Category: Hem/Onc Updates

Late Breaking Abstract – ASCO 2026: CEL MoDs Significantly Extend Progression-Free Survival in Relapsed and Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,000 new cases will be diagnosed in 2026, and 10,850 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes.

Modern therapies,including Proteasome Inhibitors, Immunomodulatory drugs, and anti-CD38 antibodies, have extended survival to nearly a decade. However, patients whose disease becomes resistant to these treatments face poor outcomes with a median survival of less than 1 year. There is a critical need for novel, effective therapies with new mechanisms of action.

Targeted Protein Degradation

Cereblon is a key human protein encoded by the CRBN gene that acts as a primary target for immunomodulatory drugs (IMiDs) like Lenalidomide, Pomalidomide, and Thalidomide. It functions as a receptor that labels specific proteins for cellular destruction, driving tumor cell death and activating the immune system.

CELMoDs (Cereblon E3 Ligase Modulators) are a new class of highly potent oral medications designed primarily to treat multiple myeloma. They work as targeted “molecular glue” by binding to the cereblon protein, similar to immunomodulatory drugs. However, they bind with much higher affinity and induce a more active, “closed” conformation. This enhanced biochemical grip allows them to be effective even in patients whose disease has become resistant to standard IMiDs. Once cereblon is activated by the CELMoD, it acts as a garbage disposal signal (ubiquitin) to mark specific target proteins, most notably Ikaros (IKZF1) and Aiolos (IKZF3), for destruction by the cell’s proteasome.

Ikaros (IKZF1) and Aiolos (IKZF3) are zinc-finger transcription factors that regulate lymphocyte development. These transcription factors in many hematological malignancies such as multiple myeloma and leukemia act as rogue cancer-driving proteins, supporting cancer cell survival by repressing tumor suppressors and driving oncogene expression, and are heavily relied upon by myeloma cells to survive and multiply.

When CELMoDs destroy these proteins, it arrests the cancer cell’s growth cycle and actively triggers apoptosis (programmed cell death). Further, Destroying Ikaros and Aiolos removes the natural brakes that suppress immune function, allowing T cells and Natural Killer (NK) cells to better attack the tumor.

Prominent CELMoDs under study include Iberdomide and Mezigdomide, and are being investigated both as standalone therapies and in combination with other treatments like monoclonal antibodies for patients who have Relapsed/Refractory Multiple Myeloma (RRMM).

Mezigdomide, an investigational oral cereblon E3 ligase modulator (CELMoD), has been specifically engineered to promote rapid and potent degradation of the transcription factors Ikaros and Aiolos. Compared with earlier immunomodulatory agents, Mezigdomide demonstrates enhanced anti-myeloma activity and greater immune stimulation in preclinical studies, including restoration of T-cell function and reversal of immune exhaustion. The Phase 3 SUCCESSOR-2 trial evaluated whether adding Mezigdomide to Carfilzomib and Dexamethasone could improve outcomes in this difficult-to-treat patient population.

SUCCESSOR-2 Study Design

SUCCESSOR-2 (NCT05552976) is a global, randomized, open-label, Phase 3 trial enrolling adults with RRMM who had received at least one prior line of therapy, including both Lenalidomide and an anti-CD38 monoclonal antibody. The study used a seamless two-stage design, with the initial stage identifying the optimal Mezigdomide dose before proceeding to the confirmatory efficacy comparison.

Patients received Mezigdomide combined with weekly Carfilzomib and Dexamethasone (MeziKd), or Carfilzomib plus Dexamethasone (Kd). Following dose optimization, the 1.0-mg Mezigdomide dose was selected for the second stage of the study. The Primary endpoint was Progression-Free Survival (PFS), while Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response, Minimal Residual Disease negativity, time to next treatment, and patient-reported Quality of Life.

Clinically Meaningful Improvement in Disease Control

The efficacy analysis included 479 patients, with 288 receiving MeziKd and 191 receiving Kd alone. Participants represented a heavily pretreated population with substantial treatment resistance. More than 92% had prior exposure to all three major therapeutic classes, nearly 86% were refractory to anti-CD38 therapy, and approximately 76% were refractory to Lenalidomide. Over one-third had previously received Pomalidomide, and a smaller proportion had been exposed to anti-BCMA therapy.

After a median follow-up of 10.6 months, MeziKd significantly prolonged PFS compared with Kd alone. Median PFS reached 18.0 months with the Mezigdomide regimen versus 8.3 months for the control arm, corresponding to a 52% reduction in the risk of disease progression or death (HR=0.48; P<0.0001). Importantly, the benefit was consistently observed across clinically relevant subgroups, including patients treated at first relapse, those with more than two prior lines of therapy, individuals with high-risk cytogenetic abnormalities, patients with extramedullary disease, and those aged 75 years or older.

Treatment responses also favored the investigational regimen. The ORR increased to 80.2% with MeziKd compared with 53.4% for Kd alone, while Complete Responses or better were achieved in 26.7% and 8.9% of patients, respectively. Patients receiving MeziKd also remained on therapy longer than those receiving the standard regimen.

Safety Profile Remains Predictable

The safety findings were consistent with previous clinical experience using Mezigdomide and with the known toxicities of the individual treatment components. Grade 3 or 4 treatment-emergent adverse events occurred more frequently with MeziKd than with Kd alone, largely reflecting higher rates of neutropenia and infections. Grade 3-4 neutropenia was observed in 61.1% of patients receiving MeziKd compared with 9.1% in the control arm, while Grade 3-4 infections occurred in 34.0% and 15.6% of patients, respectively. Despite these differences, fatal infections remained uncommon in both treatment groups, and adverse events were generally considered manageable with appropriate supportive care and monitoring.

Clinical Perspective

SUCCESSOR-2 provides compelling evidence that Mezigdomide combined with Carfilzomib and Dexamethasone can substantially improve clinical outcomes in patients with RRMM previously exposed or refractory to Lenalidomide and anti-CD38 therapy. The nearly 10-month improvement in median PFS, together with higher response rates across multiple high-risk subgroups, highlights the potential of cereblon E3 ligase modulation as an important therapeutic strategy in contemporary myeloma management.

As treatment sequencing continues to evolve and more patients become refractory to frontline therapies, MeziKd has the potential to become an important option beginning at first relapse and may represent a future standard-of-care regimen pending regulatory review and longer-term survival follow-up.

Mezigdomide, carfilzomib, and dexamethasone (MeziKd) vs carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM): Results from the phase 3 SUCCESSOR-2 trial. Richardson PG,  Schjesvold F, Fu C, et al. J Clin Oncol 44, LBA7506(2026)

Late Breaking Abstract – ASCO 2026: BREAKWATER Cohort 3 Expands First-Line Targeted Therapy Options for BRAF V600E-Mutant Metastatic Colorectal Cancer

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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.

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.

BRAF V600E mutations are found in approximately 8-10% of metastatic CRC and are associated with aggressive tumor biology, poor prognosis, and limited response to conventional first-line therapies. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention.

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. Cetuximab (ERBITUX®) is an anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibody.

Design of the BREAKWATER Study

BREAKWATER is a multicenter, open-label Phase III trial evaluating targeted treatment strategies for patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. Cohort 1 and 2 evaluated Encorafenib plus Cetuximab with or without mFOLFOX6 chemotherapy and results demonstrated significant clinical efficacy, leading the FDA to grant full approval to the Encorafenib combination regimen for first-line mCRC. However, because both FOLFOX and FOLFIRI remain widely used chemotherapy backbones in metastatic colorectal cancer, an important unanswered question was whether similar benefits could be achieved using a FOLFIRI-based regimen.

To address this, investigators evaluated the combination of Encorafenib, Cetuximab, and FOLFIRI in Cohort 3 of the BREAKWATER trial. Cohort 3 enrolled 147 patients with measurable disease and an ECOG Performance Status of 0 or 1. Patients were randomized 1:1 to receive either Encorafenib plus Cetuximab and FOLFIRI or standard FOLFIRI with or without Bevacizumab. The Primary endpoint was Objective Response Rate (ORR) assessed by Blinded Independent Central Review (BICR), while Progression-Free Survival (PFS) served as the key Secondary endpoint. Overall Survival (OS) and safety were also evaluated. Baseline demographic and disease characteristics were well balanced between treatment arms.

Significant Improvements across Multiple Clinical Endpoints

Earlier analyses demonstrated a marked improvement in tumor response with the targeted combination, and the final analysis confirmed durable benefits across efficacy endpoints.

The addition of Encorafenib and Cetuximab to FOLFIRI reduced the risk of disease progression or death by 56% compared with standard chemotherapy (HR=0.44; P=0.0002). Median PFS nearly doubled, increasing from 8.3 months in the control arm to 15.2 months with the targeted regimen.

Overall Survival also improved substantially. Median OS had not yet been reached in the investigational arm at the time of analysis, compared with 20.3 months for the control group, corresponding to a 44% reduction in the risk of death (HR=0.56). The estimated 18-month OS rate reached 72% with the targeted combination versus 54.5% with standard therapy.

Objective responses remained consistently superior. The confirmed ORR was 64.4% with Encorafenib plus Cetuximab and FOLFIRI compared with 39.2% for chemotherapy alone, representing a statistically significant improvement.

Importantly, treatment benefit was observed consistently across all predefined patient subgroups, including age, sex, ECOG performance status, tumor sidedness, liver metastases, and extent of disease.

Durable Disease Control

Patients receiving the targeted regimen remained on treatment considerably longer than those receiving standard therapy. The median duration of treatment was 67.9 weeks with Encorafenib plus Cetuximab and FOLFIRI compared with 32.1 weeks in the control arm. At the January 2026 data cutoff, 38.4% of patients receiving the investigational regimen remained on treatment, compared with only 9.5% of patients receiving standard chemotherapy.

These findings suggest not only improved tumor control but also sustained clinical benefit over time.

Safety Profile Remains Consistent

The addition of targeted therapy did not introduce unexpected toxicities and no new safety signals emerged during longer follow-up. Treatment-emergent adverse events were consistent with the established safety profiles of Encorafenib, Cetuximab, and FOLFIRI. Although adverse events occurred in nearly all patients, the incidence of Grade 3 or 4 treatment-emergent adverse events was numerically lower with the targeted regimen (70.4%) than with standard chemotherapy (80.9%).

Regulatory Impact

The BREAKWATER program has rapidly influenced clinical practice. In December 2024, the FDA granted accelerated approval to Encorafenib plus Cetuximab with mFOLFOX6 for patients with previously untreated BRAF V600E-mutant metastatic colorectal cancer. Following the positive results from Cohort 3, the FDA expanded approval in February 2026 to include Encorafenib plus Cetuximab combined with Fluorouracil-based chemotherapy, providing clinicians with the option of either mFOLFOX6 or FOLFIRI as chemotherapy backbones. This expanded indication increases treatment flexibility while preserving the benefits of precision-targeted therapy.

Clinical Implications

The findings from BREAKWATER Cohort 3 further strengthen the role of biomarker-directed therapy in the first-line treatment of BRAF V600E-mutant metastatic colorectal cancer. By demonstrating significant improvements in response rate, PFS, and OS with a FOLFIRI backbone, the study expands treatment flexibility beyond the previously established mFOLFOX6 regimen.

These results also underscore the critical role of early comprehensive molecular testing. Identifying a BRAF V600E mutation before initiation of first-line therapy enables patients to receive biomarker-directed treatment that significantly improves response rates, prolongs disease control, and extends survival compared with conventional chemotherapy alone.

The study supports Encorafenib plus Cetuximab and FOLFIRI as an additional standard-of-care option, enabling clinicians to tailor chemotherapy backbone selection according to individual patient characteristics and treatment goals.

Conclusion

The final analysis of BREAKWATER Cohort 3 establishes Encorafenib plus Cetuximab and FOLFIRI as an important new first-line standard-of-care option for patients with BRAF V600E-mutant metastatic colorectal cancer. Together with earlier BREAKWATER findings, these results expand first-line treatment options for this high-risk molecular subtype and further establish biomarker-driven therapy as the preferred approach for delivering personalized care.

BREAKWATER: Progression-free and overall survival analyses of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). Kopetz S, Tabernero J, Lorandi S, et al. J Clin Oncol. 2026;44(suppl 17):LBA3503.

Late Breaking Abstract – ASCO 2026: ctDNA-Guided Early Treatment Escalation Improves Outcomes in EGFR-Mutated Advanced NSCLC

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SUMMARY: 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21.

The management of advanced EGFR-mutated NSCLC has evolved substantially with the introduction of third-generation EGFR tyrosine kinase inhibitors (TKIs), particularly Osimertinib (TAGRISSO®), which has become the preferred first-line therapy because of its superior efficacy, CNS activity, and favorable tolerability. Nevertheless, a substantial proportion of patients experience early molecular persistence despite treatment initiation, suggesting the presence of residual resistant tumor clones that ultimately drive disease progression.

The recently reported Phase II FLAME study introduces an innovative precision oncology strategy by demonstrating that early circulating tumor DNA (ctDNA)-guided treatment escalation can identify these high-risk patients and significantly improve clinical outcomes. Unlike conventional management that relies primarily on baseline molecular profiling followed by radiographic assessment every few months, FLAME leveraged serial plasma ctDNA monitoring as a dynamic biomarker to evaluate treatment response within just three weeks of initiating Osimertinib. Persistent detection of EGFR mutations in plasma at this early time point has previously been associated with inferior Progression-Free Survival (PFS) and Overall Survival (OS), suggesting incomplete molecular response despite ongoing targeted therapy.

The FLAME investigators hypothesized that these patients might benefit from immediate treatment intensification rather than waiting for radiographic progression.

Study Design

FLAME was a multicenter, randomized, open-label Phase II study enrolling patients with previously untreated locally advanced or metastatic NSCLC harboring common sensitizing EGFR exon 19 deletion or L858R mutations. All patients initially received first-line Osimertinib monotherapy. Plasma samples obtained after three weeks of treatment were analyzed using the highly sensitive Super ARMS-PCR assay to detect persistent EGFR-mutant ctDNA. Among 448 screened patients, 134 (approximately 30%) continued to demonstrate detectable plasma EGFR mutations after three weeks, identifying a molecularly high-risk subgroup. Eighty eligible patients (N=80) were randomized in a 1:1 ratio either to continue Osimertinib alone or to receive intensified treatment with Osimertinib combined with Carboplatin and Pemetrexed.  Both treatment groups were well balanced. Median age was 59 yrs, 58% were female and 35% had CNS metastases. Randomization was stratified according to baseline CNS metastases and EGFR mutation subtype (exon 19 deletion versus L858R). The Primary endpoint was investigator-assessed PFS according to RECIST version 1.1, while Secondary endpoints included Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate, 18-month OS rate, safety, mechanisms of resistance, and exploratory analyses evaluating dynamic multi-omics biomarkers and patient-reported Quality of Life.

Significant Improvement in Progression-Free Survival

With a median follow-up corresponding to 67.5% PFS maturity, the addition of Platinum-Pemetrexed chemotherapy to Osimertinib resulted in a statistically significant and clinically meaningful improvement in PFS. Median PFS increased from 12.7 months with continued Osimertinib alone to 23.1 months with combination therapy, representing an absolute improvement of more than 10 months. The risk of disease progression or death was reduced by 47% (HR 0.53; 95% CI 0.31–0.92; P=0.024).

Tumor response also favored the intensified treatment strategy. The investigator-assessed ORR increased from 35% with Osimertinib monotherapy to 50% with combination therapy, while median Duration of Response improved from 10.5 months to 15.6 months. Although OS data remain immature, the observed PFS benefit suggests that intervening before overt clinical resistance develops may substantially delay disease progression in patients identified as molecular nonresponders.

ctDNA as an Early Response Biomarker

Perhaps the most important contribution of FLAME extends beyond the chemotherapy comparison itself. The study provides prospective validation of ctDNA-guided adaptive therapy, demonstrating that serial molecular monitoring can identify patients requiring treatment modification weeks before conventional imaging would reveal progressive disease.

Approximately one-third of screened patients exhibited persistent plasma EGFR mutations after three weeks of Osimertinib, confirming that early molecular clearance is heterogeneous despite identical initial therapy. These findings support the concept that molecular response kinetics reflect treatment sensitivity and residual tumor burden more accurately than baseline genomic profiling alone.

This adaptive treatment paradigm differs fundamentally from traditional precision oncology, which generally bases therapeutic decisions on static genomic testing performed before treatment initiation. Instead, FLAME illustrates how longitudinal ctDNA assessment may enable real-time therapeutic adjustment according to evolving tumor biology.

Relationship to FLAURA2

The FLAME findings complement the landmark Phase III FLAURA2 trial while addressing a distinct clinical question. FLAURA2 demonstrated that administering Osimertinib together with Platinum-Pemetrexed chemotherapy upfront for all eligible patients significantly prolonged PFS and subsequently improved OS, compared with Osimertinib alone, establishing the combination as an important first-line option for selected patients.

In contrast, FLAME evaluated a biomarker-directed strategy in which chemotherapy was reserved only for patients who demonstrated persistent ctDNA positivity after three weeks of Osimertinib. This selective escalation approach may allow clinicians to spare patients who achieve rapid molecular clearance from chemotherapy-related toxicities while intensifying treatment only in those at highest risk for early progression.

If validated in larger studies, this strategy could represent a more individualized alternative to universal upfront combination therapy.

Safety Profile

As expected, the improved efficacy of combination treatment was accompanied by increased toxicity. Grade 3 or higher treatment-related adverse events occurred in 65% of patients receiving Osimertinib plus Carboplatin-Pemetrexed compared with 10% of patients receiving Osimertinib alone. Importantly, the adverse-event profile remained consistent with the known toxicities of platinum-based chemotherapy and Osimertinib, and investigators reported no unexpected safety signals. Toxicities were considered manageable with standard supportive care and dose modifications.

Clinical Implications

The FLAME study represents one of the strongest prospective demonstrations that serial ctDNA monitoring can directly inform treatment decisions in metastatic EGFR-mutated NSCLC. Rather than serving solely as a prognostic biomarker, ctDNA becomes an actionable tool capable of identifying patients who benefit from early therapeutic intensification before radiographic progression develops.

This strategy has several potential clinical advantages.

1) Early molecular assessment may allow oncologists to intervene during a window when resistant clones remain limited in number, potentially delaying the emergence of clinically significant resistance.
2) It also introduces a risk-adapted treatment model in which chemotherapy is selectively administered to patients with demonstrated molecular persistence rather than universally to all patients at diagnosis.

The study further supports growing interest in integrating serial liquid biopsy into routine management of oncogene-driven lung cancers, not only for resistance mutation detection at progression but also for monitoring early treatment effectiveness and guiding adaptive therapeutic strategies.

Future Directions

Although highly encouraging, FLAME remains a Phase II study with a relatively modest sample size. Longer follow-up will be needed to determine whether the substantial improvement in PFS translates into an OS advantage. Planned analyses examining resistance mechanisms, dynamic multi-omics biomarkers, and Quality-of-Life outcomes may further refine patient selection and clarify which molecular features predict the greatest benefit from treatment escalation.

Larger Phase III studies will be essential before ctDNA-guided escalation becomes a routine component of first-line EGFR-mutated NSCLC management. Nevertheless, FLAME establishes an important proof of concept that precision oncology can evolve beyond baseline genomic testing toward continuous molecular monitoring that dynamically informs treatment decisions throughout the course of therapy.

Clinical Perspective  

FLAME introduces a paradigm shift in the management of EGFR-mutated advanced NSCLC by demonstrating that early molecular response, rather than baseline genotype alone, can guide individualized therapy. Patients with persistent plasma ctDNA after three weeks of Osimertinib experienced a marked improvement in PFS when chemotherapy was introduced early, providing prospective evidence that adaptive, biomarker-driven treatment intensification can improve outcomes in a biologically defined high-risk population. As liquid biopsy technologies become increasingly integrated into routine oncology practice, ctDNA-guided treatment adaptation may represent the next major step toward truly personalized therapy for patients with oncogene-driven lung cancer.

Osimertinib with/without chemotherapy in patients with persistent ctDNA EGFR mutant (EGFRm) NSCLC at 3 weeks after 1L osimertinib: A randomized phase II study (FLAME study). Wang Z, Zhong J, Duan J, et al. J Clin Oncol 44, LBA101(2026)

FDA Approves WELIREG® with KEYTRUDA® for Adjuvant Treatment of Renal Cell Carcinoma

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SUMMARY: The FDA on June 12, 2026, approved Belzutifan (WELIREG®) in combination with Pembrolizumab (KEYTRUDA®) or Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) for the adjuvant treatment of adults with renal cell carcinoma with a clear cell component (ccRCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

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 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 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)

FDA Approves IBRANCE® with HER2 Targeted Therapy and Endocrine Therapy as Maintenance Treatment in HR-positive, HER2-positive Advanced Breast Cancer

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SUMMARY: The FDA on June 24, 2026, approved IBRANCE® (Palbociclib) in combination with Trastuzumab, with or without Pertuzumab, and endocrine therapy for the maintenance treatment of adults with Hormone Receptor (HR)–positive, HER2-positive locally advanced or metastatic breast cancer following induction treatment.

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, HR–positive, HER2-negative tumors represent the most common subtype (60-70%). However, 15%–20% of primary breast cancers overexpress HER2, a historically aggressive phenotype. Hormone Receptor (HR)-positive, HER2-positive, breast cancer occurs in about 8% to 10% of all invasive breast cancer cases, 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 – ASCO 2026: Ivonescimab Plus Chemotherapy Delivers Superior Overall Survival Benefit in Advanced Squamous NSCLC

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SUMMARY: 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. Of the three main subtypes of NSCLC, 25% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large cell carcinomas. Non-Small Cell Lung Cancer patients with Squamous Cell histology have been a traditionally hard- to-treat, patient group, with less than 5% of patients with advanced SCC, surviving for five years or longer.

Background

The advent of Immune Checkpoint Inhibitors (ICIs) has fundamentally transformed the treatment landscape of advanced NSCLC. By targeting immune regulatory pathways such as programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), these therapies restore T-cell activity and enhance antitumor immune responses. Biomarkers including PD-L1 expression, Tumor Mutational Burden (TMB), and mismatch repair (MMR) status have become important tools for predicting response; however, many patients, particularly those with low PD-L1 expression, continue to experience suboptimal outcomes.

While PD-1 inhibitors have established immunotherapy as a cornerstone of first-line treatment in advanced NSCLC, therapeutic progress has been slower in patients with squamous histology. Squamous NSCLC accounts for approximately 25% of all NSCLC cases and is associated with poorer clinical outcomes and fewer effective treatment options than nonsquamous disease. In addition, the use of conventional VEGF inhibitors has historically been limited in this population because of concerns regarding severe pulmonary hemorrhage.

Rationale for Dual PD-1 and VEGF Inhibition

Ivonescimab (AK112) is a novel bispecific antibody designed to simultaneously target PD-1 and vascular endothelial growth factor (VEGF). This dual-targeting strategy combines immune checkpoint inhibition with antiangiogenic therapy within a single molecule, with the goal of enhancing antitumor activity while minimizing off-target effects.

Preclinical and early clinical evidence suggests that simultaneous inhibition of PD-1 and VEGF may produce synergistic antitumor effects by improving immune cell infiltration, suppressing tumor angiogenesis, and enhancing T-cell activation. Importantly, previous studies demonstrated encouraging efficacy even among patients with low PD-L1 expression, without the excess bleeding complications traditionally associated with VEGF inhibitors in squamous NSCLC.

TEVIMBRA® (Tislelizumab) is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.

The HARMONi-6 Study Design

HARMONi-6 is a multicenter, randomized, double-blind, Phase III trial conducted across 50 hospitals in China. The study enrolled 532 patients aged 18–75 years with previously untreated, unresectable Stage IIIB, IIIC, or Stage IV squamous NSCLC and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The median age was 64 yrs and 93% of patients were male.

Patients were randomized equally to receive:

  • Ivonescimab plus Paclitaxel and Carboplatin for four induction cycles followed by maintenance Ivonescimab, or
  • Tislelizumab plus Paclitaxel and Carboplatin followed by maintenance Tislelizumab.

The Primary endpoint was Progression-Free Survival (PFS), while Overall Survival (OS) served as a key Secondary endpoint.

Improved Disease Control

Earlier analyses from HARMONi-6 demonstrated that Ivonescimab significantly delayed disease progression compared with Tislelizumab. Median PFS improved to approximately 11 months versus 9 months, supporting the potential advantage of combining PD-1 and VEGF inhibition over PD-1 blockade alone.

Overall Survival Benefit

The prespecified interim Overall Survival analysis further strengthened the clinical significance of these findings.

After a median follow-up of 21.4 months, patients receiving Ivonescimab plus chemotherapy achieved a median OS of 27.9 months, compared with 23.7 months for those receiving Tislelizumab plus chemotherapy. This translated into a 34% reduction in the risk of death (Hazard Ratio 0.66; 95% CI 0.50–0.87; P=0.0017).

At the time of data cutoff, 84 deaths had occurred in the Ivonescimab arm compared with 120 deaths in the control arm, demonstrating a durable survival advantage for the investigational regimen.

Consistent Benefit Regardless of PD-L1 Expression

One of the most compelling observations from HARMONi-6 was the consistency of benefit across PD-L1 expression subgroups.

Among patients treated with standard immunochemotherapy, survival remained strongly influenced by PD-L1 status. Individuals with PD-L1 expression ≥1% experienced substantially longer survival than those with PD-L1-negative tumors.

In contrast, patients treated with Ivonescimab demonstrated prolonged survival irrespective of PD-L1 expression. Median OS had not yet been reached in either the PD-L1-high or PD-L1-low subgroups at the time of analysis, suggesting that dual PD-1/VEGF inhibition may overcome one of the major limitations of conventional checkpoint inhibitor therapy.

Safety Profile

The safety profile of Ivonescimab was generally consistent with expectations for combination immunochemotherapy.

Grade 3 or higher treatment-related adverse events occurred in 69% of patients receiving Ivonescimab compared with 59% in the Tislelizumab group. The most common severe adverse events included:

  • Neutropenia
  • Decreased white blood cell count
  • Anemia

Given the historical concern regarding VEGF inhibition in squamous NSCLC, bleeding events were carefully monitored. Grade 3 or higher hemorrhage occurred in 3% of patients receiving Ivonescimab versus 1% of those treated with Tislelizumab, indicating that serious bleeding remained relatively uncommon despite the incorporation of VEGF blockade.

Clinical Significance

Historically, advanced squamous NSCLC has been associated with limited therapeutic advances and inferior outcomes compared with nonsquamous disease. HARMONi-6 is among the few Phase III studies in this setting to demonstrate a median OS approaching 28 months, representing an important milestone for this patient population.

The findings suggest that simultaneous inhibition of PD-1 and VEGF using a bispecific antibody can provide clinically meaningful improvements in both disease control and OS while maintaining a manageable safety profile.

Looking Ahead

Although these results are highly encouraging, confirmation in more geographically diverse populations will be essential. Ongoing global studies, including the Phase III HARMONi-3 trial, will further evaluate the efficacy and safety of Ivonescimab across broader patient populations.

Key Clinical Takeaways

  • Ivonescimab is a first-in-class bispecific antibody targeting both PD-1 and VEGF.
  • HARMONi-6 demonstrated significant improvements in both Progression-Free and Overall Survival compared with Tislelizumab plus chemotherapy.
  • Median Overall Survival improved from 23.7 months to 27.9 months, reducing the risk of death by 34%.
  • Clinical benefit was observed regardless of PD-L1 expression, potentially expanding treatment options for patients with PD-L1-low disease.
  • Serious hemorrhagic events remained uncommon despite VEGF inhibition.
  • Dual PD-1/VEGF blockade represents a promising first-line therapeutic strategy for patients with advanced squamous NSCLC and may redefine future standards of care pending global validation.

Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: Overall survival results of the phase 3 HARMONi-6 trial. Zhiwei C, Yang F, Luo Y, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA4)

Late Breaking Abstract – ASCO 2026: Evidence for Comprehensive PI3K/AKT/mTOR Pathway Inhibition in HR-Positive, HER2-Negative Advanced Breast Cancer

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

Therapeutic Challenges Following CDK4/6 Inhibitor Progression

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors). The treatment landscape for this group of patients has evolved substantially with the incorporation of CDK4/6 inhibitors in combination with endocrine therapy. However, disease progression following a CDK4/6 inhibitor and Aromatase Inhibitor remains a common clinical challenge, and the optimal approach after progression continues to evolve.

Targeting the PI3K/AKT/mTOR signaling pathway has become an established strategy in this setting, particularly for tumors harboring PIK3CA mutations. Several approved therapies, including PI3K, AKT, and mTOR inhibitors, have demonstrated clinical benefit, but each acts at a single point within the pathway. This approach may permit compensatory signaling through alternative pathway components, potentially contributing to treatment resistance. In addition, class-associated toxicities such as hyperglycemia and diarrhea can affect treatment delivery and patient experience.

Gedatolisib was developed as a comprehensive inhibitor of the PI3K/AKT/mTOR pathway. Unlike currently available agents that target individual nodes within the pathway, Gedatolisib inhibits all four class I PI3K isoforms while also targeting both mTORC1 and mTORC2. Because its activity is not dependent on a specific PIK3CA mutation, the agent has been investigated in both PIK3CA-mutated and PIK3CA wild-type disease.

VIKTORIA-1 Trial Design

The Phase 3 VIKTORIA-1 trial was designed to evaluate Gedatolisib-based regimens in patients with HR-positive, HER2-negative advanced breast cancer whose disease had progressed during or after treatment with a CDK4/6 inhibitor and an Aromatase Inhibitor. The study enrolled patients with measurable disease who had not received chemotherapy for advanced disease and had no prior exposure to PI3K, AKT, or mTOR inhibitors. Patients with PIK3CA-mutated disease were randomized in a 3:3:1 ratio to receive one of three treatment regimens:

  • Gedatolisib, Palbociclib, and Fulvestrant
  • Alpelisib and Fulvestrant
  • Gedatolisib and Fulvestrant

Gedatolisib was administered at 180 mg IV weekly for three consecutive weeks followed by one week off treatment. Palbociclib was administered according to the standard 125 mg orally, 21-days-on, 7-days-off schedule, while Fulvestrant was administered 500 mg IM every 2 weeks in cycle 1 then every 4 weeks. Alpelisib was administered orally at 300 mg daily.

The Primary endpoint was Progression-Free Survival (PFS) comparing the Gedatolisib triplet regimen with Alpelisib plus Fulvestrant. Secondary endpoints included PFS for the Gedatolisib doublet versus Alpelisib plus Fulvestrant, Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), Clinical Benefit Rate (CBR), Quality of Life (QOL) measures, pharmacokinetics, and Safety.

Progression-Free Survival Results in PIK3CA-Mutated Disease

The Primary analysis included 362 patients with PIK3CA-mutated disease and a median Progression-Free Survival follow-up of 11 months.

The trial met its Primary endpoint. Patients treated with the Gedatolisib, Palbociclib, and Fulvestrant combination experienced a median PFS of 11.1 months compared with 5.6 months for those receiving Alpelisib plus Fulvestrant. This translated into a 50% reduction in the risk of disease progression or death (Hazard Ratio [HR], 0.50; 95% confidence interval [CI], 0.37–0.68; P<0.0001).

A PFS benefit was also observed with the Gedatolisib and Fulvestrant doublet. Median PFS was 11.3 months compared with 5.6 months for Alpelisib plus Fulvestrant (HR, 0.51; 95% CI, 0.33–0.79; P=0.0013).

The magnitude of benefit observed with both Gedatolisib-containing regimens resulted in an absolute improvement in median PFS of approximately 5.5-5.7 months relative to the comparator arm.

Response Outcomes

Additional efficacy analyses demonstrated higher ORR with Gedatolisib-based therapy.

Objective Response Rates were:

  • 48.9% with Gedatolisib, Palbociclib, and Fulvestrant
  • 35.7% with Gedatolisib and Fulvestrant
  • 26.0% with Alpelisib and Fulvestrant

Responses also appeared more durable in the Gedatolisib-containing treatment groups. Median Duration of Response was:

  • 15.7 months with the Gedatolisib triplet
  • 24.2 months with the Gedatolisib doublet
  • 7.5 months with Alpelisib plus Fulvestrant

Overall Survival data remain immature and continue to be evaluated.

Findings Across PIK3CA Mutation Subgroups

The results from the PIK3CA-mutated cohort build on findings previously reported from the PIK3CA wild-type cohort of VIKTORIA-1.

In the wild-type population, both Gedatolisib plus Fulvestrant and Gedatolisib plus Palbociclib and Fulvestrant demonstrated significant improvements in PFS compared with Fulvestrant alone. These earlier findings suggested that comprehensive pathway inhibition may provide benefit regardless of PIK3CA mutation status.

The consistency of efficacy observed across both molecular subgroups supports further evaluation of Gedatolisib as a treatment option beyond the traditionally defined PIK3CA-mutated population.

Safety Profile

Safety analyses showed distinct differences in adverse event patterns between Gedatolisib-containing regimens and Alpelisib plus Fulvestrant.

Hyperglycemia, a commonly observed toxicity associated with PI3K inhibition, occurred less frequently in patients receiving Gedatolisib-based therapy: 15.0% with the Gedatolisib triplet, 11.5% with the Gedatolisib doublet and 57.9% with Alpelisib plus Fulvestrant. Grade 3 hyperglycemia occurred in 2.6% of patients receiving the Gedatolisib triplet, 0% receiving the Gedatolisib doublet and 13.8% receiving Alpelisib plus Fulvestrant.

Similarly, diarrhea was reported less frequently with Gedatolisib-containing regimens than with Alpelisib plus Fulvestrant.

Treatment discontinuation due to treatment-related adverse events was also less common in the Gedatolisib arms: 2.6% with the Gedatolisib triplet, 3.8% with the Gedatolisib doublet and 7.1% with Alpelisib plus Fulvestrant. In contrast, stomatitis was observed more frequently with Gedatolisib-based therapy. Grade 3 stomatitis occurred in 16.3%, 5.8%, and 5.3% of patients, respectively.

Implications for Treatment Sequencing

The VIKTORIA-1 findings contribute to ongoing discussions regarding optimal sequencing of targeted therapies after progression on first-line CDK4/6 inhibitor-based treatment.

The trial provides randomized Phase 3 evidence supporting comprehensive inhibition of the PI3K/AKT/mTOR pathway compared with approaches directed at a single pathway component. Whether Gedatolisib should be introduced immediately after progression on a CDK4/6 inhibitor or reserved for later lines of therapy following exposure to other targeted agents remains an area for further investigation. The availability of multiple pathway-directed therapies raises additional questions regarding resistance mechanisms, treatment sequencing, and patient selection that are not fully addressed by the current analysis.

Practical Considerations

A distinguishing feature of Gedatolisib is its route of administration. Unlike currently available oral PI3K, AKT, and mTOR inhibitors, Gedatolisib requires IV on a weekly schedule for three weeks of each four-week cycle. This treatment schedule introduces logistical considerations related to infusion visits, patient convenience, and healthcare resource utilization. These factors may influence treatment selection in clinical practice, particularly when multiple active therapeutic options are available.

As treatment decisions increasingly incorporate both efficacy and patient preference, the balance between clinical benefit, toxicity profile, and treatment burden will likely play a role in determining how Gedatolisib-based regimens are incorporated into routine care.

Conclusion

The Phase 3 VIKTORIA-1 trial demonstrated significant improvements in PFS with both Gedatolisib-containing regimens compared with Alpelisib plus Fulvestrant in patients with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor and Aromatase Inhibitor. Improvements were also observed in Objective Response Rates and Duration of Response.

The findings complement previously reported results in PIK3CA wild-type disease and support further evaluation of comprehensive PI3K/AKT/mTOR pathway inhibition across molecular subgroups. Ongoing follow-up will determine the impact on Overall Survival and help clarify the role of Gedatolisib within the evolving treatment sequence for HR-positive, HER2-negative advanced breast cancer.

A randomized, open-label, phase 3 study of gedatolisib + fulvestrant ± palbociclib vs standard of care in HR+/HER2−/PIK3CA-mutant (MT) advanced breast cancer (VIKTORIA-1 Study 2). Hurvitz SA, Curigliano G, Andre F, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1008)

FDA Approves All-Oral Treatment for Newly Diagnosed Acute Myeloid Leukemia

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SUMMARY: The FDA on May 13, 2026, approved an oral combination of Decitabine and Cedazuridine tablets (INQOVI®) with Venetoclax for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in adults 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

The American Cancer Society estimates that in 2026, 22,720 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,500 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy.

Advancing Convenience Without Compromising Efficacy

The treatment landscape for older adults with AML who are not candidates for intensive induction chemotherapy has evolved significantly with the introduction of Venetoclax-based combinations. However, despite improved outcomes, current standards of care still rely heavily on parenteral HypoMethylating Agents (HMAs), requiring frequent visits to healthcare facilities and creating substantial logistical and quality-of-life challenges for patients and caregivers.

Findings from the Phase 1–2 ASCERTAIN-V trial offer compelling evidence that an entirely oral regimen consisting of Decitabine–Cedazuridine (INQOVI®) and Venetoclax (VENCLEXTA®) may provide a clinically effective alternative, while reducing the treatment burden associated with injectable therapies. The study evaluated the safety, pharmacokinetics, and efficacy of this oral combination in patients with newly diagnosed AML who were either 75 years of age or older or considered unsuitable for intensive chemotherapy due to significant comorbidities.

The Rationale for an All-Oral Approach

Venetoclax combined with Azacitidine or Decitabine has become the established frontline treatment for patients with AML who are ineligible for intensive chemotherapy. While these regimens have demonstrated meaningful survival benefits, they require repeated administration of intravenous or subcutaneous HMAs over several days during each treatment cycle.

Decitabine–Cedazuridine was developed to address this challenge by delivering oral Decitabine exposure comparable to IV administration. Cedazuridine inhibits cytidine deaminase, preventing premature degradation of Decitabine in the gastrointestinal tract and allowing therapeutic systemic exposure through oral dosing. Previous studies have demonstrated pharmacokinetic equivalence between oral Decitabine–Cedazuridine and intravenous Decitabine, paving the way for evaluation in AML.

The ASCERTAIN-V investigators sought to determine whether combining oral Decitabine–Cedazuridine with oral Venetoclax could maintain the efficacy expected from HMA-Venetoclax therapy while improving treatment convenience and potentially enhancing patient experience.

Study Design and Patient Population

ASCERTAIN-V was a multicenter, open-label, nonrandomized Phase 1–2 study conducted across 34 academic and community treatment centers in the United States, Canada, and Spain.

The trial enrolled patients with newly diagnosed AML who met one of two criteria:

  • Age 75 years or older, or
  • Younger patients with significant comorbidities that precluded intensive chemotherapy.

Qualifying comorbid conditions included severe cardiac or pulmonary disease, impaired renal function, moderate hepatic dysfunction, or reduced performance status.

All participants received:

  • Oral Decitabine–Cedazuridine (35 mg/100 mg) on days 1–5 of each 28-day cycle
  • Oral Venetoclax, initiated with a standard ramp-up schedule and continued at 400 mg daily

A total of 189 patients were enrolled across the study, including 101 patients in the pivotal Phase 2b cohort that served as the primary efficacy population.

Pharmacokinetic Findings Confirm Combination Feasibility

A key objective of the study was to determine whether coadministration of Venetoclax altered exposure to Decitabine–Cedazuridine or vice versa.

Results demonstrated no clinically meaningful drug–drug interactions between the two agents. Pharmacokinetic analyses showed that systemic Decitabine exposure remained consistent with previous studies evaluating oral Decitabine–Cedazuridine alone, supporting the feasibility of combining the two oral therapies without compromising drug delivery. These findings are particularly important because maintaining predictable drug exposure is essential when replacing established IV regimens with oral alternatives.

Encouraging Clinical Activity in a High-Risk Population

The pivotal Phase 2b cohort met its predefined efficacy objective and demonstrated substantial antileukemic activity.

Among evaluable patients:

  • Complete remission (CR) was achieved in 47% of patients.
  • The combined rate of Complete Remission and Complete Remission with incomplete hematologic recovery (CR + CRi) reached 63%.
  • Median Overall Survival was 15.5 months.
  • Among patients achieving Complete Remission, 75% maintained their response at 12 months.

Minimal Residual Disease (MRD) analyses, although exploratory and not standardized, also provided encouraging signals. More than half of responding patients achieved MRD negativity by multiparameter flow cytometry, a finding often associated with deeper remissions and improved long-term outcomes.

Managing Myelosuppression Through Adaptive Treatment Strategies

As expected with Venetoclax-based AML therapy, myelosuppression remained the principal toxicity observed during treatment.

The most common grade 3 or higher adverse events in the pivotal phase 2b cohort included Anemia (30%), Neutropenia (26%) and Febrile neutropenia (25%). Early mortality remained within expected ranges for this older and medically complex population, with 30-day and 60-day mortality rates of 3% and 10%, respectively.

Importantly, the investigators incorporated treatment modifications during the Phase 2b portion of the study to reduce prolonged cytopenias. Early bone marrow assessments were used to confirm blast clearance before completion of a full 28-day course of Venetoclax. Once remission was documented, Venetoclax exposure was shortened and treatment schedules for both agents were adjusted to facilitate hematologic recovery.

This strategy appeared successful. As treatment progressed, the duration of Venetoclax administration decreased, accompanied by reductions in serious adverse events and febrile neutropenia. Similarly, Decitabine–Cedazuridine exposure was individualized over time, supporting a treatment paradigm that emphasizes intensive disease control during induction followed by tailored maintenance of remission.

Clinical Implications for Practice

The ASCERTAIN-V results reinforce the growing recognition that effective AML treatment can potentially be delivered outside traditional infusion-based settings.

For clinicians, the findings highlight several practical considerations:

  • Early bone marrow evaluation may help identify patients who can benefit from abbreviated Venetoclax exposure.
  • Dose modifications should be incorporated proactively to mitigate prolonged cytopenias.
  • Growth factor support should be considered in patients with severe or persistent neutropenia.
  • Venetoclax dosing must be adjusted appropriately when azole antifungal prophylaxis is required.
  • Close monitoring remains essential despite the convenience of oral administration.

The trial also underscores the importance of adherence monitoring, as treatment success with oral regimens depends on consistent medication use. Investigators reported high adherence rates through the use of patient diaries and pill counts.

A Potential Alternative to Infusion-Based HMA-Venetoclax Therapy

Cross-trial comparisons should be interpreted cautiously, particularly given the single-arm design of ASCERTAIN-V. Nevertheless, the observed remission rates, overall survival outcomes, and safety profile appear broadly comparable to those reported historically with Azacitidine-Venetoclax and IV Decitabine-Venetoclax combinations.

Given that oral Decitabine–Cedazuridine achieves systemic exposure equivalent to intravenous Decitabine, the study supports the concept that an all-oral HMA-Venetoclax regimen can deliver clinically meaningful outcomes without introducing new safety concerns.

Beyond efficacy, the potential reduction in travel, clinic visits, caregiver burden, and treatment-associated disruption may represent a significant advantage for older patients who often face mobility limitations and competing medical challenges.

Looking Ahead

The ASCERTAIN-V trial marks an important step toward more patient-centered AML care. By demonstrating meaningful remission rates, durable responses, and survival outcomes with a fully oral treatment strategy, the study provides evidence that convenience and clinical efficacy do not necessarily need to be mutually exclusive.

While randomized comparative studies and formal Quality-of-Life assessments would further strengthen the evidence base, these findings suggest that oral Decitabine–Cedazuridine plus Venetoclax may emerge as a valuable frontline option for patients with newly diagnosed AML who are not candidates for intensive chemotherapy.

As the AML treatment landscape continues to evolve, the ability to deliver effective therapy through a fully oral regimen has the potential to reshape care delivery and improve the treatment experience for a vulnerable patient population.

All-Oral Treatment of Newly Diagnosed Acute Myeloid Leukemia. Roboz GJ,  Zeidan AM, Mannis GN, et al. N Engl J Med 2026;394:2107-2116.

HERIZON-GEA-01 and the Future of HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma

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Written by: Benjamin L. Kitchens, MD
Sponsored by: Jazz Pharmaceuticals

Gastroesophageal adenocarcinoma (GEA) includes cancers of the gastroesophageal junction (GEJ) and stomach.  In 2026, U.S. estimates project 31,510 new cases of gastric cancer and 22,530 new cases of esophageal cancer [1,2].  Gastric and GEJ cancer are often diagnosed at advanced stages due to lack of screening programs in the US; this portends a poor prognosis.  The 5-year relative survival for gastric cancer is 78.1% for localized disease, 39.0% for regional disease, and 8.1% for distant metastatic disease [1].  Similarly, esophageal cancer 5-year relative survival rates are 48.6% for localized disease, 29.1% for regional disease, and 5.3% for distant metastatic disease [2].  The poor prognoses for patients with metastatic GEA underscore the need for continued advances in early detection and innovative therapies to improve outcomes.

Biomarker-driven therapy has transformed the treatment landscape for metastatic GEA.  Approximately 14 to 22% of GEAs are HER2-positive [3-5], and HER2-targeted therapy has become central to treatment.  First line therapy for advanced GEA currently consists of FOLFOX plus trastuzumab, with the addition of pembrolizumab for PD-L1 positive (combined positive score ≥ 1) disease, based on the Keynote-811 trial [6].  This trial showed a median overall survival (OS) of 20 months for pembrolizumab added to trastuzumab and chemotherapy, versus 16.8 months for trastuzumab and chemotherapy alone.  Median progression-free survival (PFS) was 10.0 versus 8.1 months, respectively [6].  HER2-directed therapy remains relevant in the second line setting, with the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) available.  While these treatments reflect impactful progress, there remains a critical need for advanced HER2-directed therapies that deliver deeper and more durable responses.  Zanidatamab is a dual HER2-targeted bispecific immunoglobulin G1-like antibody that binds to two separate extracellular domains of HER2 (domains 2 and 4) [7].  Zanidatamab has already received accelerated approval for previously treated unresectable or metastatic HER2-positive biliary tract cancer, and is under investigation for the treatment GEA [7].

The ongoing Herizon-GEA-01 study is a phase 3 randomized trial evaluating first-line zanidatamab in combination with chemotherapy, plus or minus anti-PD-1 immunotherapy [8].  Participants were 18 years or older with histologically confirmed unresectable, locally advanced, recurrent or metastatic HER2-positive GEA [8].  HER2 positivity consisted of a HER2 immunohistochemistry (IHC) score of 3+, or IHC2+ with positive in situ hybridization.  Other inclusion criteria were an ECOG performance status of 0 or 1, assessable disease defined by RECIST 1.1 criteria, adequate organ function, and left ventricular ejection fraction at least 50%.  Select exclusion criteria were untreated or symptomatic CNS metastases, prior treatment for locally advanced/metastatic GEA, prior HER2-targeted treatment, and prior immunotherapy including anti-PD-1 and anti-PD-L1 agents.

In Herizon-GEA-01, 914 patients were stratified based on geographic region, HER2 status, and ECOG performance status.  Participants were randomly assigned 1:1:1 to one of three treatment arms [8,9].  Arm A patients received trastuzumab plus physician’s choice of chemotherapy (CAPOX or FP).  Arm B received IV zanidatamab 1800mg (weight <70kg)/2400mg (weight ≥70kg) Q3W plus physician’s choice of chemotherapy.  Arm C received IV zanidatamab plus IV tislelizumab 200mg Q3W plus physician’s choice of chemotherapy.

Patients continued treatment until death, disease progression, or unacceptable toxicity.  Chemotherapy could be discontinued after 6 cycles.  The median age in the treatment arms ranged from 62.5 to 64.  Most patients were male (77.3 to 80.8%), ECOG performance status of 1 (55.9 to 61%), metastatic disease (94 to 97.1%), HER2 IHC 3+ (82.6 to 83.1%) and with a PD-L1 tumor area positivity (TAP) score of 1% or greater (58.6 to 61.9%) [10].  Dual primary endpoints were PFS by blinded independent central review and OS.  Secondary endpoints included objective response rate, duration of response, safety, health-related quality of life, and pharmacokinetics.

Interim analysis of HERIZON-GEA-01 demonstrates deeper and more durable responses in the zanidatamab arms than those seen in the trastuzumab plus chemotherapy control arm [10,11].  The median PFS was 12.4 months in both zanidatamab-treated arms compared to 8.1 months in the control arm.  Median overall survival was 24.4 months in the zanidatamab plus chemotherapy arm, and 26.4 in the zanidatamab plus tislelizumab plus chemo arm, compared to 19.2 months in the control arm.  Objective response rates were 65.7% in the control arm, 69.6% in the zanidatamab plus chemotherapy arm, and 70.7% in the zanidatamab plus tislelizumab plus chemotherapy arm.  Median duration of response was 8.3 months in the control arm, 14.3 months in the zanidatamab plus chemotherapy arm, and 20.7 months in the zanidatamab plus tislelizumab plus chemotherapy arm.

Safety data from HERIZON-GEA-01 interim analysis reveals expected results and a manageable zanidatamab toxicity profile.  Diarrhea was the most common adverse event across all three arms, occurring in 82% and 76% of patients in the zanidatamab-treated arms [10].  Other common adverse events across all groups included nausea, vomiting and decreased appetite [11].  Of note, diarrhea prophylaxis was mandatory for patients treated with zanidatamab.  Therefore, appropriate antidiarrheal prophylaxis in the clinic will be very important.  This trial is ongoing and we anticipate further survival data in the future.

This pivotal data from HERIZON-GEA-01 is anticipated to have a meaningful impact on this patient population.  This is particularly in light of the deeper and more long-lasting responses.  Over time, we will see if this translates into statistically significant overall survival and progression-free survival benefits.

References:

  1. Cancer Stat Facts: Stomach Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/stomach.html.  Accessed May 13, 2026.
  2. Cancer Stat Facts: Esophageal Cancer. National Cancer Institute. Surveillance, Epidemiology, and End Results Program.  https://seer.cancer.gov/statfacts/html/esoph.html.  Accessed May 13, 2026.
  3. Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer.  Gastric Cancer.  2015;18(3):476-484.  doi:10.1007/s10120-014-0402-y.
  4. Janjigian YY, Werner D, Pauligk C, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA International collaborative analysis.  Ann Oncol.  2012;23(10):2656-2662.  doi:10.1093/annonc/mds104.
  5. Kim WH, Gomez-Izquierdo L, Vilardell F, et al. HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study.  Appl Immunohistochem Mol Morphol.  2018;26(4):239-245.  doi:10.1097/PAI.0000000000000423.
  6. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer.  N Engl J Med. 2024;391(14):1360-1362.  doi:10.1056/NEJMc2408121.
  7. Ziihera ® (zanidatamab-hrii) | Official Website for US Healthcare Professionals. Jazz Pharmaceuticals.  https://www.ziiherahcp.com/.  Accessed May 13, 2026.
  8. A Study of Zanidatamab in Combination With Chemotherapy With or Without Tislelizumab in Subjects With HER2-positive Unresectable Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma (GEA). gov.  https://clinicaltrials.gov/study/NCT05152147.  Accessed May 13, 2026.
  9. Tabernero J, Shen L, Elimova E, et al. HERIZON-GEA-01: Zanidatamab + chemo ± tislelizumab for 1L treatment of HER2-positive gastroesophageal adenocarcinoma.  Future Oncol.  2022;18(29):3255-3266.  doi:10.2217/fon-2022-0595.
  10. Elimova E, Rha SY, Shitara K, et al. Zanidatamab + chemotherapy (CT) ± tislelizumab for first-line (1L) HER2-positive (HER2+) locally advanced, unresectable, or metastatic gastroesophageal adenocarcinoma (mGEA): Primary analysis from HERIZON-GEA-01.  J Clin Oncol.  2026;44(2 suppl):LBA285.  doi:10.1200/JCO.2026.44.2_suppl.LBA285.
  11. Zanidatamab With or Without Tislelizumab Yields Clinically Meaningful Survival Benefit in HER2-Positive Advanced Gastroesophageal Adenocarcinoma. ASCO Daily News.  https://dailynews.ascopubs.org/do/zanidatamab-without-tislelizumab-yields-clinically-meaningful-survival-benefit-her2.  Accessed May 13, 2026.

Late Breaking Abstract – ASCO 2026: Perioperative Apalutamide Plus ADT in High-Risk Localized and Locally Advanced Prostate Cancer

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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.

Background
Patients with high-risk localized prostate cancer and locally advanced prostate cancer remain at substantial risk for recurrence following definitive local therapy. Radical prostatectomy with pelvic lymph node dissection is a potentially curative treatment option. However, disease recurrence occurs in up to 50% of patients within five years of surgery. Long-term outcomes remain suboptimal despite advances in surgical techniques and patient selection.

The use of neoadjuvant systemic therapy before surgery is established in several solid tumors, but previous studies evaluating neoadjuvant approaches in prostate cancer have not resulted in changes to clinical practice. Earlier trials were limited by heterogeneous patient populations, including lower-risk disease, and by reliance on endpoints such as Prostate-Specific antigen (PSA) response rather than long-term oncologic outcomes.

Phase 2 studies investigating Androgen Receptor Pathway Inhibitors in the neoadjuvant setting demonstrated reductions in residual tumor burden and increased rates of pathological response, providing the rationale for larger randomized studies. Apalutamide (ERLEADA®) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.

The Phase 3 PROTEUS trial was designed to determine whether perioperative treatment with Apalutamide plus Androgen Deprivation Therapy (ADT) could improve pathological and long-term clinical outcomes in patients with high-risk localized or locally advanced prostate cancer undergoing radical prostatectomy.

Study Design and Patient Population

PROTEUS was a Phase 3, randomized, double-blind, placebo-controlled trial that enrolled patients with newly diagnosed high-risk localized or locally advanced prostate cancer.

A total of 2,109 patients were randomized in a 1:1 ratio to receive either:

  • Apalutamide 240 mg daily plus ADT (N=1,057), or
  • Placebo plus ADT (N=1,052)

Treatment was administered for six 28-day cycles before surgery, followed by radical prostatectomy with pelvic lymph node dissection. After surgery, patients received an additional six cycles of their assigned treatment. A two-week treatment break was incorporated before surgery, followed by a four-week break after surgery before treatment resumed.

Eligible patients had high-risk localized or locally advanced disease based on histologic and clinical criteria, including PSA level and nodal status assessed by conventional imaging. The median age of enrolled patients was 66 years, and 95.8% had a Gleason score of 8 or higher. The median follow-up was 61.7 months.

Study Endpoints

The trial had two Primary endpoints:

  • Pathological Complete Response (pCR) or minimal residual disease, defined as pathological Stage ypT2 or lower with residual tumor measuring no more than 5 mm in greatest dimension.
  • Metastasis-Free Survival (MFS), assessed by Blinded Independent Central Review using conventional imaging and/or Prostate-Specific Membrane Antigen Positron Emission Tomography (PSMA PET).

Secondary endpoints included:

  • Event-Free Survival (EFS)
  • Time to first subsequent treatment
  • Time to distant metastasis
  • Safety

Exploratory analyses included assessment of residual cancer burden and investigator-assessed Metastasis-Free Survival.

Primary Endpoint: Pathological Response

The addition of Apalutamide to ADT resulted in higher rates of pathological Complete Response or minimal residual disease at the time of surgery.

Pathological Complete Response or minimal residual disease was achieved in 8.9% of patients receiving Apalutamide plus ADT versus 1.0% of patients receiving placebo plus ADT. This corresponded to an odds ratio of 10.17 (95% CI, 5.27–19.64; P<0.0001).

These findings indicate a substantially greater proportion of patients had limited or no residual tumor identified in the surgical specimen following neoadjuvant treatment with Apalutamide plus ADT.

Primary Endpoint: Metastasis-Free Survival (MFS)

The Second Primary endpoint, Metastasis-Free Survival, was also met.

Treatment with Apalutamide plus ADT was associated with a reduction in the risk of distant metastasis or death compared with placebo plus ADT (Hazard ratio: 0.80; 95% CI: 0.67–0.96; P=0.0169). At five years, MFS rates were 78.2% in the Apalutamide group and 73.5% in the placebo group. Median MFS was not reached in either treatment arm. Investigator-assessed MFS showed similar results, with a Hazard Ratio of 0.74 (95% CI, 0.62–0.87).

Secondary Efficacy Endpoints

All key secondary efficacy endpoints favored the Apalutamide-containing regimen.

Event-Free Survival (EFS) was prolonged with Apalutamide plus ADT (Hazard ratio: 0.71; 95% CI: 0.63–0.80; P<0.0001). Median EFS was 57.1 months with Apalutamide plus ADT versus 38.4 months with placebo plus ADT

The addition of Apalutamide delayed the need for additional local, regional, or systemic therapy, including re-initiation of ADT (Hazard Ratio: 0.65; 95% CI: 0.57–0.73; P<0.0001). Median time to first subsequent treatment was 74.2 months in the Apalutamide arm and 41.5 months in the placebo arm.

Time to distant metastasis also favored Apalutamide plus ADT (Hazard Ratio: 0.68; 95% CI: 0.55–0.83; P=0.0002). Median time to distant metastasis was not reached in either treatment group.

Residual Cancer Burden Analysis

Exploratory analyses evaluating residual cancer burden also demonstrated lower residual disease following treatment with Apalutamide. Minimal residual disease based on residual cancer burden criteria was observed in 30.6% of patients receiving Apalutamide plus ADT versus 11.7% of patients receiving placebo plus ADT. The odds ratio was 3.36 (95% CI, 2.67–4.23; P<0.0001). These findings support the association between intensified Androgen Receptor Pathway Inhibition and reduction in residual tumor burden at surgery.

Role of PSMA PET Imaging

PROTEUS incorporated both conventional imaging and PSMA PET imaging in the assessment of Metastasis-Free Survival. The inclusion of PSMA PET reflects changes in prostate cancer staging and recurrence assessment during the conduct of the trial. PSMA PET has greater sensitivity than conventional imaging, particularly at low PSA levels, and is increasingly incorporated into routine clinical practice. The study authors noted that increasing use of PSMA PET may influence assessment of disease recurrence and should be considered in future clinical trial designs evaluating localized prostate cancer.

Safety

The safety profile of Apalutamide plus ADT was consistent with previous studies of Apalutamide. Grade 3 or 4 treatment-emergent adverse events occurred in 39.6% of patients receiving apalutamide plus ADT and 31.0% of patients receiving placebo plus ADT. The difference was primarily attributable to a higher incidence of rash in the Apalutamide arm. Treatment discontinuation due to adverse events occurred in 7.4% of patients receiving Apalutamide and 2.7% of patients receiving placebo. No new safety signals were identified during the study.

Clinical Implications

PROTEUS is the first Phase 3 trial to demonstrate improvements in both pathological response and Metastasis-Free Survival with perioperative Androgen Receptor Pathway Inhibition in patients undergoing radical prostatectomy for high-risk localized or locally advanced prostate cancer.

Treatment with Apalutamide plus ADT before and after surgery resulted in higher rates of pathological Complete Response or minimal residual disease, improved Metastasis-Free Survival, prolonged Event-Free Survival, delayed need for subsequent treatment, and longer time to distant metastasis compared with ADT alone.

These findings provide evidence supporting perioperative treatment intensification with Apalutamide plus ADT in patients with high-risk localized or locally advanced prostate cancer who are candidates for radical prostatectomy.

Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study. Mary-Ellen Taplin M-E, Gleave M, Shore ND, et al. J Clin Oncol 44, 2026 (suppl 17; abstr LBA1)