Category: Hem/Onc Updates

Late Breaking Abstract – 2026 ASCO GU Symposium: Advancing Adjuvant Therapy in Clear Cell Renal Cell Carcinoma

RR

SUMMARY: The American Cancer Society estimates that 80,450 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2026 and about 15,160 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

Adjuvant immunotherapy has become an important component of treatment for patients with clear cell Renal Cell Carcinoma (ccRCC) who are at elevated risk for recurrence following nephrectomy. The role of adjuvant immune checkpoint blockade was established by the Phase 3 KEYNOTE-564 study, which demonstrated that adjuvant Pembrolizumab (KEYTRUDA®) significantly improves outcomes in this patient population.

Updated results from KEYNOTE-564 with a median follow-up of approximately 57 months confirmed a statistically significant Overall Survival (OS) benefit with adjuvant Pembrolizumab compared with placebo. Median OS was not reached in either group, but treatment with Pembrolizumab reduced the risk of death by 38% (HR 0.62; P=0.0024). At 48 months, the estimated OS rate was 91.2% among patients treated with Pembrolizumab versus 86.0% for those receiving placebo. The survival advantage was consistent across clinically relevant subgroups, including patients with M0 disease, those with M1 disease rendered no evidence of disease (M1 NED), and across PD-L1 expression levels and sarcomatoid histology status.

Building upon these findings, investigators have explored whether combining immunotherapy with other targeted agents could further reduce recurrence risk. The Phase 3 LITESPARK-022 trial evaluated the addition of the Hypoxia-Inducible Factor-2α inhibitor Belzutifan (WELIREG®) to adjuvant Pembrolizumab in patients with high-risk ccRCC following surgery.

Study Design

LITESPARK-022 is a randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 1,841 patients with ccRCC at increased risk of recurrence after nephrectomy.

Eligible patients included those with:

  • Intermediate-to-high risk M0 disease
    • pT2 tumors with grade 4 or sarcomatoid features, N0
    • pT3 tumors of any grade, N0
  • High-risk M0 disease
    • pT4 tumors of any grade, N0
    • Any pT stage with nodal involvement (N+)
  • M1 NED disease
    • Patients with metastatic disease who had undergone surgery and achieved no radiographic evidence of disease

Participants were randomized in a 1:1 ratio to receive either Pembrolizumab plus Belzutifan (N=921), Pembrolizumab plus placebo (N=920). Treatment consisted of Pembrolizumab 400 mg IV every 6 weeks for 9 cycles (approximately 1 year) and Belzutifan 120 mg orally once daily or placebo. Randomization was stratified according to risk category and tumor grade. The Primary endpoint was Disease-free survival (DFS) assessed by investigators and Secondary endpoints included Overall Survival (OS), Safety and tolerability.

Results discussed here represent the first interim analysis, conducted after a median follow-up duration was 28.4 months. Treatment completion rates were similar between groups (about 70%)

Efficacy Outcomes

The addition of Belzutifan to Pembrolizumab resulted in a statistically significant improvement in Disease-Free Survival, compared to Pembrolizumab plus placebo, meeting the Primary endpoint of the study (HR=0.72; 95% CI: 0.59–0.87; P=0.0003. This corresponds to a 28% reduction in the risk of recurrence or death with the combination regimen. The Median DFS had not yet been reached in either arm at the time of analysis. The estimated 24-month DFS rates were 80.7% in the Pembrolizumab plus Belzutifan group and 73.7% in the Pembrolizumab plus placebo group.

This represents the first Phase 3 adjuvant RCC trial demonstrating superiority of a combination therapy over active immunotherapy alone.

Overall Survival

Overall survival results remain immature. At the time of the interim analysis, only 29% of the events required for the final OS analysis had occurred, preventing definitive conclusions regarding survival benefit.

Safety Profile

As expected with the addition of Belzutifan, the combination regimen was associated with higher rates of treatment-related toxicity. Grade ≥3 Adverse Events for Pembrolizumab plus Belzutifan combination was 52.1% versus 30.2% for the Pembrolizumab plus placebo group. The most frequently reported grade ≥3 events included Anemia (12.1% vs 0.4%), Elevated ALT (6.4% vs 2.0%) and Hypoxia (4.6% vs 0%). Despite increased toxicity, grade 5 adverse events were rare and similar between arms, and no new safety signals were identified.

Clinical Implications

The findings from LITESPARK-022 suggest that combining Belzutifan with Pembrolizumab may further improve outcomes for patients with high-risk ccRCC following nephrectomy. However, the improved DFS must be balanced against the increased toxicity profile. Experts emphasize that careful patient selection will be essential if this regimen is adopted in clinical practice. Patients with baseline pulmonary or cardiovascular comorbidities, who may be more vulnerable to Belzutifan-associated hypoxia or anemia, may require additional consideration.

Furthermore, longer follow-up will be necessary to determine whether overall survival benefit emerges, as well as the impact on quality of life, and long-term safety of the combination regimen

Key Takeaways for Clinical Practice

  • Adjuvant Pembrolizumab remains a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy.
  • The LITESPARK-022 trial demonstrated a significant improvement in DFS when Belzutifan was added to Pembrolizumab.
  • The combination reduced the risk of recurrence or death by 28% compared with Pembrolizumab alone.
  • Toxicity was higher, particularly with respect to anemia and hypoxia, but was generally manageable with dose modification and supportive care.
  • Ongoing follow-up will determine whether Overall Survival and Patient-Reported Outcomes support broader adoption of this strategy.

Conclusion

The Phase 3 LITESPARK-022 trial represents an important step forward in the adjuvant treatment landscape for clear cell Renal Cell Carcinoma. By demonstrating a clinically meaningful improvement in Disease-Free Survival with the addition of Belzutifan to Pembrolizumab, the study introduces a promising new therapeutic approach for patients at high risk of recurrence after nephrectomy. Continued follow-up will clarify the long-term survival benefit and help define the role of this combination in routine clinical practice.

Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): The randomized phase 3 LITESPARK-022 study. Choueiri TK, Motzer RJ, Karam JA, et al. 2026 ASCO Genitourinary Cancers Symposium. J Clin Oncol 44, 2026 (suppl 7; abstr LBA418)

Expanding Targeted First-Line Options in BRAF V600E–Mutant Metastatic Colorectal Cancer: Insights From the BREAKWATER Trial

RR

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

RR

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

 

Adjuvant Nivolumab for Resected Melanoma: 9 Year Outcomes

RR

SUMMARY: The American Cancer Society estimates that in the US, approximately 112,000 new cases of melanoma will be diagnosed in 2026 and about 8510 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades.

Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease specific survival rates of 59% and 40% respectively.

Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Immune checkpoint proteins (“gate keepers”) suppress antitumor immunity. Antibodies targeting these membrane bound, inhibitory, immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc., block the immune checkpoint proteins and unleash T cells, resulting in T cell proliferation, activation and a therapeutic response.

Ipilimumab (YERVOY®) was approved by the FDA for the adjuvant treatment of patients with completely resected Stage III melanoma, based on an improvement in Relapse Free Survival, when compared to placebo, in a randomized Phase III trial. In this study however, over 50% of the patients treated with the recommended high dose Ipilimumab experienced Grade 3/4 toxicities. There is therefore an unmet need for adjuvant therapies, with improved benefit-risk ratio, for this patient group.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. Monotherapy with Nivolumab, in heavily pretreated advanced melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment.

Study Details

CheckMate 238 trial is a double-blind Phase III study that included 906 patients with completely resected, Stage IIIB/C or Stage IV melanoma. Patients were randomized in a 1:1 ratio to receive either Nivolumab 3 mg/kg IV, every 2 weeks (N=453) or Ipilimumab 10 mg/kg IV, every 3 weeks (N=453) for 4 doses, then every 12 weeks beginning at week 24, for up to 1 year. Both treatment groups were well balanced. Patients were stratified according to disease stage and PD-L1 status (positive vs. negative or indeterminate according to tumor-cell PD-L1 expression with a 5% cutoff). The Primary end point was Recurrence Free Survival (RFS).

Data from the primary analysis showed that adjuvant Nivolumab was superior to Ipilimumab with respect to RFS and Distant Metastasis–Free Survival (DMFS), and had a more favorable safety profile. This benefit was seen regardless of BRAF mutational status with Nivolumab, and was sustained at a minimum follow-up of up to 7 years. The Overall Survival at 4 years and 7 years was 71% with Nivolumab and 69% with Ipilimumab, and was not significantly different.

In this publication, the researchers provided the final results from CheckMate 238, with a minimum follow-up of 9 years (107 months).

Efficacy at 9 Year Follow-up

The median duration of RFS was 61.1 months with Nivolumab and 24.2 months with Ipilimumab (HR for recurrence or death=0.76) and the 9-year RFS was 44% and 37%, respectively. This benefit was seen across nearly all subgroups analyzed.

The median duration of DMFS in Stage III melanoma patients was more than 9 years with Nivolumab and 83.8 months with Ipilimumab, with 9-year survival of 54% and 48%, respectively (HR for distant metastasis or death=0.81).

The median OS was more than 9 years in both treatment groups, with 9-year survival of 69% in the Nivolumab group and 65% in the Ipilimumab group (HR for death=0.88). The rates of death from melanoma at 9 years were 26% with Nivolumab and 30% with Ipilimumab (HR=0.87; 95% CI, 0.67 to 1.13). It is still uncertain whether OS is improved when treatment is administered in the adjuvant setting compared with initiation at the time of metastatic disease. These outcomes indicate that, similar to trends in metastatic therapy, many patients receiving adjuvant treatment now live long enough to succumb to causes unrelated to melanoma.

Fewer patients in the Nivolumab group required subsequent systemic therapy compared to those in the Ipilimumab group (37.3% vs. 44.6%), with no new late-onset adverse events reported.

Conclusion

Final 9-year data from the CheckMate 238 trial confirms that adjuvant Nivolumab provides sustained improvements in Recurrence-Free Survival (RFS) and Distant Metastasis–Free Survival compared to Ipilimumab, in high-risk melanoma patients, maintaining a safer profile. The results highlight the need for ongoing long-term monitoring.

Nivolumab for Resected Stage III or IV Melanoma at 9 Years. Ascierto PA, Vecchio MD, Merelli B, et al. N Engl J Med 2026;394:333-342

Expert Perspectives on MRD Testing in Multiple Myeloma

RR

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.

FDA Approves CALQUENCE® with VENCLEXTA® for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

RR

SUMMARY: The FDA on February 19, 2026, approved Acalabrutinib (CALQUENCE®) in combination with Venetoclax (VENCLEXTA®) for adults with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

The American Cancer Society estimates that for 2026, about 22,760 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4350 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab (GAZYVA®), or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and non-covalent BTKi, Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. Venetoclax is frequently combined with the infusion-based drug Obinutuzumab, which can impose a logistical burden on patients. The combination of Acalabrutinib plus Venetoclax, were noted to be synergistic.

The AMPLIFY trial is a randomized, global, multi-center, open-label Phase III study designed to assess the efficacy and safety of Acalabrutinib in combination with Venetoclax, with or without Obinutuzumab, compared to investigators choice of standard chemoimmunotherapy. In this study, 867 patients (N=867) across 171 locations worldwide with previously untreated CLL were randomized 1:1:1 to receive a fixed-duration regimen of Acalabrutinib and Venetoclax with Obinutuzumab (AVO; N=286), Acalabrutinib and Venetoclax without Obinutuzumab (AV; N=291), or Standard-of-Care chemoimmunotherapy with either Fludarabine plus Cyclophosphamide and Rituximab (FCR) or Bendamustine plus Rituximab (BR) (FCR/BR; N=290). The median patient age was 61 years, 64.5% were male, and 58.6% had CLL with unmutated IGHV. Eligible patients had an ECOG performance status of 0 to 2 and active disease, requiring treatment as per the International Workshop on CLL 2018 criteria. Patients with prior CLL-specific treatments, 17p deletions, TP53 mutations, transformation of CLL to aggressive Non-Hodgkin Lymphoma, Central Nervous System involvement, or a history of Progressive Multifocal Leukoencephalopathy were excluded. The Primary endpoint of the trial was Progression Free Survival (PFS) as assessed by an Independent Review Committee (IRC). Key Secondary endpoints included PFS assessed by investigators, undetectable Minimal Residual Disease (uMRD; 10-4 cutoff) rate assessed in peripheral blood in the treatment groups, Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, and Time to next treatment.

Efficacy Outcomes (Median Follow-Up: 41 Months)

Progression-Free Survival (PFS) — BICR Assessed

  • AVO vs FCR/BR
    • HR: 0.42
    • P < 0.0001
    • 58% reduction in risk of progression or death
  • AV vs FCR/BR
    • HR: 0.65
    • P = 0.0038
    • 35% reduction in risk of progression or death
  • 36-Month PFS Rates
    • AVO: 83%
    • AV: 76.8%
    • FCR/BR: 66.5%
  • Median PFS
    • AVO: Not reached
    • AV: Not reached
    • FCR/BR: 47.6 months

Overall Response Rate (ORR) — BICR Assessed

  • AVO: 92.7%
  • AV: 92.8%
  • FCR/BR: 75.2%
  • P < 0.0001 for both AVO vs FCR/BR and AV vs FCR/BR

Overall Survival (OS)

  • AV vs FCR/BR
    • HR: 0.33
    • P < 0.0001
    • Demonstrated a strong trend toward improved Overall Survival

Serious Adverse Events occurred in 38.4% (AVO group), 24.7% of patients (AV group), and 27.4% (FCR/BR group). Grade 3 or more neutropenia among the treatment groups, was noted in 35.2%, 26.8% and 32.4%, respectively. COVID-19-related deaths affected 25 patients in the AVO group, 10 patients in the AV group, and 21 patients in the FCR/BR group.

Conclusion

The AMPLIFY study met its Primary endpoint, demonstrating superior Progression-Free Survival (PFS) with both AVO and AV compared with standard chemoimmunotherapy.

Key Takeaways

  • Both combinations produced deep and durable responses
  • Represent a more effective, fixed-duration treatment strategy
  • Offer a shift away from traditional chemoimmunotherapy

Clinical Distinction Between Regimens

AV (Acalabrutinib + Venetoclax):

  • First all-oral, fixed-duration regimen
  • Designed for fit, treatment-naïve CLL patients
  • Provides meaningful convenience
  • Demonstrates a manageable safety profile

AVO (Acalabrutinib + Venetoclax + Obinutuzumab):

  • Further improved efficacy outcomes
  • Associated with:
    • Higher rates of serious adverse events
    • Increased COVID-19–related deaths

 

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. Brown JR, Seymour JF, Wojciech Jurczak, et al. for the AMPLIFY investigators. N Engl J Med 2025;392:748-762

FDA Approves KEYTRUDA® with Paclitaxel for Platinum-Resistant Epithelial Ovarian, Fallopian tube, or Primary Peritoneal Carcinoma

RR

SUMMARY: The FDA on February 10, 2026, approved Pembrolizumab (KEYTRUDA®) as well as Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) in combination with Paclitaxel, with or without Bevacizumab (AVASTIN®), for adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to identify patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) for treatment with Pembrolizumab.

It is estimated that in the United States, approximately 21,010 women will be diagnosed with ovarian cancer in 2026 and 12,450 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

Platinum-resistant recurrent ovarian cancer therefore remains a significant therapeutic challenge, with historically limited options and modest improvements in survival. Previous studies, such as the Phase III AURELIA trial, established weekly Paclitaxel with Bevacizumab as an effective chemotherapy regimen. The potential for chemotherapy to enhance antitumor immune responses provided the rationale for combining Pembrolizumab, an anti–PD-1 antibody, with Paclitaxel, with or without Bevacizumab, in this patient population.

Trial Design

The ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189) was a multicenter, randomized, double-blind, placebo-controlled Phase III study that enrolled 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Eligible patients had received one to two prior systemic therapies, including at least one platinum-based regimen, and had evidence of disease progression within six months after platinum therapy. Patients with primary platinum-refractory disease were excluded.

Participants were randomized 1:1 to receive Pembrolizumab 400 mg every six weeks or placebo, in combination with weekly Paclitaxel 80 mg/m² on days 1, 8, and 15 of each 3-week cycle, with or without Bevacizumab 10 mg/kg every 2 weeks. Prior use of PARP inhibitors, Bevacizumab, or PD-1/PD-L1 agents was allowed. Patients had an ECOG performance status of 0–1, with a median age of 61–62 years and predominance of high-grade serous histology (86%). Approximately one-third of patients had PD-L1 CPS ≥10.

Efficacy Results

The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1, with Overall Survival (OS) as a key Secondary endpoint.

  • First interim analysis (median follow-up 15.6 months):
    • Overall population: median PFS 8.3 months with Pembrolizumab vs 6.4 months with placebo (HR 0.70; P<0.0001).
    • PD-L1 CPS ≥1 population: median PFS 8.3 months vs 7.2 months (HR 0.72; P=0.0014).
  • Second interim analysis (median follow-up 26.6 months):
    • PD-L1 CPS ≥1 population: OS improved to 18.2 months with Pembrolizumab vs 14.0 months with placebo (HR 0.76; P=0.0053).
    • Benefits were observed across subgroups, including older patients, prior PARP inhibitor exposure, and short platinum-free interval.
    • Objective Response Rates were higher with Pembrolizumab (53.0% vs 46.6% in PD-L1 CPS ≥1 patients) with longer Duration of Response.

The PFS and OS improvements were consistent regardless of Bevacizumab use, supporting both doublet and triplet strategies in routine practice.

Safety Profile

Pembrolizumab combined with weekly Paclitaxel, with or without Bevacizumab, demonstrated a manageable safety profile. Adverse events were consistent with known toxicities of checkpoint inhibitors and chemotherapy, including immune-mediated events, infusion reactions, and myelosuppression. No unexpected safety signals were reported, confirming the feasibility of this regimen in a platinum-resistant population.

Clinical Implications

KEYNOTE-B96 demonstrates a clinically meaningful improvement in both Progression-Free and Overall Survival, representing one of the longest reported OS durations in platinum-resistant ovarian cancer. The regimen leverages the immune-modulating effects of weekly Paclitaxel and the potential vascular-normalizing and immunosuppressive effects of Bevacizumab, addressing multiple barriers to effective immune activation.

These results support PD-L1 CPS as a predictive biomarker while emphasizing the importance of integrating immunotherapy with established chemotherapy backbones. The findings provide a foundation for sequencing this strategy alongside emerging therapies, including antibody-drug conjugates and other targeted agents, in this difficult-to-treat population.

Conclusion

KEYNOTE-B96 establishes Pembrolizumab plus weekly Paclitaxel, with or without Bevacizumab, as a viable and effective treatment option for patients with platinum-resistant ovarian cancer, delivering meaningful improvements in survival with a manageable safety profile. This trial highlights the potential of immunotherapy combinations in a disease historically considered immunologically “cold” and provides a new evidence-based option in a setting of high unmet need.

Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Colombo N, Zsiros E, Sebastianelli A, et al. Presented at: European Society of Medical Oncology Congress 2025; October 17–20, 2025; Berlin, Germany. Abstract LBA3.

TRODELVY® plus KEYTRUDA® in Metastatic Triple Negative Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 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 Persistent Therapeutic Gap in Metastatic TNBC

Triple-Negative Breast Cancer (TNBC) which accounts for roughly 10-15% of breast cancers remains one of the most biologically aggressive breast cancer subtypes, defined by the absence of estrogen and progesterone receptor expression and lack of HER2 overexpression. Despite therapeutic advances, metastatic TNBC carries a dismal prognosis, with 5-year relative survival rates near 15%.

Approximately 40% of TNBC tumors express PD-L1 (combined positive score [CPS] ≥10). Based on results from KEYNOTE-355, the combination of Pembrolizumab (KEYTRUDA®) and chemotherapy (Taxane or Gemcitabine–Carboplatin backbone) became the standard first-line regimen for PD-L1–positive metastatic TNBC, improving both Progression-Free Survival (PFS) and Overall Survival (OS), compared with chemotherapy alone.

However, Real-World Data suggest that nearly half of patients with metastatic TNBC do not receive therapy beyond first line due to rapid progression or early mortality. This underscores the importance of maximizing disease control early in the treatment course.

The Rationale for ADC–Immunotherapy Combination

Sacituzumab govitecan (TRODELVY®) is a Trop-2–directed Antibody–Drug Conjugate (ADC) delivering the topoisomerase I inhibitor SN-38 via a hydrolyzable linker. It previously demonstrated significant survival benefit over chemotherapy in heavily pretreated metastatic TNBC (ASCENT), as well as significantly prolonged Progression-Free Survival compared with standard chemotherapy in the first-line treatment of advanced or metastatic TNBC among patients who are not candidates for PD-1/PD-L1 inhibitors (ASCENT-03).

Given the complementary mechanisms of cytotoxic payload delivery and immune checkpoint inhibition, combining Sacituzumab govitecan with Pembrolizumab represents a biologically compelling strategy to deepen and prolong response in earlier lines of therapy.

ASCENT-04/KEYNOTE-D19: Trial Design

ASCENT-04/KEYNOTE-D19 is a global, randomized, open-label Phase 3 trial conducted across 186 sites in 28 countries.

Eligible patients included:

  • Adults with locally advanced unresectable or metastatic TNBC
  • No prior therapy for advanced disease
  • PD-L1–positive tumors (CPS ≥10, centrally confirmed using PD-L1 IHC 22C3 pharmDx assay)

A total of 443 patients were randomized 1:1:

  • Sacituzumab govitecan (10 mg/kg IV days 1 and 8, q21 days) plus Pembrolizumab (200 mg IV q3 weeks)
  • Physician’s choice chemotherapy plus Pembrolizumab

Stratification factors included:

  • Disease status (de novo metastatic vs. early relapse)
  • Geographic region
  • Prior exposure to anti–PD-1/PD-L1 therapy in curative-intent setting

The Primary endpoint was PFS by Blinded Independent Central Review. Secondary endpoints included OS, Objective Response Rate (ORR), Duration of Response (DoR), and Safety.

Efficacy Outcomes

At a median follow-up of 14 months, the study met its Primary endpoint.

  • Median PFS:
    • 11.2 months with Sacituzumab govitecan plus Pembrolizumab
    • 7.8 months with chemotherapy plus Pembrolizumab
  • Hazard Ratio for progression or death: 0.65 (95% CI, 0.51–0.84; P<0.001)

Investigator-assessed PFS results were concordant. The PFS benefit was consistent across predefined subgroups, including patients with liver metastases and those with early relapse (6–12 months after curative-intent therapy). Notably, median PFS approached one year with the ADC–immunotherapy combination, exceeding historical benchmarks from chemo-immunotherapy trials in this setting.

  • ORR:
    • 60% with Sacituzumab govitecan plus Pembrolizumab
    • 53% with chemotherapy plus Pembrolizumab
  • Complete Response rate: 13% vs. 8%
  • Median Duration of Response:
    • 16.5 months vs. 9.2 months

Although formal hypothesis testing was not performed for secondary endpoints, responses with the ADC combination were notably more durable. Importantly, despite a higher-than-expected ORR in the control arm, responses with chemotherapy were less sustained, likely explaining the PFS separation.

OS data remain immature at this analysis (26% event rate), with medians not yet reached in either arm.

Safety and Treatment Adherence

Grade ≥3 adverse events occurred at similar rates in both groups (about 70%). However, treatment discontinuation due to adverse events was substantially lower with the ADC combination (12% vs. 31%). This difference may reflect the nature of toxicities. ADC-associated events such as diarrhea are generally manageable with supportive care, whereas chemotherapy-related toxicities such as neuropathy may be cumulative and less reversible. Adverse events leading to death occurred in 3% of patients in each arm.

Clinical Interpretation

ASCENT-04/KEYNOTE-D19 establishes the first positive Phase 3 data evaluating an ADC combined with immunotherapy in the frontline treatment of PD-L1–positive metastatic TNBC.

The magnitude of PFS benefit (HR 0.65), prolonged response durability, and lower discontinuation rate suggest that Sacituzumab govitecan plus Pembrolizumab may represent an evolution of first-line therapy in this population.

Given that many patients will not reach subsequent lines of treatment, intensifying effective therapy upfront is clinically meaningful. The ADC backbone may offer sustained tumor control beyond what is achievable with chemotherapy-based combinations.

Limitations and Ongoing Questions

Key limitations include:

  • Open-label design
  • Crossover to Sacituzumab govitecan in the control arm
  • Immature OS data
  • Limited representation of patients previously treated with adjuvant immunotherapy

Future analyses will clarify survival impact and optimal sequencing, particularly as additional ADCs enter earlier lines of therapy. Ongoing trials such as ASCENT-05 (NCT05633654) and SASCIA (NCT04595565) are evaluating Sacituzumab govitecan in high-risk early-stage settings, potentially broadening its therapeutic footprint.

Bottom Line for Practice

For patients with previously untreated, PD-L1–positive, locally advanced unresectable or metastatic TNBC, Sacituzumab govitecan plus Pembrolizumab significantly prolongs Progression-Free Survival compared with chemotherapy plus Pembrolizumab, with durable responses and manageable toxicity.

These findings position ADC–immunotherapy combinations as a potential new backbone strategy in frontline TNBC management, pending maturation of Overall Survival data.

Sacituzumab Govitecan plus Pembrolizumab for Advanced Triple-Negative Breast Cancer. Tolaney SM, de Azambuja E, Kalinsky K, et al. for the ASCENT-04/KEYNOTE-D19 Clinical Trial Investigators. N Engl J Med 2026;394:354-366.

Final Overall Survival Results from the EMBARK trial: Practice-Changing Evidence in High-Risk Biochemical Recurrence

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 333,830 new cases of Prostate cancer will be diagnosed in 2026 and 36,320 men will die of the disease. Androgen Deprivation Therapy (ADT) or testosterone suppression has been the cornerstone of treatment of advanced Prostate cancer, and is the first treatment intervention.

The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following radiation therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following radiation therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment, and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

Enzalutamide (XTANDI®) is a potent oral Androgen Receptor Pathway Inhibitor with demonstrated efficacy in patients with both localized and advanced prostate cancer.

EMBARK is a randomized, double-blind, placebo-controlled, multi-national, Phase III trial, conducted to evaluate the efficacy and safety of Enzalutamide plus Leuprolide and Enzalutamide monotherapy, as compared with Leuprolide alone, in patients with non-metastatic Hormone/Castration-Sensitive Prostate Cancer (nmHSPC or nmCSPC) prostate cancer, who have had high-risk biochemical recurrence. In this study, a total of 1068 eligible patients were randomly assigned 1:1:1 to receive Enzalutamide at 160 mg orally once daily plus Leuprolide IM every 12 weeks (N=355), single agent Enzalutamide at 160 mg orally once daily (N=355) or Leuprolide alone (N=358). All patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent. High risk disease was defined as a PSA doubling time of 9 months or less and a PSA level of 2 ng/ml above nadir after radiation therapy, or 1 ng/ml or more after radical prostatectomy with or without postoperative radiation therapy. The baseline characteristics were well balanced among the treatment groups. The median age was 69 years, the median PSA doubling time was 4.9 months and the median PSA level was 5.2 ng/ml. The Primary end point was Metastasis-Free Survival (MFS), as assessed by Blinded Independent Central Review (BICR) in the combination group, as compared with the Leuprolide-alone group. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first. Secondary end points included MFS in the Enzalutamide monotherapy group, as compared with the Leuprolide-alone group, Overall Survival (OS), Patient-Reported Outcomes and Safety.

At a median follow up 60.7 months, the 5 year MFS was 87.3% in the Enzalutamide combination group and 71.4% with Leuprolide alone (HR for metastasis or death 0.42; P<0.001). This represented a 58% lower risk of metastasis or death in the combination group than Leuprolide alone among patients with biochemically recurrent prostate cancer. At the time of this analysis, Overall Survival data were immature.

In this publication, the final Overall Survival (OS) analysis of the Phase 3 EMBARK trial provided compelling long-term evidence supporting intensified Androgen-Receptor Pathway Inhibition in patients with high-risk biochemical recurrence of prostate cancer and no evidence of metastasis on conventional imaging. At the time of this final analysis, 277 deaths had occurred: 73 in the combination arm, 111 in the Leuprolide-alone arm, and 93 in the Enzalutamide monotherapy arm. Median follow-up exceeded 93 months across all treatment groups, offering a robust long-term perspective on survival outcomes.

Overall Survival: Durable and Clinically Meaningful Benefit

The combination of Enzalutamide plus Leuprolide demonstrated a statistically and clinically significant improvement in OS compared with Leuprolide alone:

  • 8-year OS:
    • 78.9% (95% CI, 73.9–83.1) with combination therapy
    • 69.5% (95% CI, 64.0–74.3) with Leuprolide alone
  • Hazard ratio for death: 0.60 (95% CI, 0.44–0.80; P<0.001)

This 40% relative reduction in mortality risk translates into an absolute improvement of nearly 10% at 8 years, a notable achievement in a population historically managed with Androgen Deprivation Therapy (ADT) alone.

By contrast, Enzalutamide monotherapy did not significantly improve OS relative to Leuprolide alone:

  • 8-year OS: 73.1% (95% CI, 67.6–77.9)
  • Hazard ratio: 0.83 (95% CI, 0.63–1.10; P=0.19)

While monotherapy previously demonstrated improvements in key Secondary endpoints, including Metastasis-Free Survival, it did not confer a statistically significant survival advantage in this final OS analysis.

Descriptive updates of Secondary endpoints were consistent with earlier reports. Time to first use of new antineoplastic therapy and time to first symptomatic skeletal event continued to favor combination therapy.

Although fractures were numerically more frequent in the combination arm, this reflected a broader category of bone and joint injuries. Importantly, the time to first symptomatic skeletal event was prolonged with Enzalutamide plus Leuprolide compared with Leuprolide alone, suggesting lower clinically meaningful skeletal morbidity despite the higher overall reporting of fractures.

Safety Profile: No New Signals

The long-term safety data remained consistent with earlier analyses. No new safety signals emerged, and the adverse-event profile of Enzalutamide, whether used in combination or as monotherapy, aligned with prior experience in metastatic castration-resistant and metastatic castration-sensitive prostate cancer settings.

Clinical Context: Imaging Evolution and Treatment Implications

Interpretation of these results must consider the evolving imaging landscape. At the time of trial enrollment, staging relied on CT or MRI for soft-tissue assessment and radionuclide bone scans for osseous disease. With the increasing use of PSMA PET imaging, it is likely that a proportion of patients categorized as nonmetastatic in the trial may have harbored occult locoregional or oligometastatic disease detectable by more sensitive modalities. Nevertheless, the study reflects real-world practice standards at the time and provides a pragmatic framework for treatment decision-making in high-risk biochemical recurrence.

Treatment Suspension Strategy: A Unique Feature

An important protocol component was treatment suspension at week 37 for patients achieving undetectable PSA (<0.2 ng/mL), with reinitiation upon PSA rise to predefined thresholds. This strategy aimed to mitigate toxicity and preserve quality of life. Notably, the OS benefit of combination therapy was achieved despite these mandated treatment interruptions.

Future research should clarify:

  • Which patients may safely undergo treatment suspension,
  • Whether continuous therapy could further optimize outcomes in select populations,
  • And how molecular imaging findings should inform early intensification strategies.

Positioning in the Treatment Paradigm

The final OS data reinforce earlier MFS findings and establish Enzalutamide plus ADT as a preferred standard of care for patients with Castration-Sensitive Prostate Cancer and high-risk biochemical recurrence without conventional radiographic metastases.

Although Enzalutamide monotherapy remains a reasonable option, particularly for patients prioritizing preservation of sexual function based on patient-reported outcomes, shared decision-making remains essential, balancing efficacy, toxicity, and quality-of-life considerations.

Conclusion

With nearly eight years of follow-up, the EMBARK trial confirms that intensification of Androgen-Receptor Pathway Inhibition with Enzalutamide plus Leuprolide delivers a durable Overall Survival advantage in high-risk biochemical recurrence. These findings extend the survival benefits observed with Enzalutamide across earlier disease states and further reshape management strategies in this evolving therapeutic space.

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. Shore ND, Luz MA, Giorgi UD, et al. N Engl J Med 2026;394:563-575.

Redefining First-Line Maintenance in HR-Positive, HER2-Positive Metastatic Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 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