New in Oncology - June 27, 2025
TP53 refolding is working! PI3K breakthroughs in breast cancer. Plus wins in HNSCC, NSCLC, AML, and more...
THIS WEEKโS BREAKTHROUGHS:
PI3K Power, p53 Refolding, and STING-Driven Immunity
Precision PI3K blockade, first-in-class p53 refolding, intratumoral STING agonism, and a menin-based triplet are vaulting past incremental gains.
๐ T-DXd Crushes T-DM1 Across Genomics: PFS 21-37 mo vs 5-10 mo regardless of HER2 copy-number, PI3K, or HRD status.
๐ Pan-PI3K/mTOR Triplet Rockets to 85% ORR: Gedatolisib + palbociclib + ET hits 85% front-line ORR and 63% post-CDK4/6.
๐ Mutant-Selective PI3Kฮฑ Shrinks Tumors in 31% with Minimal Hyperglycemia: RLY-2608 posts 9.2-mo mPFS and just 2% grade-3 glucose spikes.
๐ ADC + TKI Combo Posts 100% Responses First-Line: T-DXd + pyrotinib delivers 4/4 partial responses in HER2-positive mBC.
๐ p53 Refolder Rezatapopt Yields 38% ORR in TP53 Y220C: First chemo-free option to reactivate mutant p53 function.
๐ Chemo-Free DTP Triplet Hits 49% pCR: Durvalumab + trastuzumab + pertuzumab rivals docetaxel pCR rates in HER2-enriched early disease.
๐ Peri-Op Nivolumab Lifts 30-mo EFS to 61%: CheckMate 77T pushes median EFS to 46.6 mo vs 16.9 mo with surgery-alone standard.
๐ Menin Triplet Delivers 88% ORR & 100% MRD-Clearance: Revumenib + AZA + VEN induces rapid, deep remissions in older NPM1m/KMT2Ar AML.
๐ STING Agonist + Pembrolizumab Hits 50% ORR: Ulevostinag doubles first-line response versus pembrolizumab alone.
And thatโs just the headlinersโscroll, click, or search for the other 20+ detailed findings in this weekโs issue.
28 NEW FINDINGS
Breast Cancer (19), NSCLC (2), Acute Leukemia (2), HNSCC (1), Melanoma (1), Follicular Lymphoma (1), Glioblastoma (1), CLL / SLL (1)
THIS WEEKโS NEW TRIALS:
11 New Oncology Trials: Front-Line CAR-T, PSMA Radioligand Therapy, and Personalized Vaccines
Some trials to watch:
Lisocabtagene Maraleucel Front-Line in Primary CNS Lymphoma: CD19-directed CAR-T moves up to first-line therapy for transplant-ineligible PCNSLโpoised to replace high-dose chemo/radiation if safety holds.
177Lu Vipivotide Tetraxetan ยฑ ARPI in mCRPC: Phase II randomizes PSMA-positive, ARPI-progressed prostate cancer to radioligand alone or with androgen blockadeโtesting synergy to prolong rPFS.
NeoVax Personalized Neo-Antigen Vaccine + Nivolumab: First-in-human, multi-tumor study pairs bespoke long-peptide vaccine with PD-1 and poly ICLC to drive potent cytolytic T-cell responses.
The slate also features a CSF1R-mAb + radiotherapy + pembrolizumab combo tackling myeloid suppression in post-IO TNBC, plus FGFR2-triplet cholangiocarcinoma, intermittent venetoclax dosing in CLL/SLL, CD5-CAR-T for T-cell malignancies, CMV-Triplex vaccine after transplant, and more.
11 NEW TRIALS
Breast Cancer (2), NSCLC (1), Solid Tumor (1), Cholangiocarcinoma (1), CNS Lymphoma (1), Glioblastoma (1), Prostate Cancer (1), CLL / SLL (1), Non-Hodgkin Lymphoma / ALL Trial (1), Hematological Malignancies (1)
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28 New Findings This Week
Breast Cancer
๐ SPOTLIGHT: HER2 ADC clears genomic hurdlesT-DXd Outscores T-DM1 Across HER2 Copy-Number, PI3K, and HRD Genomic Subsets in DESTINY-Breast03
In this ctDNA biomarker dive from the Phase III DESTINY-Breast03 trial (nโ420), researchers profiled >700 genes at baseline and progression. Despite wide heterogeneityโPIK3CA 48%, TP53 73%, HER2 amplifications detected in only 56% of plasma samplesโtrastuzumab deruxtecan kept its edge: ORR 77-87% and median PFS 21-37 mo regardless of high vs low vs undetectable HER2 copy number, PI3K-pathway mutation, or HRD/BRCA status. By contrast, trastuzumab emtansine faltered when HER2 copy number or HRD markers were low/positive (ORR 31-50%, mPFS 5-10 mo; HR for PI3K-mut 0.41 vs wild-type). T-DXdโs 22-month PFS gain over T-DM1 held steady across every genomic slice examined.
Take Home: These data cement T-DXd as the go-to second-line choice in HER2-positive metastatic breast cancerโits payload delivery seems impervious to the usual genomic troublemakers, whereas T-DM1 performance craters when HER2 copy or repair competency wane.
๐ SPOTLIGHT: Pan-PI3K triplet rockets ORR to 85%Gedatolisib (pan-PI3K/mTOR) Triplet Hits 85% ORR in HR+/HER2- mBC
Gedatolisib 180 mg IV weekly plus palbociclib and letrozole/fulvestrant was explored in the phase 1b NCT02684032 dose-expansion (four cohorts by prior therapy). ORR reached 85% with 72% 12-mo PFS in treatment-naรฏve Arm A, 77%/55% after prior ET (Arm B), 36%/24% post-CDK4/6 (Arm C) and 63%/53% in an alternate-schedule post-CDK4/6 arm (Arm D); median OS is still immature. For context, palbociclib + letrozole alone records โ44% front-line ORR, while real-world alpelisib after CDK4/6 failure delivers ORR โฒ13%, highlighting the tripletโs potency across lines.
Take Home: If confirmed in randomized trials, adding a pan-PI3K/mTOR layer could lift response rates well above CDK4/6 standards and rescue activity after CDK4/6 exposure, but durability, toxicity, and biomarker selection still need proving.
๐ SPOTLIGHT: More tolerable mutant-selective PI3Kฮฑ shows promiseRLY-2608 Mutant-Selective PI3Kฮฑ Inhibitor Achieves 31% ORR and 9-Month mPFS with Minimal Grade 3 Hyperglycemia in Post-CDK4/6 HR+/HER2โป mBC
RLY-2608 is an oral, allosteric PI3Kฮฑ inhibitor that binds only oncogenic PIK3CA variants, sparing wild-type signaling to reduce metabolic toxicity. In the phase 1 ReDiscover trial, 52 heavily pre-treated HR+/HER2โป metastatic breast-cancer patients lacking PTEN/AKT co-alterations received the RP2D 600 mg BID plus standard-dose fulvestrant; all had prior endocrine therapy and CDK4/6 inhibition, 22% had prior chemo/ADC. Confirmed objective response rate was 30.8% (8/26 evaluable), 69% showed any tumor shrinkage, and median PFS reached 9.2 months (95% CI 5.5โ12.4). Safety was dominated by low-grade hyperglycemia (42% any grade, 2% grade 3), nausea (40%, 1% grade 3) and rash-diarrhea โค 1% grade 3โcontrasting with alpelisibโs 36% grade 3 hyperglycemia and 14% grade 3 rash in SOLAR-1.
Take Home: Early data suggest RLY-2608 could finally make PI3K targeting tolerableโmatching alpelisib-like efficacy after CDK4/6 failure while largely sidestepping the glucose and skin toxicities that cripple current class members; a randomized study is the next hurdle.
๐ SPOTLIGHT: ADC-TKI combo hits 100% first-line responsesT-DXd + Pyrotinib Hits 100% PR in Phase Ib First-Line HER2-Positive mBC (TROPHY)
Trastuzumab deruxtecan (T-DXd), a HER2-directed topoisomerase-I ADC, was paired with the irreversible pan-HER TKI pyrotinib in the TROPHY phase Ib dose-finding study (NCT06245824). Five previously untreated metastatic HER2-positive patients (DFI >6 mo from adjuvant therapy) received T-DXd 5.4 mg/kg Q3W plus pyrotinib 400 mg (n = 2) or 320 mg (n = 3) daily. One grade 3 anorexia DLT at 400 mg set the RP2D at 320 mg. All patients experienced diarrhea, nausea, and vomiting, but grade โฅ3 events were limited (diarrhea in 1/3 at 320 mg; anorexia/ALT โ in 1/2 at 400 mg); no grade 4/5 toxicities or ILD were observed. Among four RECIST-evaluable patients, all achieved partial responses (ORR = 100%), a numerical step above the 80% ORR seen with pertuzumab-trastuzumab-docetaxel and the 75% ORR reported for T-DXd monotherapy in first-line exploratory cohorts.
Take Home: This early signal suggests ADC + TKI synergy could raise the efficacy bar in first-line HER2-positive disease, but the n = 4 response set demands cautious optimism until the phase II expansion confirms durability and safety, particularly GI and ILD risks.
๐ SPOTLIGHT: Longstanding goal of p53 refolding has been reached!Rezatapopt Restores Mutant p53, Yields 38% ORR in Heavily Pretreated TP53 Y220C-Mutated Metastatic Breast Cancer
Rezatapopt (PC14586) is an oral, first-in-class small-molecule that binds the p53 Y220C pocket, refolding the mutant protein into a wild-type conformation and reactivating tumor-suppressor function. In the Phase 1 PYNNACLE trial (NCT04585750), nine women with advanced breast cancer carrying the TP53 Y220C mutation (median 4 prior regimens; 4 TNBC) received rezatapopt 150 mg QDโ1 500 mg BID. Among eight RECIST-evaluable patients, confirmed partial responses occurred in 3 (37.5%), four achieved stable disease, and tumor shrinkage was seen in all (-2% to -55%). Treatment-related events were mostly grade 1/2 nausea (51%), vomiting (43%), and creatinine rise (27%); no grade โฅ3 GI events were reported when dosing with food. These results compare favorably with the <10% ORR typically seen with single-agent chemotherapy in this refractory setting, and they are agnostic to hormone/HER2 status.
Take Home: Although Y220C appears in only ~1โ2% of breast cancers, this molecularly tailored p53 reactivator could offer a meaningful, chemo-free option for a subset that currently has noneโPhase 2 data will show whether durability and breadth justify routine genomic screening for this hotspot.
๐ SPOTLIGHT: Chemo-free DTP neoadjuvant nears 50% pCRChemo-Free Durvalumab + Trastuzumab + Pertuzumab Yields 49% pCR (68% RCB0/1) in HER2-Enriched Early Breast Cancer
The single-arm Phase II DTP trial (NCT03820141) treated 39 stage IโIII, ER/PR-negative, (by a BluePrint [BP] 80-gene molecular subtyping test that classifies early-stage breast cancer (EBC) into Basal, Luminal, and HER2 subtypes) tumors with six 3-weekly cycles of the PD-L1 antibody durvalumab plus dual HER2 blockade (trastuzumab 6 mg/kg Q3W, pertuzumab 420 mg Q3W) without chemotherapy; 37 were evaluable. Pathologic complete response reached 18/37 (48.6%) and overall RCB0/1 25/37 (67.6%). pCR correlated positively with stromal TILs (p = 0.02) and PD-L1 CPS (p = 0.038) and inversely with tumor size and node positivity. Only five grade 3 AEs occurred, versus the โฅ40% grade 3โ4 toxicity typical of taxane-based regimens. Notably, this chemo-free pCR rivals the 49% achieved by docetaxel + trastuzumab + pertuzumab in the NeoSphere trial and far surpasses the 17% pCR seen with trastuzumab + pertuzumab alone.
Take Home: For carefully selected HER2-BP assay-enriched, immune-inflamed tumors, adding PD-L1 blockade may let some patients ditch cytotoxics altogetherโan idea ripe for randomized confirmation to see whether less really can be more.
Real-World Endocrine-Resistant HR+/HER2- mBC Progresses in โ8 mo on First-Line CDK4/6i, with 40% PIK3CA Mutations
A Flatiron Health EHR review (2015-2023) captured 7,096 U.S. patients starting first-line therapy for recurrent HR+/HER2- metastatic breast cancer. Among 922 who met INAVO120 endocrine-resistant criteria and still received an ET + CDK4/6 inhibitor (most palbociclib + fulvestrant), PIK3CA mutations were found in 39โ41%. Outcomes lagged sharply: real-world median PFS 8.2โ8.5 mo, time-to-chemotherapy 16.2โ21.7 mo, and OS 27.0โ29.7 mo versus 13.0, 33.0, and 36.8 mo in the broader HR+/HER2- cohort. Fast progression โค6 mo hit 35โ38%. Only ~11% were genotyped before starting therapy, despite 59โ61% eventually being tested. For comparison, pivotal first-line CDK4/6i trials (MONARCH 3) report median PFS โ29 mo, and adding the PI3Kฮฑ degrader inavolisib to palbociclib + fulvestrant extended PFS to 17.2 mo in the INAVO120 study.
Take Home: These real-world data expose a dramatic efficacy gap in endocrine-resistant, PIK3CA-mutated HR+/HER2- diseaseโhighlighting the need for routine early mutation testing and PI3K-targeted add-ons like inavolisib rather than recycling CDK4/6i alone.
Five-Fraction Ablative RT + Endocrine Therapy Achieves 53% pCR, Skips Surgery in Stage I HR+ Breast Cancer
A single-arm Phase II trial (NCT02945579) enrolled 20 women โฅ 50 y with unicentric, stage I HR+/HER2- tumors (Oncotype โค25). After three months of endocrine therapy and hypofractionated ablative radiotherapy (37.5 Gy/5 fx, every other day), vacuum-assisted biopsies at 6โ12 mo showed pathologic CR in 10/19 (52.6%) and near-CR in another 7/19 (36.8%); pCR rate rose from 45% at 6 mo to 63% at 12 mo. Only 7 patients required surgery, and among the 12 who avoided it, no local recurrences have emerged at a median 26 mo. By contrast, neoadjuvant endocrine therapy alone rarely tops 10% pCR in ER+ disease, underscoring the boost from ablative RT.
Take Home: Early data hint that endocrine + ultra-short RT could let carefully selected low-risk HR+ patients skip the knife, but the tiny cohort and short follow-up mean definitive trialsโand vigilant long-term surveillanceโare essential before practice changes.
Olaparib + Durvalumab (PARP/PD-L1) Achieve 70% pCR, Early CD8+ Spike in TNBC
In the window-of-opportunity MEDIOLA Phase II trial (NCT03594396), 54 stage II/III triple-negative or ER-low breast-cancer patients received 4 weeks of olaparib (PARP inhibitor) with a single durvalumab dose before standard anthracycline/taxane neoadjuvant chemotherapy. Pathologic complete response reached 38/54 (70.4%), outstripping the ~33% pCR historically seen with chemotherapy alone and topping the 64.8% achieved with pembrolizumab-chemo in KEYNOTE-522. Homologous-recombination-deficient tumors (50%) showed higher early metabolic responses, and multiplex IHC revealed a two-week surge of exhausted (PD-1+/TIM3+) and activated (CD25+) CD8+ T-cells plus CD4+/CXCL13+ helpers that persisted through week 4, signalling rapid immune priming by PARP blockade. Baseline immune cell densities alone were not predictive.
Take Home: If larger randomized studies confirm that a brief PARP + PD-L1 lead-in pushes pCR above current chemo-immunotherapy benchmarksโespecially in HR-deficient diseaseโthis strategy could redefine how we prime early TNBC before surgery while offering real-time immune biomarkers to guide escalation or de-escalation.
Ipatasertib Triplet Doubles PFS in PI3K/AKT/PTEN-Mutant HR+/HER2- Metastatic Breast Cancer After CDK4/6
Ipatasertibโthe oral pan-AKT inhibitorโwas tested in the Phase Ib TAKTIC trial (NCT03959891) alongside fulvestrant ยฑ palbociclib in 77 pre-treated, CDK4/6-exposed HR+/HER2- MBC patients. In the 20-patient triplet cohort with baseline NGS, tumors harboring pathway mutations (PIK3CA, AKT1, or PTEN; n = 9) achieved a median PFS of 505 days (16.6 mo) versus 114 days (3.8 mo) for wild-type disease (HR 0.20, p = 0.015). FGFR1 amplification independently predicted rapid progression (HR 5.42). Overall, PI3K/AKT/PTEN alterations were present in 60% of patients and ESR1 in 25% patients, while RAS/FGFR1/ERBB2 changes trended toward resistance. Toxicities mirrored prior ipatasertib data with manageable diarrhea and rash. By comparison, the capivasertib + fulvestrant CAPItello-291 regimen prolonged PFS to 7.2 mo vs 3.1 mo for fulvestrant alone, and everolimus + exemestane delivers ~7.8 moโhighlighting the pronounced benefit in genomically selected patients here.
Take Home: These early data argue for routine PI3K/AKT/PTEN testing; when positive, adding an AKT inhibitor to endocrine + CDK4/6 blockade may more than quadruple PFS, whereas FGFR1 or other RAS-pathway lesions could signal futilityโpoints that a randomized biomarker-driven trial should now settle.
Palazestrant + Ribociclib Shows 79% Clinical Benefit After Prior CDK4/6 Exposure in ER+/HER2- Metastatic Breast Cancer
Palazestrant (OP-1250), an oral complete ER antagonist/SERD that degrades both wild-type and mutant ESR1, was dose-escalated to 120 mg once daily alongside standard ribociclib 600 mg (3 weeks on/1 week off) in a Phase 1b/2 study (n = 63; 73% previously on a CDK4/6i; 29% ESR1-mutant). No dose-limiting toxicities emerged, and pharmacokinetics were unchanged for either drug. Treatment-related AEs mirrored ribociclibโs profile (all-grade neutropenia 78%, grade 3/4 46%). Among clinical-benefitโevaluable patients (โฅ24 weeks on therapy; n = 29) the clinical benefit rate hit 79% overall and 78% in those retreated after CDK4/6i, with partial responses and disease stabilizations lasting up to 12 months. For context, first-line ribociclib + aromatase inhibitor posts a 42% ORR and 32.7 mo median PFS, while endocrine rechallenge after CDK4/6i typically yields CBR โ30%.
Take Home: If durability holds, pairing the orally convenient Palazestrant with ribociclib could revitalise CDK4/6-experienced ER-positive diseaseโpotentially leapfrogging current SERDs and warranting head-to-head trials against standard AI combinations.
Zelenectide Pevedotin (Nectin-4 BTC) Delivers 50% ORR in NECTIN4-Amplified, Heavily Pretreated TNBC
Zelenectide pevedotin is a low-molecular-weight Bicycleยฎ toxin conjugate that ferries MMAE to Nectin-4; in the Phase 1b DURAVELO-1 dose-expansion (5 mg/mยฒ weekly), 32 triple-negative breast-cancer patients with a median six prior lines were enrolled. Of 19 tumors tested, 6 (32%) carried NECTIN4 gene amplification (FISH ratio โฅ 2.0); this biomarker cohort achieved a 50% objective response rate (3/6) and 100% disease control, versus 7.7% (1/13) in non-amplified disease. Overall ORR was 13.3% (4/30), and grade โฅ3 drug-related adverse events occurred in 34% (neutropenia, neuropathy). Notably, all NECTIN4-amp responders had previously progressed on sacituzumab govitecan, whose benchmark ORR is ~35% and median PFS 5.5 mo in similar settings.
Take Home: Although numbers are small, these data hint that NECTIN4 amplification could triage refractory TNBC to a nimble BTC platform that rivalsโor rescues afterโADC therapy; a biomarker-stratified trial against sacituzumab is the logical next step.
KAT6 Inhibitor PF-07248144 + Fulvestrant Posts 37% ORR and 10.7-Month PFS After CDK4/6 Failure in ER+/HER2โป mBC
PF-07248144, an oral catalytic inhibitor of the histone acetyltransferases KAT6A/B, was given at 5 mg QD to 43 heavily pre-treated ER+/HER2โป metastatic breast-cancer patients alongside standard fulvestrant (Phase 1 dose-expansion, NCT04606446). All had progressed on CDK4/6i + endocrine therapy; 59% carried baseline ESR1 mutations. Treatment-related events were mostly grade 1โ2 dysgeusia (85%); reversible grade 3/4 neutropenia occurred in 43%, with no febrile cases. Confirmed objective response rate reached 37.2% (16/43), clinical-benefit rate 55.8%, and median PFS 10.7 monthsโoutperforming post-CDK4/6 benchmarks for fulvestrant alone (~3.8 mo) or capivasertib + fulvestrant (7.2 mo). Activity was consistent across ESR1-mutant versus wild-type tumors (~41% vs 33% ORR) and across PIK3CA/AKT1/PTEN status. ctDNA fell 95% overall; patients with undetectable ctDNA at week 8 had longer PFS.
Take Home: First-in-class KAT6 blockade may offer a genomically agnostic route to revive endocrine sensitivity after CDK4/6 failureโwarranting larger trials against current SERD or PI3K/AKT standards.
Zanidatamab + Evorpacept Delivers 56% ORR in Centrally-Confirmed HER2-Positive mBC After T-DXd
Zanidatamab is a bispecific antibody that dimerizes HER2 receptors and triggers ADCC/ADCP, while evorpacept is a โsilent-Fcโ CD47 blocker that augments macrophage phagocytosis. In the open-label phase 1b/2 trial NCT05027139, 21 heavily pre-treated HER2-positive and 15 HER2-low metastatic breast-cancer patients received zanidatamab 1.2โ1.6 g plus evorpacept 30 mg kg every 2 weeks (median six prior regimens; all HER2-positive patients and one-third of HER2-low patients had failed trastuzumab deruxtecan). In the HER2-positive cohort treated at the recommended dose (n = 19), confirmed ORR reached 37% overall and 56% (5/9) when central HER2 testing verified IHC 3+ or ISH-positive disease; disease-control was 74%. Median response duration has not yet been reached (range 2โ22 mo). HER2-low tumors showed a 20% ORR and 40% disease control. Grade 3 treatment-related events were limited to diarrhea (6%) and infusion reactions (4%); no grade 4โ5 toxicities or drug-related pneumonitis were reported. By comparison, tucatinib-trastuzumab-capecitabine produces a 40% ORR with median PFS ~7.6 mo in a similar post-T-DM1 setting.
Take Home: For patients who have already exhausted T-DXd, this chemotherapy-free HER2/CD47 doublet shows early, durable responses and a gentler safety profileโwarranting a randomized head-to-head against current tucatinib combinations to clarify its place in late-line HER2 care.
Tucatinib + Alpelisib (HER2 TKI + PI3Kฮฑ) Nets 60% Partial Responses in Heavily Pretreated HER2-Positive, PIK3CA-Mutated mBC
In the phase Ib P5-03-10 โTime-to-Eventโ dose-escalation study (NCT05230810) post-menopausal women with HER2-positive metastatic breast cancer harboring activating PIK3CA mutations (median 2 prior metastatic lines; all had trastuzumab ยฑ pertuzumab, 50% prior T-DXd, 50% prior tucatinib) received twice-daily tucatinib with daily alpelisib plus fulvestrant when ER-positive. At DL1 (tucatinib 300 mg BID + alpelisib 250 mg QD; n = 5 in DLT window, n = 8 total), no dose-limiting toxicities were seen; common all-grade AEs were hyperglycemia 75%, diarrhea 50% (grade 3 = 25%), rash 38%, and weight loss 63%, all manageable with holds, reductions, and supportive care. DL2 (alpelisib 300 mg) produced grade 3 diarrhea or rash in all 3 pts and was abandoned. Among five RECIST-evaluable DL1 patients, three achieved confirmed partial responses (ORR = 60%; all carried the H1047R hotspot), two had durable stable disease, and four of eight remained on therapy >6 months (longest = 15 months). For comparison, the chemo-based HER2CLIMB regimen (tucatinib + trastuzumab + capecitabine) posts ~40% ORR and 7.6 mo median PFS after T-DM1.
Take Home: A chemo-free double-target blockade of HER2 and mutant PI3Kฮฑ shows early but striking activity in a population that has already seen tucatinib and T-DXdโwarranting expansion at the 300 mg/250 mg dose and raising hopes of a biomarker-guided option that may out-perform tucatinib-chemo while sidestepping alpelisibโs usual grade 3/4 toxicity profile.
Taxane + SC Pertuzumab/Trastuzumab Scores 86% pCR in Node-Negative HER2+/HRโป Early Breast Cancer (DECRESCENDO)
Neoadjuvant weekly taxane plus fixed-dose subcutaneous pertuzumab-trastuzumab for 12 weeks yielded pCR (ypT0/Tis N0) in 113/131 patients (86%) with 15โ50 mm, node-negative, hormone-receptor-negative HER2-positive tumors in the single-arm phase II DECRESCENDO trial (n = 139). Median age was 58 y; 51% were grade 3. Patients achieving pCR received antibody maintenance only, while residual-disease cases (14%) moved to adjuvant T-DM1 ยฑ anthracyclines. Among baseline samples, 81% of pCRs were PAM50 HER2-enriched. No new safety signals emerged, and the study halted early for slow accrual. For context, the NeoSphere THP + docetaxel regimen reports ~45% pCR overall and ~60% in HR-negative diseaseโfar below the 86% seen here, despite anthracycline sparing.
Take Home: Short, anthracycline-free THP plus taxane can deliver near-universal clearance in this very-early, HER2-enriched populationโsuggesting many node-negative HR-negative patients might safely skip both anthracyclines and post-surgical chemo if these impressive pCR rates translate into long-term control.
Bria-IMT Whole-Cell Vaccine plus PD-1 Blockade Extends Median OS to 13.4 mo in Heavily Pretreated HR+/HER2- mBC
Bria-IMT combines irradiated HER2/GM-CSFโsecreting allogeneic breast-cancer cells with low-dose cyclophosphamide, peg-IFN-ฮฑ, and pembrolizumab/retifanlimab; 54 metastatic-breast-cancer patients (median 6 prior lines) were enrolled in the phase I/II trial (NCT03328026). Grade โฅ3 treatment-related AEs were uncommon (13%, mostly diarrhea, PE, lipase rise). The phase-3 formulation without IFN-ฮณ incubation (n=37) yielded median OS 13.4 mo vs 6.9 mo for the earlier lot, median PFS 3.6 mo vs 2.6 mo (P 0.01), ORR 9.5%, and clinical-benefit rate 55%. Survival correlated with immune pharmacodynamic markers: patients showing a vaccine-induced delayed-type-hypersensitivity response had OS 11.9 mo vs 5.5 mo, and those with post-dose CTC < 5 had OS 13.4 mo vs 5.5 mo. These outcomes compare favorably with physicianโs-choice ET or chemo where median OS is ~8โ10 mo after CDK4/6 failure.
Take Home: A low-toxicity, off-the-shelf whole-cell vaccine may add months of survival in late-line mBCโespecially when it sparks a measurable DTH responseโ but the modest ORR and small, heterogeneous cohort mean the ongoing randomized phase III trial will be decisive.
Elacestrant (oral SERD) + Everolimus mTOR Blockade Yields 81% 24-wk CBR in Pre-treated ER+/HER2- mBC
Elacestrant 258โ345 mg QD combined with everolimus 5โ10 mg (ELEVATE phase 1b; NCT05563220) enrolled 23 heavily pre-treated ER+/HER2- metastatic breast-cancer patients (all post-CDK4/6i); safety was dominated by mostly grade 1โ2 nausea (57%), stomatitis (52%), diarrhea (43%) and fatigue (43%), with grade โฅ3 events โค9%. Among 16 response-evaluable patients, clinical-benefit rate at 24 weeks hit 81% and investigator-assessed ORR 25%, with median PFS not yet reached (0.8โ12.3 mo follow-up). By contrast, everolimus + exemestane in BOLERO-2 achieved ORR 9% and central-review mPFS 10.6 mo, while single-agent elacestrant in EMERALD showed ORR โ12% and mPFS 3.8 mo in an all-comers population, suggesting the new oral doublet may outperform each monotherapy backbone.
Take Home: Early but encouraging efficacy and a tolerable GI-skewed safety profile position elacestrant + everolimus as a potential chemo-sparing option after CDK4/6 failureโphase 2 expansion will reveal whether the signal holds up.
Larotrectinib Delivers 53% ORRโand 83% in Secretory Subtypeโwith 73% 4-Year Durability in TRK-Fusion Breast Cancer
Larotrectinib, a highly selective CNS-penetrant TRK inhibitor, was evaluated across NAVIGATE and SCOUT (n = 16; TRK-fusion breast cancer). Notably, NTRK fusions are rare in breast cancer (0.4%) but are present in 90% of secretory carcinomas (Dietrich et al., 2025). Among IRC-evaluable patients (n = 15), ORR reached 53% (27% CR), rising to 83% in secretory carcinoma (n = 6; 38%), with responses in both TNBC and ER+ disease. Median time-to-response was 1.7 mo; median duration of response was not reached, and the 4-year DOR, PFS, and OS rates were 73%, 38%, and 38%, respectively. Median PFS was 9 mo and median OS 21 mo after 44โ47 mo follow-up. Grade 3/4 TRAEs (19%) were limited to reversible hepatic events, paresthesia, and thrombocytopenia, with no treatment-related discontinuations. By comparison, single-agent capecitabine in pretreated metastatic breast cancer achieves ~20% ORR and ~4 mo PFS, underscoring larotrectinibโs potency and durability even in heavily pretreated settings.
Take Home: For the rareโbut now eminently targetableโNTRK-fusion breast cancers, larotrectinib offers rapid, deep, and long-lived control with light toxicity, making a compelling case for routine NGS panels that capture NTRK fusions so these patients arenโt missed.
NSCLC
๐ SPOTLIGHT: Peri-op nivolumab doubles event-free survivalPerioperative PD-1 Blockade (Nivolumab) + Chemo Pushes 30-mo EFS to 61% in Resectable NSCLC
Nivolumab, an anti-PD-1 antibody, given with four neoadjuvant platinum-doublet cycles and up to a year of adjuvant monotherapy (CheckMate 77T, n = 461 stage IIAโIIIB) achieved median event-free survival of 46.6 mo vs 16.9 mo with placebo (HR 0.61) and raised 30-month EFS to 61% vs 43%; overall-survival curves are separating (30-mo OS 78% vs 72%, HR 0.85). Benefit held across PD-L1, histology, KRAS/STK11/KEAP1 status, with ctDNA clearance (56% vs 35%) and pCR predicting even longer remission, while grade โฅ3 immune AEs remained low. For comparison, cisplatin-based adjuvant chemo adds only ~5% 5-yr OS and the neoadjuvant-only CheckMate 816 regimen reached 31.6 mo median EFSโhighlighting the extra durability from full perioperative coverage.
Take Home: A one-two punch of short neoadjuvant and year-long adjuvant nivolumab appears to lock in deeper, ctDNA-confirmed remissionsโpoised to redefine perioperative management for fit patients with resectable NSCLC.
https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA8010
RiskReveal 14-Gene Assay Guides Platinum Adjuvant to 96% 2-Year DFS in Stage IAโIIA NSCLC
RiskReveal, a 14-gene expression panel, stratified 421 resected stage IAโIIA non-squamous NSCLC patients; intermediate/high-risk cases (mITT n=194 [46%]) were randomized to 4 cycles of cisplatin-based adjuvant chemotherapy (n=87) or observation (n=107). At a 19-month median follow-up, adjuvant chemo cut recurrence/death risk by 78% (HR 0.22, 95% CI 0.06โ0.76; p=0.0087) and achieved 96% disease-free survival at 24 mo versus 79% with observation, with median DFS unreached in either arm. Standard surgery-alone outcomes for localized NSCLC hover around 65% 5-year survival, and prior unselected stage IB trials (CALGB 9633) showed only modest benefit from chemo, underscoring the assayโs potential to personalize treatment.
Take Home: If durability holds, integrating this inexpensive gene test could turn โchemo-sparinglyโ managed stage I lungs into a precision-adjuvant success story, sparing low-risk patients and rescuing those destined to relapse.
https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA8027
Acute Leukemia
๐ SPOTLIGHT: Menin triplet delivers MRD-negative remissionsRevumenib + AZA/VEN Hits 88% ORR and Universal MRD-Negativity in Older NPM1m/KMT2Ar AML
Revumenib, an oral menin inhibitor that disrupts the menin-KMT2A/NPM1 transcriptional axis, was added to frontline azacitidine + venetoclax in a phase I dose-escalation/expansion study (NCT03013998) enrolling 43 intensive-chemo-ineligible adults โฅ60 years with newly diagnosed NPM1-mutated or KMT2A-rearranged AML; NPM1 mutations are present in about 30% of AML patients, while KMT2A rearrangements occur in approximately 5โ10% and are mutually exclusive (non-overlapping) for a total of about 35-40% of AML patients. After a median follow-up of 27 mo, the triplet delivered an 88% overall response rate and 81% composite CR (CR/CRh/CRi), with 84% of responders achieving remission by cycle 1 and 100% (37/37) attaining flow-MRD negativity. One early death (2%) occurred; grade โฅ3 QTcF prolongation (44%) and differentiation syndrome (19%) were manageable without permanent drug discontinuation. For context, the VIALE-A doublet (azacitidine + venetoclax) posts a 66% CRc and 14.7-mo median OS in unselected IC-ineligible AML, while AGILEโs azacitidine + ivosidenib shows 47% CR and 24-mo OS in IDH1-mut casesโmaking the menin-based triplet the current efficacy frontrunner in genetically defined, older AML
Take Home: If these deep, rapid, and MRD-clean remissions translate into durable survival, menin-inhibitor triplets could supplant HMA/VEN doublets in NPM1m and KMT2Ar AMLโrandomized head-to-head trials are the next gatekeeper.
https://pubmed.ncbi.nlm.nih.gov/40504618
IDH Triplet (AZA/DEC + Venetoclax + Ivo/Enas) Delivers 92% CRc and 69% 2-Year OS in Intensive chemo-Ineligible AML
A single-center series (NCT03471260/NCT04774393) treated 60 newly diagnosed, intensive-chemoโineligible IDH-mutated AML patients with a hypomethylating agent (HMA) azacitidine or oral decitabine plus venetoclax and an IDH inhibitor (ivosidenib for IDH1, enasidenib for IDH2). ); 20% of AML cases express an IDH1 or IDH2 mutation (8% and 12% of cases, respectively, according to a 2021 study. Early mortality was 2%. Composite complete remission reached 92% (CR/CRi 55/60; ORR 95%), and with 27 mo median follow-up median OS is still unreached; 2-year OS stands at 69% with a 24% relapse rate. Outcomes dipped for treated-secondary AML (CRc 71%, 2-yr OS 34%), while de-novo cases saw 84% OS. Toxicities mirrored HMA-VEN or HMA-IDH doublets, and 32% proceeded to transplant. For context, the VIALE-A azacitidine-venetoclax doublet posts CRc 66% and mOS 15โ25 mo, while the AGILE azacitidine-ivosidenib doublet shows CR 47% and mOS 24 moโmaking this oral triplet the current efficacy high-water mark for frail IDH-mut AML.
Take Home: These striking remission and survival figures argue that adding venetoclax to HMA-IDH doublets could redefine frontline therapy for unfit IDH-mut AML, but randomized head-to-head trials are essential before practice changes.
https://pubmed.ncbi.nlm.nih.gov/40513054
Head and Neck Cancer
๐ SPOTLIGHT: STING agonist super-charges PD-1Ulevostinag (STING agonist) + Pembrolizumab Scores 50% ORR in First-Line R/M HNSCC
Ulevostinag, a cyclic-dinucleotide STING agonist given intratumorally at its RP2D 540 ยตg, was tested with pembrolizumab 200 mg Q3W in a phase 1 dose-escalation (n = 156) and a small randomized phase 2 head-to-head in untreated recurrent/metastatic head-and-neck SCC (combo n = 8, pembro-alone n = 10). Pyrexia was the leading AE (70% in phase 1; 5 of 18 (28%) in phase 2), with 10 (6.4%) dose-limiting toxicities across all doses; no grade โฅ3 immune flares reported. The combo achieved 4/8 responses (50% ORR) versus 1/10 (10%) for pembrolizumab, out-punching the ~17% ORR seen for pembro monotherapy in the KEYNOTE-048 registrational trial. Intratumoral delivery showed clear PK/PD activation of IFN-ฮณ and CXCL10 without proportional cytokine escalation beyond 540 ยตg. For context, pembrolizumab + chemo typically posts ~36% ORR in this setting, so a chemo-free doublet cracking 50% is notableโthough confirmation will hinge on larger cohorts.
Take Home: A tantalising 50% response in a tiny cohort hints STING agonism could turbo-charge PD-1 blockade in HNSCC, but the field will need bigger, biomarker-driven trials to prove this is more than a flash of cytokine heat.
https://pubmed.ncbi.nlm.nih.gov/40499147
Melanoma
Nivolumab + Relatlimab Posts 52% 4-Year OS in First-Line Advanced Melanoma
Nivolumab (PD-1) plus relatlimab (LAG-3) fixed-dose (Opdualag) outperformed nivolumab alone in the phase 2/3 RELATIVITY-047 trial (n = 714 treatment-naรฏve stage III/IV melanoma): 4-year PFS 30.6% vs 23.6%, OS 52.0% vs 42.8%, and ORR 43.9% vs 33.4%. Grade 3-4 treatment-related adverse events were 21% versus 11%, markedly lower than the 59% seen with nivolumab + ipilimumab in CheckMate 067, with no new safety signals.
Take Home: The combination delivers checkpoint-level durability with a far lighter toxicity burden than PD-1/CTLA-4, positioning PD-1/LAG-3 blockade as a patient-friendly frontline backbone while we await direct comparisons to nivo + ipi.
https://pubmed.ncbi.nlm.nih.gov/40513285
Follicular Lymphoma (FL)
Obinutuzumab + Lenalidomide Delivers 93% 2-Year PFS in First-Line High-Tumor-Burden FL
Obinutuzumab, a type II anti-CD20 antibody with enhanced ADCC, paired with the IMiD lenalidomide (G-Len) was tested in a single-center phase 2 trial (NCT02871219) in 90 untreated grade 1-3a, stage IIโIV follicular-lymphoma patients meeting GELF high-tumor-burden criteria. Six induction cycles were followed by 24 maintenance cycles. After 70.7 mo median follow-up, 2-year PFS reached 93% (95% CI 88โ99) and median PFS was not reached; 30-mo complete-response rate hit 90%. Any-grade diarrhea (61%), rash (53%), and fatigue (52%) dominated; grade โฅ3 neutropenia 19%, rash 11%, pneumonia 7%. By comparison, obinutuzumab-chemo in the GALLIUM study posted ~88% 2-year PFS with grade โฅ3 neutropenia 46%, while the chemo-free Rยฒ regimen (lenalidomide + rituximab) achieved ~81% at 2 yearsโplacing G-Len at the top of the frontline PFS leaderboard so far.
Take Home: A chemo-free doublet that beats both G-chemo and Rยฒ on early PFS and spares much of the myelosuppression could reshape frontline FL careโif multicenter randomized data replicate these single-site results.
https://pubmed.ncbi.nlm.nih.gov/40517417
Glioblastoma
Anlotinib Adds ~4 Months PFS to STUPP in Newly Diagnosed GBM
Anlotinib, an oral VEGFR/FGFR/PDGFR multi-kinase inhibitor, was combined with standard chemoradiation (temozolomide + 54โ60 Gy RT) in a double-blind, multicenter phase II trial (n = 153). Versus placebo, anlotinib prolonged IRC-assessed median PFS from 5.85 mo to 9.89 mo (HR 0.59; p = 0.004) and lifted ORR to 17% vs 5%. Grade โฅ3 toxicities were mostly hematologic (thrombocytopenia 8%, neutropenia 6%) and hypertension 5%, adding modest risk to the Stupp backbone. Historical RT + temozolomide yields ~6.7 mo PFS, while adding bevacizumab pushed PFS to 10.6 mo without an OS winโplacing anlotinibโs benefit in the same ballpark but with fewer vascular AEs.
Take Home: A statistically solidโbut clinically incrementalโPFS gain suggests angiokinase blockade may inch the frontline bar upward, yet mature OS, MGMT-stratified data, and phase III validation will decide if anlotinib merits a seat alongside or instead of bevacizumab in GBM.
https://ascopubs.org/doi/10.1200/JCO.2025.43.17_suppl.LBA2000
CLL / SLL
Zanubrutinib Holds a 72% 5-Year PFS in del(17p) Front-Line CLL/SLL
Zanubrutinib, a selective next-gen BTK inhibitor, was given as continuous monotherapy to 111 treatment-naรฏve CLL/SLL patients with high-risk del(17p) in the non-randomized SEQUOIA arm C (NCT03336333). After a median 65.8 months of follow-up, median PFS and OS remain unreached; 60-month estimates are 72% for PFS and 85% for OS. Investigator-assessed ORR reached 97% (18% CR/CRi). Grade โฅ3 safety signals per 100 patient-years included infection 33%, neutropenia 16%, hypertension 8%, bleeding 6%, and atrial fibrillation/flutter 5%; 62% of patients are still on drug. For context, 6-year PFS with acalabrutinib monotherapy in del(17p)/TP53-mutated CLL is 56%, and earlier ibrutinib real-world cohorts show inferior durability in this genotype. Zanubrutinib therefore sets a new bar for long-term disease control in this historically refractory subgroup.
Take Home: Five-year data suggest zanubrutinib may now be the durability frontrunner for del(17p) CLL, outlasting other BTK inhibitors with a manageable toxicity footprintโbut head-to-head trials will be key before practice fully shifts.
https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7011
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11 New Trials This Week
๐ First-in-humanโ| ๐ Expansionโ| โ
RegistrationalBreast Cancer Trials
๐ Phase 1b Study of Axatilimab (CSF1R mAb) in Metastatic TNBC
This open-label, single-arm trial evaluates the combination of pembrolizumab, radiotherapy, and axatilimab for patients with metastatic or recurrent TNBC who have received prior immunotherapy. Conducted in Los Angeles and sponsored by Stephen Shiao, the study aims to assess safety and early efficacy by targeting myeloid suppression in a post-immunotherapy setting.
๐ Phase 1 trial of [68Ga]Ga DOTA-5G, somatostatin receptor-targeted PET/CT diagnostic agent.
This prospective trial at University of California, Davis evaluates [68Ga]Ga DOTA-5G PET/CT imaging after a 5 mCi injection in patients with advanced invasive lobular breast cancer. The study examines the safety and performance of this diagnostic agent, and findings may inform future imaging protocols in this patient population.
NSCLC Trial
๐ Phase II: Durvalumab PD-L1 inhibitor with Tremelimumab CTLA-4 inhibitor and chemotherapy
This trial by Georgetown University evaluates the safety and efficacy of platinum-based chemotherapy combined with durvalumab and tremelimumab, followed by durvalumab maintenance, in HIV-positive patients with stage IV non-small cell lung cancer treated in Baltimore and Washington.
2 Locations | NCT04499053
Solid Tumor Trial
๐ Phase I NeoVax Personalized Neo-Antigen Vaccine Targeting Patient-Specific Tumor Mutations
This study evaluates the safety and immune response of NeoVax combined with poly ICLC and nivolumab in patients with metastatic or refractory melanoma, breast cancer, and non-small cell lung cancer. Conducted at Fred Hutchinson Cancer Center in Seattle, the trial explores a personalized approach to generate cytolytic T cell responses against patient-specific tumor neo-antigens.
Cholangiocarcinoma Trial
๐ Phase I/II trial of Pemigatinib FGFR1-3 inhibitor in advanced cholangiocarcinoma
This study, sponsored by M.D. Anderson Cancer Center, evaluates pemigatinib combined with atezolizumab and bevacizumab in patients with unresectable, advanced cholangiocarcinoma harboring FGFR2 fusion. The trial features a dose-escalation phase followed by expansion at the recommended dose to assess safety and preliminary efficacy.
CNS Lymphoma Trial
๐ Phase 1 trial lisocabtagene maraleucel, a CD19-directed CAR-T for frontline PCNSL.
This study evaluates the safety and efficacy of lisocabtagene maraleucel as first-line treatment in transplant-ineligible adults with Primary CNS Lymphoma in investigational and expansion arms. Sponsored by Juno Therapeutics, Inc., a Bristol-Myers Squibb Company, it represents a novel approach in CAR-T therapy for this indication.
38 Locations | NCT07015242
Glioblastoma Trial
๐ Phase 1 study of bicalutamide, an androgen receptor inhibitor.
This trial investigates whether daily oral bicalutamide combined with brain re-irradiation is safe for patients with recurrent high-grade glioma or glioblastoma. Conducted at the University of Nebraska, the dose-escalation study aims to determine the maximum tolerated dose over a sixโmonth treatment period.
Prostate Cancer Trial
๐ Phase II Trial: 177Lu Vipivotide Tetraxetan, PSMA-Directed Beta Emitter
This Phase II study randomizes men with PSMA-positive metastatic castration-resistant prostate cancer who progressed on prior ARPI to receive 6 cycles of 177Lu Vipivotide Tetraxetan either in combination with an androgen receptor pathway inhibitor or as monotherapy. Conducted by Novartis at multiple centers including Omaha, the trial evaluates improvements in radiographic progression-free survival.
CLL / SLL Trial
๐ Phase II venetoclax (BCL2 inhibitor) plus acalabrutinib in first-line CLL/SLL
This randomized Phase II study compares intermittent (7-day) versus continuous (28-day) venetoclax dosing with acalabrutinib in previously untreated CLL/SLL patients. Conducted in Cincinnati, the trial aims to determine the optimal dosing schedule for efficacy and safety.
Non-Hodgkin Lymphoma / ALL Trial
๐ Phase 1 CD5.CAR/28zeta CAR-T: engineered T cells targeting CD5 in T-cell malignancies
This trial investigates the safety and persistence of autologous or allogeneic CD5.CAR/28zeta T cells in patients with relapsed or refractory T-cell non-Hodgkin lymphoma and acute lymphocytic leukemia. Conducted by Baylor College of Medicine in Houston, the study evaluates a novel approach that combines CD5-targeting with CD28 co-stimulation to enhance T cell expansion and longevity.
Hematological Malignancies Trial
๐ Phase 1b CMV-MVA Triplex Vaccine, MVA-based CMV immunotherapy
This trial by City of Hope evaluates the safety and potential efficacy of the vaccine alone or with antiviral agents in haploidentical stem cell transplant donors and recipients at risk for CMV viremia. Eligible patients include those with hematologic malignancies undergoing transplant at sites in Duarte, Atlanta, and Boston.
3 Locations | NCT07020533
This summary is produced by Sagely Health. AI is used in creating some summarizations. Please check the source links.
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