Giredestrant (GIRE) + Palbociclib (PALBO) vs Letrozole (LET) + PALBO As First-Line (1L) Therapy in Patients (Pts) with Estrogen Receptor–Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer (ER+, HER2– LA/mBC): Primary Analysis of The Phase III PersevERA BC Trial

Presenter: Nicholas Turner

• Background: Endocrine therapy plus a CDK4/6 inhibitor is the standard first-line treatment for ER+, HER2− locally advanced/metastatic breast cancer (LA/mBC). Giredestrant (GIRE), a next-generation oral SERD, has shown efficacy in earlier and later disease settings. The phase III persevERA BC trial evaluated GIRE + palbociclib versus letrozole (LET) + palbociclib in the first-line setting.
• Methods: Patients with de novo or recurrent ER+, HER2− LA/mBC and no prior systemic therapy for advanced disease were randomized 1:1 to GIRE + palbociclib or LET + palbociclib. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, response outcomes, and safety.
• Results: A total of 992 patients were randomized (495 GIRE; 497 LET). At a median follow-up of 52.2 months, the hazard ratio for PFS was 0.89 (95% CI 0.76–1.05; p=0.1553), with median PFS of 33.1 months for GIRE + palbociclib versus 28.2 months for LET + palbociclib. Although numerically improved, the difference did not reach statistical significance. Grade 3–4 adverse events were mainly hematologic and consistent with palbociclib use. Endocrine therapy discontinuation due to adverse events was low and similar between arms.

  	GIRE + PALBO (n = 495)	LET + PALBO (n = 497)
  Median PFS, mo (95% CI)	33.1 (30.2, 38.3)	28.2 (25.0, 33.1)
  HR* (95% CI); p-value†	0.89 (0.76, 1.05); 0.1553
  Median OS, mo (95% CI)	NE (NE)	NE (61.3, NE)
  HR* (95% CI); p-value†	1.03 (0.83, 1.28); 0.777
  ORR, %	60.2	58.8
  Median DoR, mo (95% CI)	38.5 (30.4, 48.7)	30.4 (25.3, 36.1)
  HR* (95% CI); p-value†	0.80 (0.63, 1.01); 0.056
  CBR, %	82.6	82.1

  *Stratified.

  ^†Stratified log-rank.

  NE, not evaluable.

   

• Conclusion: GIRE + palbociclib showed a numerical but not statistically significant PFS improvement over LET + palbociclib in first-line ER+, HER2− LA/mBC, with a tolerable and expected safety profile

First-line (1L) Camizestrant (CAMI) for Emergent ESR1 Mutations (ESR1m) in Advanced Breast Cancer (ABC): Final Progression-free Survival 2 (PFS2) from the Phase III SERENA-6 Trial

Presenter: Francois Clement Bidard

• Background: CAMI is a next-generation SERD and complete ER antagonist. In SERENA-6, patients with HR+/HER2− advanced breast cancer on first-line aromatase inhibitor (AI) + CDK4/6 inhibitor who developed emerging ESR1 mutations—but had not yet progressed—benefited from switching to CAMI while continuing CDK4/6 inhibition. This significantly improved PFS; final PFS2 results are now reported.
• Methods: SERENA-6 evaluated investigator-assessed PFS2 as a key secondary endpoint, defined as time from randomization to progression after first subsequent therapy or death. Patients underwent imaging every 8–12 weeks after first progression. Secondary endpoints included chemotherapy/ADC-free survival.
• Results: A total of 157 patients received CAMI + CDK4/6i and 158 received continued AI + CDK4/6i. After a median follow-up of 23.5 months (cutoff: January 3, 2026), median PFS2 was 25.7 vs 19.1 months (HR 0.63; 95% CI 0.46–0.86; p=0.00373), favoring CAMI. CAMI also prolonged chemotherapy/ADC-free survival (HR 0.64) and delayed deterioration in global health status/quality of life. The original PFS benefit was maintained with longer follow-up, with 30-month PFS rates of 30.4% vs 2.7%. Benefit was consistent regardless of common PIK3CA or TP53 co-mutations. OS data remain immature (HR 0.87). Safety was consistent with prior analyses.

  DCO3		CAMI+ CDK4/6i (n=157)	AI + CDK4/6i (n=158)	HR (95% CI)
  PFS	Events, n (%) Median, mo 24-mo rate, % 30-mo rate, %	99 (63.1) 16.8 34.9 30.4	124 (78.5) 9.2 14.2 2.7	0.45 (0.34–0.59); p<0.00001
  PFS2	Events, n (%) Median, mo 24-mo rate, % 30-mo rate, %	80 (51.0) 25.7 50.8 41.5	90 (57.0) 19.1 36.3 29.7	0.63 (0.46–0.86); p=0.00373
  Chemotherapy/ADC-free survival	Events, n (%) Median, mo	85 (54.1) 22.6	98 (62.0) 18.7	0.64 (0.47–0.87); nominal p=0.00375

• Conclusion: Switching to CAMI + CDK4/6i at ESR1 mutation emergence during first-line AI + CDK4/6i significantly improved PFS2, prolonged chemotherapy/ADC-free survival, and delayed QoL deterioration compared with continuing AI + CDK4/6i. These results support early switching to CAMI to delay progression.

Selinexor Plus Ruxolitinib in JAK Inhibitor–Naïve Myelofibrosis: Phase 3 SENTRY Trial

Presenter: John Mascarenhas

• Background: Myelofibrosis (MF) is a symptomatic myeloproliferative neoplasm with splenomegaly, constitutional symptoms, and poor survival. Although ruxolitinib is standard frontline therapy, only about one-third of patients achieve meaningful spleen reduction, and disease-modifying effects remain limited. Selinexor, an XPO1 inhibitor, has shown biologic activity in MF and synergy with ruxolitinib. The phase III SENTRY trial evaluated selinexor plus ruxolitinib in JAK inhibitor–naïve MF.
• Methods: Patients with JAK inhibitor–naïve MF were randomized 2:1 to selinexor + ruxolitinib or placebo + ruxolitinib. Co-primary endpoints were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (TSS, excluding fatigue) at Week 24. Secondary endpoints included safety and overall survival (OS), with variant allele frequency (VAF) changes explored.
• Results: A total of 353 patients were randomized (235 to selinexor + ruxolitinib; 118 to ruxolitinib alone). At Week 24, SVR35 was achieved in 49.8% vs 28.0% (OR 2.58; P<0.0001), with earlier and more durable spleen responses seen with the combination. Mean spleen volume change at Week 24 was −40.0% vs −26.7%. Symptom improvement was comparable between arms, and the TSS endpoint was not met. With median follow-up of ~12 months, OS favored the combination (HR 0.43; nominal P=0.022). VAF reduction ≥20% occurred more often with selinexor + ruxolitinib (32.0% vs 23.9%). Adverse events were more frequent with the combination, but discontinuation rates remained low.
• Conclusion: Selinexor plus ruxolitinib significantly improved spleen responses over ruxolitinib alone, with durable activity, an early OS signal, and manageable safety. These findings support this combination as a promising frontline treatment option for MF.

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)

Presenter: Sara Hurvitz

• Background: In HR+/HER2-/PIK3CA-mutant advanced breast cancer (ABC), currently available PI3K/AKT/mTOR pathway inhibitors improve outcomes but are often limited by class-related toxicities such as hyperglycemia and diarrhea. Gedatolisib is a potent IV pan-PI3K/mTOR inhibitor with broad pathway coverage and favorable preclinical activity. The phase III VIKTORIA-1 trial evaluated gedatolisib-based regimens after progression on CDK4/6 inhibitor plus aromatase inhibitor; here, the primary results of the PIK3CA-mutant cohort are reported.
• Methods: Patients with HR+/HER2- ABC, prior CDK4/6 inhibitor + AI, no prior chemotherapy for advanced disease, and no prior PI3K/AKT/mTOR inhibitor were randomized 3:3:1 to gedatolisib + palbociclib + fulvestrant, alpelisib + fulvestrant, or gedatolisib + fulvestrant. The primary endpoint was progression-free survival (PFS) for the gedatolisib triplet versus alpelisib/fulvestrant. Secondary endpoints included PFS for the gedatolisib doublet, OS, response, safety, and quality of life.
• Results: At the March 9, 2026 data cutoff (N=362), median follow-up for PFS was 11.0 months. The trial met its primary endpoint: median PFS was 11.1 months with the gedatolisib triplet versus 5.6 months with alpelisib/fulvestrant (HR 0.50; 95% CI 0.37–0.68; P<0.0001). The gedatolisib doublet also improved PFS versus alpelisib/fulvestrant (11.3 vs 5.6 months; HR 0.51; 95% CI 0.33–0.79; P<0.0013). Discontinuation due to treatment-related adverse events was low across arms. Hyperglycemia was markedly lower with gedatolisib regimens, while stomatitis was more frequent.
• Conclusion: Gedatolisib-based combinations significantly improved PFS versus alpelisib/fulvestrant in PIK3CA-mutant HR+/HER2- ABC, with manageable safety. These findings support gedatolisib combinations as a promising new second-line treatment option, potentially regardless of PIK3CA mutation status.

A Phase III, Randomized, Open-Label Study of Tunlametinib Plus Vemurafenib Versus Investigator's Choice of Therapy in Patients with Previously Treated BRAF^V600E-mutant Metastatic Colorectal Cancer

Presenter: Ting Xu

• Background: BRAF V600E–mutant metastatic colorectal cancer (mCRC), found in ~10% of cases, is associated with poor prognosis and limited chemotherapy benefit. Tunlametinib is a novel oral MEK1/2 inhibitor, and early-phase data showed promising synergy with vemurafenib in BRAF-mutant tumors. This phase III trial evaluated the combination in previously treated BRAF V600E–mutant mCRC.
• Methods: In this randomized, open-label phase III study (NCT06008119), patients with BRAF V600E–mutant mCRC after ≥1 prior therapy were randomized 2:1 to tunlametinib + vemurafenib (T+V) or investigator’s choice of treatment. The primary endpoint was progression-free survival (PFS) by blinded independent review per RECIST v1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.
• Results: As of March 5, 2026, 157 patients were included (105 T+V; 52 control). Based on investigator assessment, T+V significantly improved median PFS versus control (4.2 vs 1.5 months; HR 0.374; 95% CI 0.252–0.555; P<0.001). ORR was 37.1% vs 7.7%, and disease control rate was 81.9% vs 38.5% (both P<0.0001). OS data were immature. Grade ≥3 treatment-related adverse events occurred in 62.0% vs 44.2%, while discontinuation due to toxicity was low in both arms (0.9% vs 3.8%).
• Conclusion: Tunlametinib plus vemurafenib significantly improved PFS and response rates over conventional therapy in previously treated BRAF V600E–mutant mCRC, with manageable safety and the convenience of an all-oral regimen.

  Prevalence of Symptomatic Skeletal Events (SSE) with Reduced Denosumab (Dmab) Dose Density (Every 12 Weeks versus Every 4 Weeks): A Randomized Phase III Non-Inferiority Trial SAKK 96/12 REDUSE

  Presenter: Roger Von Moos

• Background: Denosumab (Dmab) 120 mg every 4 weeks (Q4W) is the standard for patients with bone metastases. Although 12-weekly (Q12W) dosing is established for zoledronic acid, prospective evidence for Dmab using skeletal-related events is lacking. The SAKK 96/12 REDUSE trial evaluated whether Q12W Dmab, after an initial loading phase, is non-inferior to standard Q4W dosing in preventing symptomatic skeletal events (SSEs).
• Methods: In this international, multicenter, randomized phase III trial, patients with metastatic breast cancer (BC) or castration-resistant prostate cancer (CRPC) and ≥3 bone metastases were randomized 1:1 to Dmab 120 mg Q4W (Arm A) or 4 loading doses Q4W followed by Q12W dosing (Arm B). The primary endpoint was time to first on-trial SSE. Secondary endpoints included time to first and subsequent SSEs, hypocalcemia, and osteonecrosis of the jaw (ONJ).
• Results: A total of 1,380 patients were enrolled between July 2014 and March 2024 (784 BC; 596 CRPC), with a median follow-up of 37 months. The trial met its primary endpoint, showing Q12W Dmab was non-inferior to Q4W (HR 1.023; 90% CI 0.874–1.197). Non-inferiority was also demonstrated for first and subsequent SSEs (HR 1.043; 90% CI 0.907–1.198). Toxicity was lower with Q12W dosing: hypocalcemia occurred in 30% vs 46%, and ONJ in 6.9% vs 8.5%.
• Conclusion: Dmab Q12W, after a 3-month loading phase, was non-inferior to Q4W in patients with bone-metastatic BC or CRPC and showed a better safety profile. This schedule may reduce toxicity, treatment burden, and costs, supporting Q12W as a potential new standard of care.

First-Line Datopotamab Deruxtecan (Dato-DXd) vs Chemotherapy in Patients with Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer (TNBC) for whom Immunotherapy was Not an Option: Additional Efficacy Endpoints from the TROPION-Breast02 Study

Presenter: David Cescon

• Background: In the phase 3 TROPION-Breast02 study, first-line Dato-DXd significantly improved overall survival (HR 0.79; p = 0.0291) and progression-free survival (HR 0.57; p < 0.0001) versus investigator’s choice chemotherapy (ICC) in patients with unresectable or metastatic TNBC not eligible for immunotherapy, with a manageable safety profile.
• Methods: Adults with previously untreated locally recurrent inoperable or metastatic TNBC were randomized 1:1 to Dato-DXd 6 mg/kg every 3 weeks or ICC ([nab]-paclitaxel, capecitabine, eribulin, or carboplatin). Dual primary endpoints were OS and PFS by BICR, while secondary endpoints included PFS2, TFST, and TSST.
• Results: Among 644 randomized patients (Dato-DXd: 323; ICC: 321), with a median follow-up of 27.5 months, Dato-DXd improved PFS2 (15.6 vs 11.8 months; HR 0.61), TFST (10.9 vs 5.6 months; HR 0.49), and TSST (16.7 vs 12.6 months; HR 0.67) versus ICC. More patients remained on treatment with Dato-DXd than ICC (14.1% vs 2.6%).
• Conclusion: Dato-DXd improved secondary efficacy endpoints in addition to OS and PFS, further supporting it as a potential new first-line standard of care for patients with metastatic TNBC who are not candidates for immunotherapy.

Safety and Efficacy of Eganelisib in Adults with Higher-Risk Myelodysplastic Syndrome (HR-MDS) or Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Presenter: Mendel Goldfinger

• Background: PI3Kγ is a myeloid-specific signaling target that supports AML leukemic stem cell self-renewal, marrow homing, and resistance to venetoclax and nucleoside analogues. Eganelisib, a selective PI3Kγ inhibitor with prior safety data in solid tumors, was evaluated as monotherapy in relapsed/refractory AML or high-risk MDS.
• Methods: Patients with ECOG PS <2 and relapsed/refractory AML or IPSS-R intermediate to very high-risk MDS with ≥10% bone marrow blasts received oral eganelisib at 45 mg or 60 mg once daily in 28-day cycles. Primary endpoints were safety, efficacy, and recommended dose for expansion; pharmacokinetics and pharmacodynamic inhibition of AKT phosphorylation were also assessed.

  	45 mg (n=7)	60 mg (n=8)	All (n=15)
  Age (median/range)	78 (71-85)	59 (20-74)	72 (20-85)
  AML | MDS	7 | 0	7 | 1	14 | 1
  Prior MDS or MDS-related changes	6	5	10
  Prior therapies (median/range)	2 (1-3)	2 (1-6)	2 (1-6)
  Adverse-risk ELN	86%	71%	79%
  TP53mutation	43%	43%	43%
  Prior intensive chemo/venetoclax	14%/71%	50%/100%	33%/87%

    

• Results: 15 patients were treated (n=7 at 45 mg; n=8 at 60 mg) with no dose-limiting toxicities at either dose. At 60 mg, eganelisib produced about 90% reduction in AKT phosphorylation. Among 10 evaluable patients, 4 showed anti-leukemic activity, including 1 complete response at 45 mg; 3 additional patients at 60 mg showed marrow blast reduction and hematologic improvement. The longest treatment duration was 5 cycles, and plasma exposure overlapped across both dose levels.
• Conclusion: Eganelisib showed effective PI3Kγ inhibition, single-agent activity, and no intrinsic hematologic toxicity in heavily pretreated poor-risk AML/MDS, supporting PI3Kγ as a therapeutic vulnerability. Based on these findings, 60 mg once daily has been selected for planned combination studies in previously untreated high-risk MDS and AML.

Revumenib as Maintenance for AML Following Allogeneic Stem Cell Transplantation

Presenter: Hannah Goulart

• Background: Relapse after allogeneic SCT remains a major challenge in AML. Although revumenib is approved for relapsed/refractory NPM1-mutant or KMT2A-rearranged acute leukemia, its role as post-SCT maintenance is unclear. We report institutional outcomes of revumenib maintenance in adult and pediatric patients.
• Methods: Patients with NPM1-mutant, KMT2A-rearranged, or NUP98-rearranged AML who responded to pre-SCT revumenib (alone or in combination on trial) received post-SCT revumenib maintenance, resumed at the pre-SCT dose with azole-based dose adjustments.
• Results: Among 21 patients (11 adults, 10 pediatric; median age 20 years), most had KMT2A-rearranged AML (76%), followed by NPM1-mutant (19%) and NUP98-rearranged (5%). Patients had received a median of 3 prior therapies, 57% had prior SCT, and post-SCT revumenib was started at a median of 2.8 months for 6.7 months. At a median follow-up of 18.2 months, median OS and EFS were not reached; 1-/2-year OS was 89%, and 1-/2-year EFS was 84%/73%. The 1-year relapse incidence was 11% and death 5%; in CR2+, 2-year OS was 93% and 1-year relapse incidence 13%. Thrombocytopenia was the most common AE (86%; grade ≥3, 43%), prompting dose modification in 48% and discontinuation in 10%; no QTc prolongation was observed. Compared with a historical cohort, outcomes appeared favorable (2-year OS 93% vs 33%; 1-year relapse 13% vs 46% in CR2+).

  	N	1-yr OS (%)	2-yr OS (%)	1-year CIR (%)	Median F/U (mos)
  Rev	21	89	89	11	18.2
  Rev CR2+	17	93	93	13	33.3
  Hist.	320	60	51	39	76
  Hist. CR2+	124	45	33	46	92

    

• Conclusion: Revumenib maintenance after SCT was feasible in this heavily pretreated cohort. Thrombocytopenia was the main toxicity, often requiring dose modification, while other significant toxicities were uncommon. Outcomes appeared favorable versus historical cohorts, supporting prospective evaluation of menin inhibition as maintenance.

Comparative Analysis of Tirzepatide versus Metformin and Insulin in Type 2 Diabetes Patients Across the 13 Most Common Cancers

Presenter: Viraj Shah

• Background: Emerging glucose-lowering therapies may affect cancer risk in type 2 diabetes mellitus (T2DM). However, evidence for tirzepatide—a dual GLP-1/GIP agonist with proven cardiometabolic benefits—remains limited. Therefore, evaluated the risk of incident cancers and all-cause mortality with tirzepatide versus metformin or insulin in patients with T2DM
• Methods: Performed a retrospective cohort study using the U.S.-based TriNetX electronic health record network. Adults with T2DM who initiated tirzepatide, metformin, or insulin between February 2020 and February 2025, with no prior cancer, were included. After 1:1 propensity score matching for key baseline characteristics, Cox proportional hazards models were used to estimate risks of 13 common incident cancers and all-cause mortality
• Results: After matching, baseline characteristics were balanced. Versus insulin, tirzepatide reduced the risk of lung, pancreatic, liver, colorectal, kidney, and endometrial cancers, and non-Hodgkin lymphoma (all p < 0.01). Versus metformin, it lowered the risk of lung cancer (HR 0.086; p < 0.001), pancreatic cancer (HR 0.124; p = 0.022), and breast cancer (HR 0.462; p = 0.009), with no significant differences for most other cancers. Tirzepatide also reduced all-cause mortality versus insulin and metformin, with absolute risk reductions of 4.8% and 0.6%, respectively (both p < 0.001).
• Conclusion: In this large real-world propensity-matched analysis, tirzepatide was associated with lower all-cause mortality and reduced incidence of multiple cancers versus insulin and metformin, suggesting a potentially favorable oncologic profile that warrants prospective confirmation.

Reference: Annual Meeting of the American Society of Clinical Oncology (ASCO 2026), 29^th May – 6^th June 2026, Chicago, IL.