with aggressive disease biology. Over the past decade, the integration of dual HER2 blockade with Trastuzumab (HERCEPTIN®) and Pertuzumab (PERJETA®) alongside cytotoxic chemotherapy has substantially improved outcomes. In patients with Stage II–III disease, neoadjuvant therapy has become the standard treatment approach, enabling early assessment of treatment response and guiding postoperative therapy.

The combination of a Taxane, Carboplatin, Trastuzumab, and Pertuzumab (TCbHP) is widely endorsed by treatment guidelines as a preferred neoadjuvant regimen. However, the inclusion of Carboplatin, originally incorporated as an anthracycline-sparing strategy to mitigate cardiotoxicity, remains a subject of ongoing debate. While platinum agents may enhance antitumor activity through DNA-damaging mechanisms and potential synergy with HER2-targeted therapy, Carboplatin is also associated with increased hematologic and gastrointestinal toxicities that frequently necessitate dose reductions or treatment interruptions.

Several earlier studies have questioned the incremental benefit of Carboplatin in HER2-positive disease. Trials in both metastatic and early-stage settings have suggested that the addition of platinum compounds may not significantly improve response outcomes, while contributing to higher rates of treatment-related toxicity. At the same time, multiple investigations evaluating chemotherapy de-escalation strategies have demonstrated promising activity with taxane-based regimens combined with dual HER2 blockade alone.

Against this evolving backdrop, the Phase III neoCARHP study sought to determine whether Carboplatin could be safely omitted from neoadjuvant therapy without compromising efficacy.

Study Design and Treatment Approach

The neoCARHP trial was a multicenter, open-label, randomized Phase III noninferiority study, conducted across 15 institutions. The study enrolled women aged 18 years or older with previously untreated Stage II or III HER2-positive invasive breast cancer. Patients with metastatic disease, inflammatory breast cancer, bilateral tumors, or prior systemic therapy for breast cancer were excluded.

Participants were randomly assigned in a 1:1 ratio to receive six cycles of either the standard TCbHP regimen or a Carboplatin-free regimen consisting of a Taxane plus Trastuzumab and Pertuzumab (THP). Taxane selection, including Docetaxel, Paclitaxel, or nab-Paclitaxel, was left to investigator discretion. Importantly, Docetaxel dosing differed between arms, with a higher dose used in the THP arm to maintain treatment intensity in the absence of Carboplatin.

All patients received Trastuzumab and Pertuzumab every three weeks. Surgery was scheduled within six weeks following completion of neoadjuvant therapy. Postoperative treatment followed standard guidelines: patients achieving a pathologic Complete Response (pCR) typically continued Trastuzumab with or without Pertuzumab to complete one year of HER2-targeted therapy, while those with residual disease were eligible to receive adjuvant Trastuzumab emtansine (KADCYLA®).

Between April 2021 and August 2024, 774 patients were randomized, and 766 who received at least one dose of study therapy were included in the efficacy analysis. Baseline characteristics were well balanced between the treatment arms, with most patients presenting with Stage II disease and approximately one-third being node-negative.

The Primary endpoint of the trial was the rate of pathologic Complete Response in the breast and axilla (ypT0/is ypN0) in the modified intention-to-treat population.

Efficacy Outcomes

Pathologic Complete Response was achieved in 64.1% of patients treated with the Carboplatin-free THP regimen compared with 65.9% in the TCbHP group. The absolute difference of –1.8% fell well within the prespecified noninferiority margin, confirming that THP was statistically noninferior to the standard Carboplatin-containing regimen.

Per-protocol analyses yielded nearly identical results, with both treatment groups demonstrating a pCR rate of 68.5%. Importantly, subgroup analyses showed consistent outcomes across clinically relevant populations, including both Hormone Receptor–positive and Hormone Receptor–negative disease. Among patients with Hormone Receptor–negative tumors, pCR rates approached 78% in both treatment arms.

Safety and Tolerability

A key finding of the neoCARHP study was the improved safety profile associated with the Carboplatin-free regimen. Grade 3 or 4 adverse events occurred in 20.7% of patients receiving THP compared with 34.6% in those treated with TCbHP. Serious adverse events were also less frequent in the THP arm (1.3% vs 4.7%).

Hematologic toxicities were notably reduced with Carboplatin omission. Rates of neutropenia and leukopenia were significantly lower in the THP group, and gastrointestinal toxicities such as diarrhea occurred less frequently. Overall toxicity rates were similar between groups, but the majority of events were low grade. No treatment-related deaths were reported.

These findings suggest that eliminating Carboplatin may substantially reduce treatment-related morbidity while preserving efficacy.

Clinical Context and Emerging Evidence

The results of neoCARHP align with a growing body of evidence supporting chemotherapy de-escalation strategies in HER2-positive breast cancer. Multiple prior trials, including NeoSphere, WSG-ADAPT, COMPASS-HER2-pCR, and DAPHNe, have demonstrated that taxane-based regimens combined with dual HER2 blockade can achieve high pCR rates, particularly in Hormone Receptor–negative tumors.

Collectively, these studies suggest that approximately half of patients with Stage II–III HER2-positive breast cancer may achieve pCR after four cycles of THP, with response rates exceeding 60% after six cycles. For patients with Hormone Receptor–negative disease, pCR rates may approach 80%. Importantly, omitting Carboplatin appears to improve tolerability without compromising early efficacy outcomes, raising the possibility that selected patients with low- or intermediate-risk disease may safely receive less intensive chemotherapy.

Future Directions and Biomarker-Guided Treatment

Despite these encouraging results, several important questions remain. Long-term outcomes, including Event-Free Survival, invasive Disease–Free Survival, and Overall Survival, are still maturing in the neoCARHP trial. Because pCR is not universally validated as a surrogate for survival across all breast cancer subtypes, extended follow-up will be critical to confirm the durability of these findings.

Advances in biomarker-driven treatment selection may also play a key role in refining neoadjuvant strategies. Emerging tools such as PET-guided response assessment, genomic assays like HER2DX, and intrinsic subtype classification may help identify patients most likely to benefit from treatment de-escalation while ensuring that higher-risk individuals continue to receive optimal therapy.

Meanwhile, antibody–drug conjugates are rapidly entering the early-stage setting and could further reshape treatment paradigms. Agents such as Trastuzumab deruxtecan (ENHERTU®) are currently being investigated in neoadjuvant and adjuvant trials and may eventually offer additional Carboplatin-free therapeutic options.

Clinical Takeaway

The Phase III neoCARHP trial demonstrates that a neoadjuvant regimen consisting of a taxane combined with Trastuzumab and Pertuzumab achieves pathologic Complete Response rates comparable to the standard TCbHP regimen while significantly reducing high-grade toxicities.

These findings support the potential omission of Carboplatin in selected patients with Stage II–III HER2-positive breast cancer and represent another step toward individualized, toxicity-conscious treatment strategies in early HER2-positive disease.

Neoadjuvant Taxane Plus Trastuzumab and Pertuzumab With or Without Carboplatin in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: The Randomized Noninferiority Phase III neoCARHP Trial. Gao H-F, Ye G-L, Lin Y, et al. J Clin Oncol. DOI: 10.1200/JCO-25-02176

Expanding Targeted First-Line Options in BRAF V600E–Mutant Metastatic Colorectal Cancer: Insights From the BREAKWATER 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 158,850 new cases of CRC will be diagnosed in the United States in 2026 and about 55,230 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.

Metastatic colorectal cancer (mCRC) harboring the BRAF V600E mutation represents a biologically aggressive subtype associated with poor prognosis, higher rate of peritoneal metastasis, and historically limited responsiveness to conventional chemotherapy. Approximately 8% to 12% of patients with mCRC carry this mutation, and outcomes with traditional first-line regimens have been suboptimal. 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.

The global Phase III BREAKWATER trial was designed to evaluate whether combining targeted agents with standard chemotherapy could improve outcomes for patients with previously untreated BRAF V600E–mutant mCRC. Earlier analyses from the study demonstrated that the combination of Encorafenib and Cetuximab with modified FOLFOX6 (mFOLFOX6) significantly improved Response Rates and Progression-Free Survival compared with chemotherapy with or without Bevacizumab. These findings ultimately led to accelerated FDA approval in December 2024 for the targeted triplet regimen in the first-line setting.

However, Oxaliplatin-based therapy is not suitable for all patients. Cumulative exposure to Oxaliplatin is frequently associated with peripheral neuropathy, prompting clinicians to consider Irinotecan-based regimens such as FOLFIRI as an alternative chemotherapy backbone in the first-line setting. It is estimated that 20% to 25% of patients with newly diagnosed BRAF V600E–mutant mCRC receive FOLFIRI as part of their initial treatment strategy. To address this clinical reality, investigators expanded the BREAKWATER trial to evaluate whether targeted therapy could also enhance outcomes when combined with Irinotecan-based chemotherapy.

Study Design and Patient Population

Cohort 3 of the BREAKWATER study specifically examined the combination of Encorafenib plus Cetuximab with FOLFIRI, compared with FOLFIRI with or without Bevacizumab, representing standard care in this setting. Eligible patients had previously untreated BRAF V600E–mutant mCRC, measurable disease according to RECIST 1.1 criteria, and an ECOG Performance Status of 0 or 1.

A total of 147 patients were randomized in a 1:1 ratio to receive either the targeted therapy combination plus FOLFIRI (N=73) or the control regimen (N=74). Baseline characteristics were balanced between treatment arms, with a median patient age of 62 years, 46% male, and 60% with ECOG performance status 0. The Primary endpoint was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review, while Progression-Free Survival (PFS) served as the key Secondary endpoint. Additional endpoints included Overall Survival (OS), Duration of Response (DOR), Time To Response (TTR), and Safety.

Significant Improvement in Objective Response Rate

At the time of the March 1, 2025 data cutoff, the combination of Encorafenib, Cetuximab, and FOLFIRI demonstrated a clinically meaningful and statistically significant improvement in confirmed Objective Response Rate compared with the control regimen.

The confirmed ORR reached 64.4% with the targeted therapy combination, compared with 39.2% in the control arm, corresponding to an odds ratio of 2.76 (P=0.0011). Responses included Complete Responses in 4.1% of patients receiving the targeted regimen versus 1.4% in the control group, while Partial Responses occurred in 60.3% and 37.8% of patients, respectively.

Importantly, the responses observed with the targeted regimen were rapid and durable. The median time to response was similar between groups, occurring at approximately 6.9 weeks with Encorafenib plus Cetuximab and FOLFIRI and 7.1 weeks with the control regimen. Although the median Duration of Response had not yet been reached in either group, a greater proportion of patients receiving the targeted combination experienced sustained responses lasting at least six months (57.4% vs 34.5%). Responses lasting 12 months or longer were observed only in the experimental arm.

Clinical benefit with the targeted regimen was consistent across prespecified patient subgroups, further supporting the robustness of the treatment effect.

Early Signals for Survival Benefit

While Overall Survival data remain immature, early findings suggest a potential survival advantage with the targeted regimen. At the time of analysis, 15.1% of patients in the Encorafenib–Cetuximab–FOLFIRI group had died, compared with 27.0% in the control arm, translating to a hazard ratio of 0.49. Longer follow-up will be required to confirm the durability of this emerging survival signal.

Treatment exposure also favored the experimental arm. Nearly 70% of patients receiving the targeted regimen remained on treatment, compared with approximately one-third of patients in the control group, with a median treatment duration of 9.9 months versus 7.4 months, respectively.

Manageable Safety Profile

The safety profile of the triplet regimen was consistent with the known effects of each agent, and the addition of Encorafenib and Cetuximab did not substantially compromise treatment tolerability. The most frequently reported adverse events with the combination regimen included nausea, diarrhea, and vomiting. Serious treatment-emergent adverse events occurred in 39.4% of patients in the experimental arm vs 36.8% in the control arm. Importantly, the incorporation of targeted therapy did not lead to a meaningful increase in chemotherapy discontinuation, with FOLFIRI discontinuation rates of 9.9% in the experimental arm versus 8.8% in the control group. Investigators also reported no new safety signals, reinforcing the feasibility of combining targeted therapy with an Irinotecan-based chemotherapy backbone.

Clinical Implications

The results from BREAKWATER Cohort 3, build on the earlier success of Encorafenib and Cetuximab combined with Oxaliplatin-based chemotherapy, and provide important new insights for clinical practice. For patients who may not be optimal candidates for Oxaliplatin due to concerns such as cumulative neurotoxicity, the Encorafenib–Cetuximab–FOLFIRI regimen represents a compelling alternative.

Taken together, the findings support the growing role of targeted therapy- based combinations in the first-line treatment of BRAF V600E–mutant mCRC, offering both improved response rates and the potential for durable disease control.

Looking Ahead

The BREAKWATER trial remains ongoing, and continued follow-up will clarify the long-term durability of responses and the ultimate impact on Overall Survival. Nonetheless, the current analysis highlights the expanding therapeutic landscape for patients with this challenging molecular subtype of colorectal cancer.

If confirmed with longer follow-up, the combination of Encorafenib, Cetuximab, and FOLFIRI may emerge as another frontline standard-of-care option, providing clinicians with greater flexibility to tailor treatment strategies based on patient characteristics and toxicity considerations.

BREAKWATER: Primary analysis of first-line encorafenib + cetuximab + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer. Kopetz S, Wasan HS, Yoshino T, et al: 2026 ASCO GI Cancers Symposium. J Clin Oncol 44, 2026 (suppl 2; abstr 13)

FDA Approves First Line HERNEXEOS® for HER2-mutant Advanced NSCLC

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SUMMARY: The FDA on February 26, 2026, granted accelerated approval to Zongertinib (HERNEXEOS®), a kinase inhibitor, for an expanded indication for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations, as detected by an FDA-authorized test.

The American Cancer Society estimates that for 2026, about 229,410 new cases of lung cancer will be diagnosed and 124,990 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

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

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

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

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

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

The Phase 1b portion is an ongoing study of Zongertinib in three key Cohorts (Cohort 1, 2 and 5) and three exploratory Cohorts (Cohorts 3, 4 and 6)

  • Cohort 1: Pretreated NSCLC patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
  • Cohort 2: Treatment-naïve NSCLC with HER2 TKD mutation
  • Cohort 3: NSCLC patients whose tumor had HER2 mutations outside the TKD or HER2 TKD mutation-positive squamous NSCLC, pretreated
  • Cohort 4: NSCLC with active brain metastases with a HER2 TKD mutation
  • Cohort 5: NSCLC patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
  • Cohort 6: NSCLC patients with HER2 TKD mutation and prior systemic treatment including HER2-directed ADCs.

(Some reports define Cohort 5 as the post-ADC cohort. However, clinical trial documentation indicates Cohort 6 specifically addresses the requirement for previous HER2-directed ADC treatment in specific phases of the study)

Cohorts 3, 4 and 6 are exploratory

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance.

The FDA in August 2025, granted accelerated approval to Zongertinib, for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations and who have received prior systemic therapy. This was based on Objective Response Rate (ORR) and Duration of Response (DOR). This cohort study also suggested that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

The present accelerated approval was based on the efficacy of Zongertinib in unresectable or metastatic, non-squamous NSCLC with HER2 TKD mutation, who had not received systemic therapy for advanced disease (Cohort 2). The efficacy analysis included 72 patients (N=72) and the major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) as determined by Blinded Independent Central Review (BICR)

The ORR was 76%, with Complete Response seen in 11% and Partial Response noted in 65% of patients. Sixty four percent (64%) of responders had a DOR of 6 months or more and 44% had a DOR of 12 months or more. The researchers added that the present efficacy reinforces the existing efficacy data for Zongertinib in previously treated NSCLC tumors with HER2  TKD activating mutations.

Safety and Tolerability

In a pooled safety population, which included 292 patients with HER2-mutant NSCLC, both treatment-naïve and previously treated, the most common adverse reactions were diarrhea (54%), rash (27%), hepatotoxicity (26%), fatigue (25%), nausea (23%), and musculoskeletal pain (21%), and upper respiratory tract infection (20%). No cases of drug-related interstitial lung disease were observed. The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions

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

Conclusion

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

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-unresectable-or-metastatic-non-squamous-non-small-cell

 

Expert Perspectives on MRD Testing in Multiple Myeloma

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Learn how leading oncologists use MRD to inform treatment strategy and predict relapse risk

Written by: Dr. Gary Simmons & Dr. Kashif Ali
This educational opportunity is sponsored by Adaptive Biotechnologies

Measurable residual disease (MRD) testing has become a valuable tool across the multiple myeloma disease continuum, offering unprecedented insight into disease burden, treatment response, and relapse risk.  NCCN guidelines define MRD negativity as the absence of clonal plasma cells by next generation flow cytometry or next generation sequencing (NGS), at a sensitivity of at least 1 in 10-5 cells, and recommend assessing MRD status after induction, post-transplant, post-consolidation and during maintenance therapy.1  MRD results are shaping key decisions ranging from the role and timing of autologous stem cell transplant to strategies for monitoring and treatment adjustment.  Notably, MRD may be measured from bone marrow or peripheral blood, with data indicating that blood-based testing complements – but does not replace – bone marrow-based testing.2  In this dual-perspective Thought Leader Article, Dr. Gary Simmons (Virginia Oncology Associates) explores how MRD guides transplant decision-making, and Dr. Kashif Ali (Maryland Oncology Hematology) examines the value of blood-based MRD in monitoring response and predicting relapse in multiple myeloma.

The Role of MRD in Informing Autologous Stem Cell Transplant Decision-Making

Despite remarkable advances in multiple myeloma therapy, autologous stem cell transplant still plays a role in the treatment of many patients.  Traditionally, clinical decision-making around transplant was limited to weighing patient-specific factors such as age, comorbidities, and the limited methods that existed to gauge response to induction therapy.  MRD testing provides unprecedented, personalized insight into the induction response achieved by each patient, which directly influences the decision of whether to follow up with transplant.  MRD does not diminish the value of transplant but is rather a stratification tool to identify patients who would derive additional benefit from transplant, from those for which monitoring would suffice.  Several clinical trials including Determination, Perseus and GMMG-HD7 have demonstrated that transplant increases achievement and duration of MRD negativity.3,4,5 Thus, there is a bi-directional relationship in which MRD negativity supports the therapeutic value of transplant, and MRD results help to ensure that patients receive the minimal level of treatment required to achieve optimal outcomes.

In my practice, I evaluate MRD status alongside several variables including patient age, comorbidities, and standard- vs high-risk cytogenetics per the International Myeloma Working Group, when deciding on upfront vs deferred vs no transplant following induction therapy.  In many cases, patient-specific factors significantly influence the weight of MRD results in guiding transplant decision-making.  Notable among these is patient age.  I tend to recommend transplant in young patients, even those who are MRD negative, given data showing a substantially increased disease-free survival6 and improved clinical outcomes in younger fit patients.7  Conversely, there are populations in which MRD negativity would lead me to defer upfront transplant, especially in patients demanding a conservative approach, such as those greater than 75-years-old and/or those with significant comorbidities.  In these patients, MRD negativity often leads me to delay transplant, with the understanding that if/when the patient relapses, there are alternative treatment options to pursue, such as CAR T-cell therapy.  In general, I encourage most standard-risk myeloma patients that if they are MRD negative over the next 5 years, the disease-free is similar with or without transplant; that is encouraging to patients.

As myeloma testing and treatment options rapidly evolve, it’s increasingly important to stay abreast of the gold standard MRD testing options and latest clinical guidelines, to ensure optimal patient outcomes.  We’re always reviewing the options and the depth of MRD testing in our myeloma patients.  At this point, I tend to exclusively use the clonoSEQ assay, as it has a depth of 1×10-6 cells.  We know that depth of MRD and duration of MRD are related to improved clinical outcomes.  Therefore, despite the clinical trials using a MRD cutoff of 1×10-5 cells, we prefer the increased sensitivity offered by clonoSEQ of 1×10-6, for optimal assurance that negativity accurately identifies patients who are truly “MRD negative”.  While this piece is focused on the value of MRD in guiding transplant decisions, it’s worth nothing that assay depth and sensitivity also come to be very important post-stem cell transplant – as MRD negativity after a few years of maintenance can be used to determine if patients can stop maintenance therapy.  In the MASTER trial, MRD status and cytogenetics could predict risk of relapse in two years, highlighting the utility of MRD to help guide continuing maintenance or identify patients who may be able to stop.8 Altogether, these insights underscore how MRD drives personalized care from transplant decision-making to maintenance, ensuring optimal outcomes for patients with multiple myeloma.

The Role of Peripheral Blood-Based MRD Assessment in Monitoring Disease Response

While bone marrow evaluation remains the standard method for MRD assessment, peripheral blood-based MRD testing is an increasingly valuable approach for guiding treatment decisions and monitoring response in multiple myeloma.  MRD negativity by both peripheral blood and bone marrow is associated with an improved progression-free survival (PFS) compared to one modality alone, underscoring their complementary nature.2 Notably, peripheral blood MRD positivity has a 100% positive predictive value of bone marrow MRD positivity.10  Understandably, the negative predictive value of peripheral blood MRD is lower, demonstrating that peripheral blood MRD negativity does not exclude bone marrow disease.11 Therefore, in my practice, blood-based MRD positivity does not prompt confirmatory bone marrow testing, whereas blood-based MRD negativity should be confirmed by bone marrow biopsy, if the goal is to alter treatment.

Confidence in blood-based MRD results is influenced by several factors, including myeloma disease biology and timing.  Patients who present with circulating plasma cells at diagnosis have more aggressive disease and worse outcomes.12,13,14 In the post-transplant setting, studies have shown that patients negative for circulating DNA at three months post-transplant had significantly better PFS (84 vs 31 months) with a positive predictive value of 93.3%.15,16 Those who achieve a complete response will have no detectable plasma cells, as opposed to those who have a relapse, and blood-based MRD testing opens the door to uncover previously undetectable levels of circulating plasma cells.  There are also situations, such as patients with patchy bone marrow involvement or extramedullary disease17, in which MRD assessment of blood is more informative and bone marrow testing alone would be insufficient.18

Timing is another important consideration.  The concordance between bone marrow and blood-based MRD is lowest early after transplant and increases with time, suggesting enhanced reliability of peripheral blood MRD during maintenance.19 Peripheral blood MRD is well suited for longitudinal monitoring post-induction, post-transplant, and especially during maintenance in situations where repeated bone marrow biopsies would not be feasible.10,20 I routinely incorporate peripheral blood MRD testing at these timepoints and find it to be a less invasive alternative that enables more frequent assessment of patients who are reluctant to undergo repeat bone marrow biopsies.20,21 When the goal is to continue maintenance treatment, I utilize serial peripheral blood MRD testing and myeloma-related lab tests.  In these scenarios, I would only check a bone marrow biopsy if the goal were to discontinue or de-escalate treatment.  In the case of a blood-based MRD positivity, given the high concordance between peripheral blood and bone marrow, I would not mandate that an unwilling patient also undergo bone marrow-based MRD.  In my practice and outside of a clinical trial, most patients with blood-based MRD positivity, after hearing about data on concordance, decide not to undergo bone marrow confirmation although I do offer it to them.  Together, the expanding clinical utility of MRD assessment by blood and bone marrow underscores its value for guiding treatment decisions, monitoring response and prognosticating outcomes in multiple myeloma.

References:

  1. National Comprehensive Cancer Network. Multiple Myeloma. Updated 2025-11-26.
  2. Langerhorst P, Noori S, Zajec M, et al. Multiple Myeloma Minimal Residual Disease Detection: Targeted Mass Spectrometry in Blood vs Next-Generation Sequencing in Bone Marrow. Clinical Chemistry.  2021;67(12):1689-1698.  doi:10.1093/clinchem/hvab187.
  3. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.  The New England Journal of Medicine.  2022;387(2):132–147. doi:10.1056/NEJMoa2204925.
  4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. The New England Journal of Medicine.  2024;390(4):301-313.   doi:10.1056/NEJMoa2312054.
  5. Goldschmidt H, Bertch U, Pozek E, et al. Isatuximab, Lenalidomide, Bortezomib and Dexamethasone Induction Therapy for Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma: Final Progression-Free Survival Analysis of Part 1 of an Open-Label, Multicenter, Randomized, Phase 3 Trial (GMMG-HD7). Blood.  2024;144(Supplement 1): 769.  doi: https://doi.org/10.1182/blood-2024-193308.
  6. Ebraheem M, Kumar SK, Dispenzieri A, et al. Deepening Responses after Upfront Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction Therapy. Transplant Cell Ther.  2022;28(11):760.e1-760.e5.  doi:10.1016/j.jtct.2022.07.030.
  7. Liu J, Yan W, Fan H, et al. Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment. Cancer Res Commun.  2023;3(9):1770-1780.  doi:10.1158/2767-9764.CRC-23-0185.
  8. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol.  2022;40(25):2901-2912.  doi:10.1200/JCO.21.01935.
  9. Terpos E, Malandrakis P, Ntanasis-Stathopoulos I, et al. Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post-ASCT in myeloma. Blood.  2025;145(20):2353-2360.  doi:10.1182/blood.2024027686.
  10. Lasa M, Notarfranchi L, Agullo C, et al. Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma. J Clin Oncol.  2025;43(2):125-132.  doi:10.1200/JCO.24.00635.
  11. Chandhok NS, Sekeres MA. Measurable residual disease in hematologic malignancies: a biomarker in search of a standard. EClinicalMedicine.  2025;86:103348.  doi:10.1016/j.eclinm.2025.103348.
  12. Bertamini L, Oliva S, Rota-Scalabrini D, et al. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol.  2022;40(27):3120-3131.  doi:10.1200/JCO.21.01393.
  13. Li Q, Ai L, Zuo L, et al. Circulating plasma cells as a predictive biomarker in Multiple myeloma: an updated systematic review and meta-analysis. Ann Med.  2024;56(1):2338604.  doi:10.1080/07853890.2024.2338604.
  14. Li J, Wang N, Tesfaluul N, Gao X, Liu S, Yue B. Prognostic value of circulating plasma cells in patients with multiple myeloma: A meta-analysis. PLoS One.  2017;12(7):e0181447.  doi:10.1371/journal.pone.0181447.
  15. Dhakal B, Sharma S, Balcioglu M, et al. Assessment of Molecular Residual Disease Using Circulating Tumor DNA to Identify Multiple Myeloma Patients at High Risk of Relapse. Frontiers in Oncology.  2022;12:786451.  doi:10.3389/fonc.2022.786451.
  16. Dhakal B, Sharma S, Shchegrova S, et al. Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma. Journal of Clinical Oncology.  2021;39(Suppl 15):8029.  doi:10.1200/JCO.2021.39.15_suppl.8029.
  17. van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet.  2021;397(10272):410-427.  doi:10.1016/S0140-6736(21)00135-5.
  18. Manasanch EE. What to do with minimal residual disease testing in myeloma. Hematology Am Soc Hematol Educ Program.  2019;2019(1):137-141.  doi:10.1182/hematology.2019000080.
  19. Kubicki T, Dytfeld D, Barnidge D, et al. Mass spectrometry-based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma. Blood.  2024;144(9):955-963.  doi:10.1182/blood.2024024041.
  20. Wijnands C, Noori S, Donk NWCJV, VanDuijn MM, Jacobs JFM. Advances in minimal residual disease monitoring in multiple myeloma. Crit Rev Clin Lab Sci.  2023;60(7):518-534.  doi:10.1080/10408363.2023.2209652.
  21. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma. Lancet Oncology.  2016;17(8):e328-e346.  doi:10.1016/S1470-2045(16)30206-6.

Redefining First-Line Maintenance in HR-Positive, HER2-Positive 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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

Breast cancer remains a biologically heterogeneous disease, with approximately 70% of tumors expressing estrogen receptors (ER) and/or progesterone receptors (PR). Among patients with metastatic disease, Hormone Receptor (HR)–positive, HER2-negative tumors represent the most common subtype. However, 15%–20% of primary breast cancers overexpress HER2, a historically aggressive phenotype. Notably, more than half of HER2-positive tumors also coexpress hormone receptors, creating a biologically distinct subgroup characterized by signaling interplay between the HER2 and estrogen receptor pathways.

For patients with HR-positive, HER2-positive metastatic breast cancer, the current first-line standard consists of induction chemotherapy combined with dual HER2 blockade (Trastuzumab-HERCEPTIN® and Pertuzumab-PERJETA®), followed by maintenance HER2-targeted therapy plus endocrine therapy. While this approach has significantly improved outcomes, resistance remains inevitable for most patients. Preclinical data have consistently demonstrated bidirectional crosstalk between HER2 and ER signaling, as well as persistent activation of the cyclin D1–CDK4/6 axis, which may drive resistance to both endocrine and HER2-directed therapies. These mechanistic insights provided the scientific rationale for evaluating triple pathway inhibition, simultaneous targeting of HER2, ER, and CDK4/6 in this population.

Biological Rationale for CDK4/6 Inhibition

Cyclin-Dependent Kinases 4 and 6 (CDK4/6) regulate orderly progression from the G1 to S phase of the cell cycle through phosphorylation of the retinoblastoma (RB) protein. Aberrant activation of this pathway is implicated in tumor proliferation and therapeutic resistance across multiple breast cancer subtypes, including HER2-positive disease.

Palbociclib (IBRANCE®), an oral selective CDK4/6 inhibitor, suppresses RB phosphorylation and arrests cell-cycle progression. Preclinical HER2-positive models have demonstrated that sustained cyclin D1–CDK4/6 activity contributes to resistance to HER2-targeted therapies, and dual inhibition of CDK4/6 and HER2 has shown synergistic antitumor effects. Early-phase clinical studies further suggested that combining CDK4/6 inhibition with HER2-directed and endocrine therapy was feasible and potentially additive in efficacy. These findings led to the Phase 3 PATINA trial.

The PATINA Trial: Study Design

PATINA was an open-label, randomized Phase 3 study evaluating whether adding Palbociclib to maintenance therapy could extend disease control in patients with HR-positive, HER2-positive metastatic breast cancer.

Eligibility and Treatment Approach

Patients were enrolled after completing 4 to 8 cycles of induction chemotherapy plus HER2-targeted therapy without disease progression. Key eligibility criteria included:

  • HR positivity (≥1% nuclear staining by IHC)
  • HER2 positivity (IHC 3+ or ISH amplification per ASCO/CAP guidelines)
  • No prior systemic therapy for metastatic disease beyond induction
  • A disease-free interval ≥6 months after prior adjuvant HER2 therapy

A total of 518 patients were randomized 1:1:

  • Palbociclib arm (n=261): Maintenance HER2-targeted therapy + endocrine therapy + Palbociclib (125 mg orally, 21 days on/7 days off; dose reductions permitted)
  • Standard arm (n=257): Maintenance HER2-targeted therapy + endocrine therapy

Baseline characteristics were balanced. The median age was 53.4 years; 99% were female; 61.8% were postmenopausal. Importantly, 54.4% had de novo metastatic disease. The Primary endpoint was investigator-assessed Progression-Free Survival (PFS). Secondary endpoints included Objective Response, clinical benefit, safety, and Overall Survival.

Efficacy Outcomes: A Meaningful Extension of Disease Control

At a median follow-up of 53.5 months, the addition of Palbociclib resulted in a statistically and clinically significant improvement in PFS. The median PFS was 44.3 months in the Palbociclib group and 29.1 months in the standard therapy group (HR=0.75; P=0.02). The estimated PFS rates favored the Palbociclib arm over standard therapy at all measured time points and was 84.9% versus 73.2% at 12 months, 65,2% versus 55.3% at 24 months, and 46.5% versus 38.3% at 48 months respectively.

The depth and durability of response were also enhanced:

  • Confirmed response rate: 32.9% vs. 24.8%
  • Complete response rate: 14.3% vs. 11.3%
  • Median duration of confirmed response: 44.9 vs. 30.8 months

Importantly, when the induction phase is included, total first-line disease control in the Palbociclib arm extended beyond four years. Early mortality was uncommon, with 6-month Overall Survival exceeding 99% in both groups, reflecting favorable biology among patients who completed induction therapy.

The control arm’s median PFS of 29 months exceeded initial projections, likely reflecting mandated endocrine therapy use and the exclusion of patients who progressed during induction, factors that enriched the study population for more favorable disease biology.

Safety Profile

The safety findings were consistent with known toxicities of Palbociclib and HER2-targeted therapies. Neutropenia was the predominant toxicity and febrile neutropenia was rare. Grade 3 and Grade 4 adverse events were 79.7% and 10% in the Palbociclib group versus 30.6% and 3.6% in the standard therapy group.

Clinical Implications

The PATINA trial supports a paradigm shift in the maintenance setting for HR-positive, HER2-positive metastatic breast cancer. By targeting HER2, Estrogen Receptor signaling, and CDK4/6-mediated cell-cycle progression concurrently, this strategy addresses key resistance mechanisms.

Achieving a median PFS exceeding 44 months represents a meaningful advance in a disease subtype historically associated with aggressive biology. While antibody–drug conjugates and other potent HER2-directed agents remain appropriate for selected high-risk patients, this chemotherapy-sparing maintenance intensification strategy provides durable disease control in a substantial proportion of patients.

The open-label design and limited racial diversity are important considerations. Additional analyses evaluating patient-reported outcomes, biomarker correlates, and central nervous system outcomes are ongoing and may further refine patient selection.

Conclusion

The addition of Palbociclib to maintenance anti-HER2 and endocrine therapy significantly prolongs Progression-Free Survival in patients with HR-positive, HER2-positive advanced breast cancer, albeit with increased, but manageable, hematologic toxicity. Triple pathway inhibition targeting HER2, estrogen receptor, and CDK4/6 signaling may now represent a compelling first-line maintenance strategy capable of extending disease control beyond four years in appropriately selected patients.

Palbociclib for Hormone-Receptor–Positive, HER2-Positive Advanced Breast Cancer. Metzger O, Mandrekar S, Goel S, et al. N Engl J Med 2026;394:451-462

Late Breaking Abstract – 2026 ASCO GI Symposium: Redefining First-Line Therapy in HER2-Positive Gastroesophageal Adenocarcinoma with Zanidatamab-Based Combinations

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SUMMARY: The American Cancer Society estimates that in the US, about 31,510 new cases of Gastric cancer will be diagnosed in 2026 and about 10,740 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 stomach 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.

Persistent Unmet Need in HER2-Positive Disease

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 20% of patients with GastroEsophageal Adenocarcinoma (GEA), encompassing gastric, gastroesophageal junction, and esophageal adenocarcinomas, harbor HER2-positive tumors. Despite the incorporation of HER2-directed therapy into first-line management more than a decade ago, long-term outcomes remain suboptimal. With Trastuzumab (HERCEPTIN®) plus chemotherapy, median Progression-Free Survival (PFS) has historically hovered around 10 months, and median Overall Survival (OS) around 20 months.

More recently, the addition of immune checkpoint inhibition has modestly improved outcomes in selected patients. Based on KEYNOTE-811, Pembrolizumab (KEYTRUDA®) plus Trastuzumab and chemotherapy is now standard for PD-L1–positive tumors. However, early relapse, often within the first year, remains common, underscoring the need for more effective HER2-targeted strategies.

Zanidatamab: A Next-Generation HER2-Targeted Approach

Preclinical and clinical data suggest greater antibody saturation on HER2-expressing tumor cells than with Trastuzumab or Pertuzumab (PERJETA®).

Zanidatamab (ZIIHERA®) is a novel, humanized IgG1 bispecific monoclonal antibody designed to bind two non-overlapping extracellular domains of HER2 (ECD2 and ECD4). This biparatopic binding leads to enhanced HER2 receptor clustering, internalization, and downregulation, resulting in more complete inhibition of HER2 signaling compared with single-epitope antibodies. Beyond direct signal blockade, Zanidatamab’s unique binding geometry promotes robust immune-mediated antitumor activity, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP).

Zanidatamab’s clinical momentum was reinforced by its FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive biliary tract cancer, highlighting the platform’s broader relevance across HER2-driven gastrointestinal malignancies.

Rationale for Combining HER2 Blockade and Immunotherapy

The HERIZON-GEA-01 trial also explored synergy between dual HER2 targeting and immune checkpoint inhibition. Tislelizumab (TEVIMBRA®), a humanized IgG4 anti-PD-1 monoclonal antibody, is engineered to minimize Fc-gamma receptor binding on macrophages, potentially reducing antibody-dependent clearance of activated T cells. Tislelizumab received FDA approval in March 2024 for previously treated metastatic esophageal Squamous Cell Carcinoma, supporting its activity in upper gastrointestinal cancers.

HERIZON-GEA-01: Trial Design and Patient Population

HERIZON-GEA-01 (NCT05152147) is a global, open-label, Phase III study evaluating Zanidatamab-based regimens versus standard Trastuzumab plus chemotherapy in the first-line setting for HER2-positive metastatic GEA (GastroEsophageal Adenocarcinoma).

A total of 914 patients with unresectable, locally advanced, recurrent, or metastatic disease were enrolled between December 2021 and February 2025. More than two-thirds had gastric primaries. Patients had received no prior systemic therapy, HER2-targeted therapy, or immunotherapy in this setting.

Participants were randomized 1:1:1 to:

  • Arm A: Trastuzumab plus chemotherapy
  • Arm B: Zanidatamab plus chemotherapy
  • Arm C: Zanidatamab plus Tislelizumab plus chemotherapy

CAPOX was the chemotherapy backbone in approximately 90% of patients. Zanidatamab-based regimens in Arm B and Arm C were compared with standard Trastuzumab plus chemotherapy in Arm A. The dual Primary endpoints were PFS by Blinded Independent Review and OS.

Efficacy Results: Clinically Meaningful and Practice-Changing

At the interim analysis (data cutoff October 2025; median follow-up 26 months), there was a clear and consistent improvement in Progression-Free Survival with Zanidatamab-based therapy compared with Trastuzumab plus chemotherapy. Median PFS reached 12.4 months with Zanidatamab plus chemotherapy and 12.4 months with Zanidatamab plus Tislelizumab and chemotherapy, compared with 8.1–8.2 months in the Trastuzumab control arm. These gains translated into a 35–37% reduction in the risk of disease progression or death, with Hazard Ratios of 0.65 for Zanidatamab plus chemotherapy and 0.63 for the triplet regimen (both P <0.0001). Importantly, the separation of the PFS curves was maintained over time, highlighting the durability of benefit. The 1-year PFS was 38.0% with Zanidatamab plus chemotherapy and 43.9% with the triplet, versus 20.9% and 38.2% respectively with Trastuzumab-based therapy. The 2-year PFS was 31.5% and 20.9%, respectively, compared with 15.6% in the Trastuzumab group. These findings mark the first time a majority of patients receiving first-line HER2-targeted therapy remain progression-free at one year, a notable advance in a disease historically characterized by early relapse.

Median OS improved from 19.2 months with Trastuzumab plus chemotherapy to 24.4 months with Zanidatamab plus chemotherapy and 26.4 months with Zanidatamab plus Tislelizumab and chemotherapy. The addition of Tislelizumab yielded a statistically significant 28% reduction in the risk of death (HR 0.72; P =0.0043). While OS data for Zanidatamab plus chemotherapy alone were not yet statistically significant at this interim analysis (HR 0.80; P =0.0564), the observed survival extension of more than five months suggests meaningful clinical activity, with further analyses planned as follow-up matures. The 2-year OS was 50.3% with Zanidatamab plus chemotherapy and 54.3% with the triplet, versus 42.2% and 43.8% respectively with Trastuzumab-based therapy. The 30-month OS was 38.8% and 43.8%, respectively, compared with 30.0% in the Trastuzumab group.

Notably, the triplet regimen is the first HER2-directed first-line strategy to achieve median Overall Survival exceeding two years in a randomized phase III trial. Further, the benefits in both PFS and OS were consistent across key subgroups, including geographic region and PD-L1 status, an especially notable finding given that checkpoint inhibitor benefit has traditionally been restricted to PD-L1–positive tumors.

Depth and Durability of Response

Zanidatamab-based regimens also produced deeper and more durable responses. Confirmed Objective Response Rates approached 70% in both Zanidatamab arms, with Complete Response rates nearing 20% when Tislelizumab was added. Median duration of response was particularly striking, exceeding 20 months with the triplet regimen and substantially longer than the 8-month duration observed with Trastuzumab plus chemotherapy.

Safety and Tolerability

The safety profiles of Zanidatamab and Tislelizumab were consistent with their known toxicities. Grade ≥3 treatment-related adverse events occurred in approximately 59% of patients receiving Zanidatamab plus chemotherapy and 72% with the addition of Tislelizumab, compared with 60% in the Trastuzumab arm.

Diarrhea was the most common toxicity across all arms, typically occurring early and resolving within several weeks. Rates of HER2-targeted therapy discontinuation due to adverse events were higher with Zanidatamab-based regimens but remained manageable, with no new safety signals identified.

Clinical Implications and Future Directions

HERIZON-GEA-01 represents a landmark study in HER2-positive gastroesophageal adenocarcinoma. It is the first phase III trial to demonstrate superiority of a novel HER2-targeted agent over Trastuzumab in the first-line metastatic setting, and the first to achieve median PFS beyond one year and median OS beyond two years in this population.

While cross-trial comparisons should be interpreted cautiously, outcomes with Zanidatamab plus Tislelizumab and chemotherapy compare favorably with historical results from KEYNOTE-811. The observation of benefit irrespective of PD-L1 status further broadens the potential impact of this strategy.

As longer follow-up matures and guideline bodies evaluate these data, Zanidatamab, particularly in combination with immunotherapy appears poised to redefine the standard of care for HER2-positive metastatic gastroesophageal adenocarcinoma, offering patients a meaningful extension of disease control and survival.

Zanidatamab + chemotherapy ± tislelizumab for first-line HER2-positive locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma: Primary analysis from HERIZON-GEA-01. Elimova E, Rha SY, Shitara K, et al. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract LBA285. Presented January 8, 2026.

Reconsidering Menopausal Hormone Therapy in BRCA1/2 Carriers: Emerging Evidence Challenges Longstanding Concerns

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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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 women will die of the disease, largely due to metastatic recurrence.

The tumor suppressor genes such as BRCA1 and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation, and the deleterious effects of the mutations are seen even when a second copy of the gene in an individual is normal. Women with germline BRCA1 or BRCA2 mutations face markedly elevated lifetime risks of breast cancer, estimated at up to 70%. More than half of these cancers occur before the age of 50, underscoring the importance of informed counseling regarding risk-modifying exposures. 

For much of the latter half of the 20th century, Hormone Replacement Therapy (HRT) was widely prescribed to alleviate menopausal symptoms and protect against long-term complications such as osteoporosis. This practice shifted dramatically in 2002, when the Women’s Health Initiative reported increased risks of cardiovascular events and breast cancer associated with hormone therapy in older, postmenopausal women. In the aftermath, both patients and clinicians largely retreated from Menopausal Hormone Therapy (MHT), and its use declined sharply.

While those findings reshaped care in the general population, their applicability to women with hereditary cancer predisposition, particularly carriers of pathogenic BRCA1 or BRCA2 variants, has remained uncertain. These women face markedly elevated risks of ovarian and fallopian tube cancers and are therefore advised to undergo risk-reducing bilateral salpingo-oophorectomy at relatively young ages. The procedure is effective for cancer prevention but induces abrupt surgical menopause, often decades earlier than natural menopause, with well-documented short- and long-term consequences including vasomotor symptoms, sexual dysfunction, bone loss, and adverse cardiovascular and cognitive effects.

Menopausal Hormone Therapy (MHT) is the most effective intervention for mitigating these outcomes of early menopause. However, concerns that hormone exposure could further increase breast cancer risk in BRCA carriers have led to substantial hesitation, misinformation, and, in many cases, prolonged untreated symptoms. Researchers have emphasized, recommending premenopausal oophorectomy without offering a safe strategy to manage its consequences creates an untenable clinical dilemma.

Study Design: Emulating a Trial in a High-Risk Population

To address this evidence gap, investigators conducted the largest prospective matched analysis to date examining MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Using data from a longitudinal cohort, the study sought to emulate a randomized clinical trial by carefully matching women who initiated MHT after menopause, predominantly surgical menopause, to those who did not.

Eligible participants had no prior cancer history, no bilateral mastectomy, and had entered menopause. A total of 676 matched pairs were created, matched one-to-one by gene mutation (BRCA1 or BRCA2), year of birth, and age at menopause. Participants ranged in age from 22 to 76 years, with a mean age of 43.8 years. MHT formulations initiated after menopause included estrogen-only therapy, combined estrogen–progestogen therapy, progestogen alone, tibolone, and conjugated equine estrogen plus bazedoxifene. Cox proportional hazards models were used to estimate breast cancer risk.

Results: No Signal of Increased Breast Cancer Risk

After a mean follow-up of 5.6 years from the date of first MHT use, breast cancer incidence was significantly lower among women who used MHT compared with their matched, unexposed counterparts. Incident breast cancer occurred in 12.9% of MHT users versus 18.9% of non-users (P = 0.002).

Notably, estrogen-only therapy was associated with a substantial reduction in breast cancer risk, corresponding to a 63% relative decrease compared with non-users. In contrast, no increased or decreased risk was observed with combined estrogen–progestogen therapy, progestogen monotherapy, or tibolone. Among the 43 women who received conjugated equine estrogen plus bazedoxifene, no breast cancer diagnoses were reported during follow-up, an exploratory finding that warrants further investigation. Importantly, risk estimates were consistent across BRCA1 and BRCA2 carriers, underscoring the relevance of these findings across mutation subtypes.

Clinical Implications

These data provide critical reassurance for clinicians managing young women with hereditary breast and ovarian cancer syndromes. In contrast to earlier studies conducted in the general population, MHT use in BRCA1/2 carriers was not associated with an increased risk of breast cancer, regardless of formulation. Estrogen-only regimens, in particular, appeared protective, although causality cannot be inferred.

While limitations include a relatively modest follow-up duration and small numbers in certain subgroups, this prospective analysis offers the strongest evidence to date supporting the safety of MHT in this high-risk population. The findings reinforce the need for individualized, evidence-based counseling that balances cancer risk reduction with quality-of-life preservation.

Moving Forward

As MHT formulations continue to evolve, ongoing research will be essential to refine risk stratification and optimize menopause management strategies in BRCA mutation carriers. For now, these results support a personalized approach to MHT use in women experiencing surgical or natural menopause after risk-reducing oophorectomy, provided there are no contraindications. For many patients, informed use of MHT may offer not only symptom relief, but also a path toward improved long-term health and wellbeing without compromising breast cancer risk.

GS3-01. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2. Kotsopoulos J, Seca M, Jacek G, et al. Presented at the 2025 San Antonio Breast Cancer Symposium (SABCS; Abstract GS3-01). 

FDA Approves First Line ENHERTU® plus PERJETA® for HER2-Positive Metastatic Breast Cancer

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SUMMARY: The FDA on December 15, 2025, approved ENHERTU® in combination with Pertuzumab for the first-line treatment of adults with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer as determined by an FDA-approved test.

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 321,910 new cases of female breast cancer will be diagnosed in 2026, and about 42,140 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®) 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®) 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 plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. Tolaney SM, Jiang Z, Zhang Q, et al. for the DESTINY-Breast09 Trial Investigators. N Engl J Med. DOI: 10.1056/NEJMoa2508668

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

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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 were diagnosed in 2025, and about 42,170 women died of the disease, largely due to metastatic recurrence.

Rationale for a Chemotherapy-Free Neoadjuvant Strategy

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

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

Study Design and Patient Population

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

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

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

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

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

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

Endpoints and Statistical Considerations

The Primary endpoints were:

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

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

Baseline Characteristics

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

Efficacy Outcomes: pCR and Residual Disease

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

Notably:

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

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

Immune Modulation and Biomarker Insights

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

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

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

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

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

Safety and Tolerability

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

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

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

Key Takeaways for Oncology Practice

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

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

 

 

 

 

Reassessing First-Line Chemotherapy Selection in Metastatic PDAC: Insights from the PASS-01 Trial

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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. Pancreatic Ductal AdenoCarcinoma (PDAC) remains one of the most lethal malignancies, with most cases diagnosed at advanced stages and few modifiable risk factors identified to date.

Pancreatic ductal adenocarcinoma is characterized by marked biological heterogeneity and limited therapeutic durability. While combination chemotherapy regimens have modestly extended survival in the metastatic setting, outcomes remain poor for the majority of patients, underscoring the urgent need for better treatment selection strategies. Molecular stratification has emerged as a promising approach in PDAC, supported by well-established predictive biomarkers such as germline BRCA2 and PALB2 alterations, which identify a subset of patients more likely to benefit from platinum-based chemotherapy and PARP inhibition. Beyond DNA damage repair defects, transcriptomic profiling has further refined the molecular landscape of PDAC, consistently identifying two dominant expression subtypes-Classical and Basal-like, with important prognostic and potentially predictive implications.

The Classical subtype is generally associated with a more differentiated epithelial phenotype and improved survival, whereas Basal-like tumors exhibit stem-like features, relative chemoresistance, and inferior outcomes. Prior nonrandomized and prospective studies have suggested differential chemotherapy sensitivity between these subtypes, raising the question of whether transcriptional classification could inform first-line regimen selection. The Pancreatic Adenocarcinoma Signature Stratification for Treatment-01 (PASS-01) trial was designed to address this gap by prospectively comparing two commonly used first-line chemotherapy regimens, modified FOLFIRINOX (mFOLFIRINOX) and Gemcitabine plus nab-Paclitaxel (GnP), while embedding comprehensive molecular and translational analyses.

PASS-01 Trial Design and Study Objectives

PASS-01 was a randomized, open-label, multinational Phase II study conducted across centers in Canada and the United States. The trial enrolled patients with de novo metastatic PDAC who were chemotherapy-naïve between October 2020 and January 2024, and excluded individuals harboring germline pathogenic variants in BRCA1, BRCA2, or PALB2, thereby removing a population with known platinum sensitivity. Patients were randomized 1:1 to receive either mFOLFIRINOX (N=80) or GnP (N=80. The Primary endpoint was Progression-Free Survival (PFS) in the intention-to-treat population, using a relaxed significance threshold appropriate for a signal-seeking Phase II design. Key Secondary objectives included Overall Survival (OS), Safety, Objective Response Rates (ORR), and exploratory analyses evaluating outcomes according to RNA expression subtype, GATA6 expression, Patient-Derived Organoid (PDO) data, and other molecular correlatives.

Importantly, PASS-01 incorporated mandatory pretreatment tumor biopsies whenever feasible. These samples underwent whole-genome and transcriptome sequencing, RNA-based subtype classification, and PDO generation, with results reviewed in a molecular tumor board to inform later-line treatment decisions. This design allowed for a real-world assessment of the feasibility and clinical relevance of upfront molecular profiling in metastatic PDAC.

First-Line Efficacy Outcomes in the Overall Study Population

With a median follow-up of 8.3 months, PFS was numerically longer with GnP compared with mFOLFIRINOX, although the difference did not reach conventional statistical significance. Median PFS in the intention-to-treat population was 5.3 months with GnP versus 4.0 months with mFOLFIRINOX. Similar trends were observed in the per-protocol analysis.

Overall Survival outcomes favored GnP more clearly. Median OS approached 10 months with GnP and was under 9 months with mFOLFIRINOX, translating into a statistically significant hazard ratio favoring the Gemcitabine-based regimen. Notably, these differences persisted after adjustment for key clinical covariates, including performance status, liver metastases, and KRAS mutation status. While absolute survival gains were modest, these findings are clinically relevant given the lack of head-to-head randomized data comparing these regimens in Western populations. Objective Response Rates were comparable between treatment arms. However, Disease Control Rate and Durability of Response favored GnP. Patients treated with GnP experienced a higher Disease Control Rate and a longer Duration of Response, suggesting more sustained benefit in a subset of patients.

Safety Profile and Treatment Tolerability

Treatment-related toxicity differed meaningfully between regimens. Hospitalizations due to adverse events were more frequent in the mFOLFIRINOX arm, driven primarily by gastrointestinal complications, febrile neutropenia, and serious infections. In contrast, severe toxicities with GnP were less common and more limited in scope. These safety differences are particularly relevant in a population with aggressive disease biology and limited physiologic reserve, where treatment tolerability may influence both quality of life and the ability to receive subsequent therapy.

Impact of Transcriptional Subtypes on Clinical Outcomes

One of the most informative aspects of PASS-01 was its prospective evaluation of RNA expression subtypes. Among patients with adequate tissue for analysis, approximately 75% were classified as Classical and 25% as Basal-like, consistent with prior reports. Across the entire cohort, Basal-like tumors were associated with numerically shorter PFS and OS compared with Classical tumors, reinforcing their adverse prognostic significance.

When outcomes were examined by treatment arm within each subtype, important patterns emerged. In patients with Classical PDAC, PFS was similar between regimens, but OS was notably longer with GnP compared with mFOLFIRINOX. Conversely, in Basal-like disease, outcomes were uniformly poor regardless of regimen, though trends consistently favored GnP across PFS, Response Rate, and Duration of Response. These findings suggest that Basal-like tumors may derive limited benefit from intensified multi-agent chemotherapy and may be particularly resistant to Fluorouracil and Irinotecan-based approaches.

GATA6 Expression as a Pragmatic Surrogate Biomarker

Given prior evidence linking GATA6 expression with the Classical subtype, PASS-01 also evaluated GATA6 RNA in situ hybridization as a pragmatic surrogate biomarker. High GATA6 expression correlated strongly with Classical transcriptional identity. While patients with high GATA6 expression demonstrated a trend toward longer PFS, GATA6 status alone did not reliably predict differential benefit from mFOLFIRINOX versus GnP. These findings suggest that while GATA6 may serve as a useful prognostic marker, its role as a standalone predictive tool for chemotherapy selection remains limited and may require integration into broader multiplex or composite biomarker platforms.

Early CA 19-9 Dynamics as a Biomarker of Treatment Response

PASS-01 also provided important insights into the utility of early CA 19-9 changes as a biomarker of treatment response. Among patients with evaluable markers, a decline in CA 19-9 within four weeks of therapy initiation was associated with significantly prolonged PFS, whereas early increases were linked to inferior outcomes. However, a subset of patients with early CA 19-9 rises subsequently achieved radiographic disease control, underscoring that CA 19-9 kinetics should not be used in isolation to prompt premature treatment discontinuation. These findings support the potential role of early biomarker dynamics, particularly when combined with emerging tools such as circulating tumor DNA, in adaptive treatment strategies.

Translational Findings and the Challenge of Second-Line Therapy

Despite the extensive molecular profiling and use of correlate-guided recommendations, outcomes in the second-line setting were uniformly poor. Only about half of patients were able to receive subsequent therapy, and survival following progression was measured in months. Correlate-guided treatment selection did not meaningfully improve outcomes compared with standard approaches, highlighting the clinical reality that opportunities for precision intervention in PDAC are often lost once patients progress beyond first-line therapy.

Clinical Implications for First-Line Treatment Selection

PASS-01 confirms that outcomes with standard first-line combination chemotherapy for metastatic PDAC remain disappointing, even in carefully selected clinical trial populations. Within this context, the modest but consistent efficacy and safety advantages observed with GnP over mFOLFIRINOX are practice-informing, particularly for patients without known DNA repair defects. More importantly, the trial reinforces the prognostic importance of transcriptional subtypes and supports the concept that molecular features should be assessed early, when they are most likely to influence meaningful treatment decisions.

As novel therapeutic strategies, including KRAS-targeted agents and rational combination approaches, move into earlier lines of therapy, transcriptional subtype may prove critical in guiding regimen selection and trial design. PASS-01 demonstrates that comprehensive upfront molecular profiling is feasible in multicenter settings and provides a framework for future biomarker-driven trials aimed at improving first-line outcomes in this highly lethal disease.

Key Takeaways and Conclusions

In the Phase II PASS-01 trial, Progression-Free Survival was similar between mFOLFIRINOX and Gemcitabine plus nab-Paclitaxel. However, Overall Survival, treatment durability, and safety trends favored the Gemcitabine-based regimen. Molecular analyses confirmed the adverse prognosis associated with Basal-like PDAC and suggested limited benefit from intensified chemotherapy in this subgroup. Collectively, these findings emphasize the critical importance of optimizing first-line treatment strategies and integrating molecular stratification early in the disease course, as opportunities for effective intervention rapidly diminish after progression.

PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer. Knox JJ, O’Kane G, King D, et al. J Clin Oncol. 2025;43:3355-3368.