Five papers — May 26–27, 2026

Journal: Nature Medicine · IF ~58 (top-tier translational medicine) · Phase 2, multi-center, single-arm trial · Published May 26, 2026 1

Study design: 24 patients with SDH-deficient GIST (SDHd-GIST) enrolled across 11 US centers (enrollment 2021–2023; data cutoff August 2024). All received oral rogaratinib 800 mg twice daily. Primary endpoint: objective response rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS) and safety. Lead investigators: Priscilla Merriam, James J. Morrow (co-first authors), Bradley Bernstein, and Suzanne George (co-corresponding authors), all at Dana-Farber Cancer Institute. ClinicalTrials.gov: NCT04595747. 1

Key results: ORR 41.7% (10/24 partial responses; tumor shrinkage ranged from −31% to −68%). Median PFS 31.0 months (95% CI 20.2–NR). 1-year PFS rate 77.4% (95% CI 61.7–97.1%). Nine patients remained on treatment at data cutoff. Responses were observed across all SDH molecular subtypes. 1

Toxicity: Hyperphosphatemia 96%, alopecia 58%, fatigue 54%, nausea 54%, diarrhea 50%. Dose reduction required in 63% of patients; the authors report no apparent efficacy penalty from dose reduction. Grade 3 events included hypertension, diarrhea, and tumor hemorrhage.

Mechanism: SDH deficiency causes global DNA hypermethylation that disrupts chromatin insulators, driving aberrant expression of FGF3 and FGF4. The resulting autocrine FGFR1 signaling is what rogaratinib targets. PDX models confirmed a class effect: infigratinib and pemigatinib (commercially available FGFR inhibitors) replicated tumor growth suppression (P < 0.0001), while sunitinib and regorafenib — standard-of-care comparators — had no activity. 1

Context: Every prior systemic therapy trialed in SDHd-GIST — KIT inhibitors, the IGF-1R inhibitor linsitinib, and the DNA methyltransferase inhibitor guadecitabine — failed to produce an objective response. A 41.7% ORR with a median PFS exceeding two years in a disease with no approved treatment represents a clinically meaningful shift. The authors note that rogaratinib itself is no longer in clinical development; however, the class effect demonstrated in PDX models means commercially available FGFR inhibitors (infigratinib, pemigatinib) are the immediate candidates for off-label use or formal confirmation trials.

Peer-review status: Published in Nature Medicine; peer-reviewed. DOI: 10.1038/s41591-026-04376-9.

Author affiliation: Dana-Farber Cancer Institute (lead); 11 US centers.

Clinical implication: SDHd-GIST is a KIT/PDGFRA wild-type GIST subtype arising from epigenetic, not mutational, oncogenesis — it has been an orphan within an orphan disease because all available targeted therapies address kinase mutations that do not drive this subtype. The epigenetic mechanism here (hypermethylation → insulator disruption → FGF/FGFR autocrine loop) is not unique to GIST; the authors explicitly flag that cancer-wide methylation profiling could identify other tumor types where the same pathway vulnerability is operative. For sarcoma oncologists managing SDHd-GIST patients, the immediate practical question is whether to seek compassionate use of pemigatinib or infigratinib pending a formal registration trial.

Journal: Nature Cancer · IF ~23 (high-impact oncology) · Randomized Phase 1 safety and efficacy run-in trial · Published May 26, 2026 2

Study design: 36 treatment-naive metastatic pancreatic ductal adenocarcinoma patients randomized to gemcitabine + nab-paclitaxel ± paricalcitol (IV or oral). Paricalcitol is an FDA-approved vitamin D analog with existing clinical use (renal secondary hyperparathyroidism). Investigators: Kimberly Perez, MD and Brian Wolpin, MD, MPH (Dana-Farber Cancer Institute), with Ronald Evans, PhD (Salk Institute for Biological Studies). DOI: 10.1038/s43018-026-01165-8. 2

Key results: Partial response rate 42% (10/24) in the paricalcitol arm vs. 9% (1/12) in the chemotherapy-alone arm. 1-year progression-free survival: 5/24 in the paricalcitol group vs. 0/12 in controls. Patients with high vitamin D receptor (VDR) expression had the longest overall survival in the paricalcitol cohort. 2

Mechanism: Paricalcitol activates the vitamin D receptor in pancreatic stellate cells, reducing their activation state (without depleting stellate cell numbers) and increasing T-cell infiltration into tumors. This stromal remodeling is the posited mechanism for improved chemotherapy access to tumor cells. 2

Safety signal: Manageable hypercalcemia in 5/12 oral paricalcitol patients — the expected on-target adverse effect of vitamin D receptor agonism.

Peer-review status: Published in Nature Cancer; peer-reviewed. DOI: 10.1038/s43018-026-01165-8.

Author affiliation: Dana-Farber Cancer Institute; Salk Institute for Biological Studies.

Clinical implication: Pancreatic cancer's desmoplastic stroma has long been identified as a barrier to drug delivery, but stromal-targeting agents have consistently failed in Phase 3 trials (PEGPH20, galunisertib). This Phase 1 dataset is small (n = 36) and unbalanced (24 paricalcitol vs. 12 control), which limits interpretation of the efficacy signal. The PR rate comparison — 42% vs. 9% — is striking but expected to regress toward the mean in a larger randomized trial. The VDR expression correlation, if it holds, could define a predictive biomarker for patient selection. Perez et al. frame this as a roadmap for a Phase 2/3 trial that could establish a new treatment standard; the gap between this run-in data and that endpoint is substantial. Paricalcitol's existing FDA approval and safety profile lower the regulatory and formulation risk for a Phase 2 program.

Journal: JAMA Neurology · IF ~27 (top-tier specialty neurology) · Phase 3 randomized withdrawal trial · Published May 26, 2026 4

Study design: 12-week open-label run-in followed by a 12-week double-blind randomized withdrawal phase. Children and adolescents with Tourette syndrome were randomized to continue ecopipam or switch to placebo. 216 subjects entered the open-label phase; 90 were randomized in the withdrawal phase (43 ecopipam, 47 placebo). Lead investigator: Donald Gilbert, MD, MS (Cincinnati Children's Hospital). Trial conducted 2023–2025. 4

Key results: In the pediatric cohort, relapse hazard ratio 0.47 (95% CI 0.26–0.84; P = 0.008) for ecopipam vs. placebo over the 24-week assessment period. Relapse rate 41.9% (18/43) ecopipam vs. 68.1% (32/47) placebo. Adult subgroup (n = 14): HR 0.51 (95% CI 0.11–2.30; P = 0.37) — directionally consistent but underpowered. 4

Adverse events: Somnolence 11.1%, anxiety 9.7%, headache 9.7%, insomnia 8.8%, tic exacerbation 7.9%, fatigue 6.5%. No clinically meaningful changes in body weight, metabolic parameters, or psychiatric scales. No drug-induced movement disorders. 4

Mechanism: Ecopipam (Emalex Biosciences, now acquired by Teva Pharmaceuticals) is a first-in-class selective dopamine D1 receptor antagonist. Antipsychotics — currently the only FDA-approved pharmacotherapy for Tourette — are D2/D3 antagonists with well-characterized liabilities: weight gain, metabolic changes, and tardive dyskinesia. The D1 selectivity profile avoids those pathways. 4

Gilbert et al. characterize the results: "Ecopipam maintained clinically meaningful Tourette symptom improvements and was well tolerated for up to 24 weeks." 5

Regulatory pathway: Teva plans to file an NDA with the FDA in 2026.

Peer-review status: Published in JAMA Neurology; peer-reviewed. DOI: 10.1001/jamaneurol.2026.1431.

Author affiliation: Cincinnati Children's Hospital (lead); multi-center.

Clinical implication: The pediatric Tourette pharmacotherapy space has been governed by off-label antipsychotic use — aripiprazole and haloperidol have approvals, but both carry metabolic and extrapyramidal risk that limits dose escalation in children, particularly those with comorbid ADHD on stimulants. A D1-selective mechanism with no drug-induced movement disorder signal and a 53% relative risk reduction in relapse fills a genuine gap if the NDA clears. The withdrawal trial design is worth noting: it selects for open-label responders, which inflates the observed treatment effect relative to a traditional superiority trial. Clinicians should interpret the 53% RRR as conditional on initial response in the run-in phase, not as an unconditional population estimate.

Journal: Cancer Research · IF ~12.7 (high-impact oncology) · Preclinical (mouse models) · Published May 27, 2026 6

Study design: In vivo PROTAC (proteolysis-targeting chimera) degradation study in mouse lung adenocarcinoma models. Because no direct KRAS G12V-targeting PROTAC exists, the team engineered a molecular tag on the KRAS G12V protein, then applied a PROTAC designed by the IRB Barcelona group of Antoni Riera to force ubiquitin-proteasome-mediated degradation. Lead authors: Inés M. García-Pérez (co-first author, IRB Barcelona), Cristina Mayor-Ruiz and David Santamaría (co-corresponding authors); institutions: IRB Barcelona (Institute for Research in Biomedicine) and Centro de Investigación del Cáncer (CSIC/USAL/FICUS, Salamanca). 7

Key results: PROTAC-mediated in vivo degradation of KRAS G12V produced significant tumor regression in mouse lung adenocarcinoma models. Initial regression was independent of a functional immune system (confirmed in immunodeficient mice), though treated tumors showed increased immune cell infiltration. Tumor relapse eventually occurred via a mechanism distinct from KRAS mutation or canonical oncogenic pathway reactivation: cancer cells progressively remodeled the ubiquitin-proteasome machinery responsible for KRAS degradation itself. 7

García-Pérez: "It is a fundamentally distinct resistance mechanism. The tumor continues to rely on KRAS, but it essentially learns to sabotage the machinery meant to destroy it." 7

Mayor-Ruiz: "We are now entering a new era where we can not only inhibit KRAS but also induce its degradation within cancer cells." 7

Peer-review status: Published in Cancer Research; peer-reviewed. DOI: 10.1158/0008-5472.CAN-26-0000.

Author affiliation: IRB Barcelona; Centro de Investigación del Cáncer (CSIC/USAL/FICUS).

Clinical implication: Covalent KRAS G12C inhibitors (sotorasib, adagrasib) are now standard in G12C-mutant NSCLC, but KRAS G12V — the second most common KRAS mutation, present in approximately 20% of KRAS-mutant lung adenocarcinomas — has no approved targeted agent. Direct KRAS G12V inhibitors have been harder to develop because the mutation geometry differs from G12C. The PROTAC approach sidesteps the binding-site problem entirely by routing the target protein to the proteasome. The resistance mechanism identified here — proteolysis machinery remodeling rather than target mutation — has direct implications for combination strategy: if cancer cells rewire ubiquitin-proteasome components under PROTAC pressure, co-targeting those components or combining degraders with inhibitors (to prevent cells from maintaining KRAS dependency via the unaffected pool) becomes the obvious next question. This study is preclinical; the molecular tag requirement for the PROTAC to function means the current tool compound is not directly translatable to patients — the path to a clinical-grade PROTAC or molecular glue degrader active at wild-type G12V remains the key engineering challenge.

Journal: NEJM Catalyst Innovations in Care Delivery · Implementation science · Pragmatic pre-post observational study · Published May 26, 2026 8

Study design: Pre-implementation period July–December 2022 vs. post-implementation period October 2023–March 2024, across 25 Kaiser Permanente Washington (KPWA) primary care clinics. The program offered HPV self-collection kits via two routes: direct mailing to eligible patients and in-clinic facilitation. Target population: approximately 121,000 women aged 30–64 due for cervical cancer screening. Lead investigator: Beverly Green, MD, MPH (KPWA Health Research Institute). DOI: 10.1056/CAT.25.0420. 9

Key results: Overall cervical cancer screening completion +2.2 percentage points (95% CI 1.74–2.66; P < 0.001). Of the kit recipients, 25% returned completed samples; self-collection accounted for 37.4% of all post-implementation screening events. Approximately 60% of self-collection was done by mail; the remainder in-clinic. The screening uptake increase was consistent across racial and ethnic groups. Colposcopy follow-up for HPV 16/18 positivity improved from 50% pre-implementation to 75.8% post-implementation (P = 0.009). 9

Context: Only 12.6% of eligible patients received mailed kits, which the authors identify as the primary constraint on the aggregate effect size. Prior KPWA RCTs of direct-to-overdue mailing showed 14–17 percentage-point increases in that subset, consistent with the current data.

Peer-review status: Published in NEJM Catalyst Innovations in Care Delivery; peer-reviewed. DOI: 10.1056/CAT.25.0420.

Author affiliation: Kaiser Permanente Washington Health Research Institute.

Clinical implication: The 2.2 pp aggregate improvement is modest and reflects the limited rollout scale (12.6% of eligible patients received kits) rather than weak efficacy of the self-collection intervention. The per-recipient response rate (25%) and the colposcopy follow-up improvement (50% → 75.8%) are the more actionable figures. Self-collection is already endorsed by the WHO for primary HPV screening in low-resource settings; this KPWA dataset adds implementation evidence from a US integrated health system. The consistent uptake across racial/ethnic groups addresses a common equity concern. Barriers to broader rollout identified by Green et al.: supply chain for kit distribution, clinician workflow integration, and safety-net clinic adaptation (currently in testing).

The rogaratinib dataset is the week's highest-signal oncology publication — a 41.7% ORR with a 31-month median PFS in a disease with no prior effective treatment is a strong proof-of-concept for epigenetically-driven oncogene reactivation as a druggable target class. The immediate clinical question is whether pemigatinib or infigratinib — both commercially available FGFR inhibitors — can replicate the response in a confirmatory trial, since rogaratinib itself is out of development.

On the paricalcitol front, the Phase 2/3 design and patient selection criteria (particularly VDR expression cutoff) will determine whether the 42% vs. 9% PR signal survives scale-up. For ecopipam, watch the FDA NDA filing timeline and whether Teva pursues an adult cohort expansion given the underpowered adult subgroup in this trial.