The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Welcoming the future: embracing novel technologies for a progressive health system.

BACKGROUND: Novel technologies offer great possibilities for improving patient care, but their adoption varies across different European countries. To successfully integrate these advancements, it is crucial to prioritize patient interests and avoid getting side-tracked by issues that seek to preserve established positions or neglect collaboration. Next-generation sequencing and liquid biopsy in cancer patients hold substantial potential for early diagnosis and reducing suffering, but only if they are effectively implemented into routine health care. METHODS: An examination of the infrastructure and governance requirements in European member states was conducted to identify significant gaps and discrepancies in the readiness to capitalize on the benefits that these technologies can provide. RESULTS: These disparities highlight the existing inequalities and missed opportunities within the European Union (EU), which are further exacerbated by varying economic statuses. CONCLUSIONS: As Europe undergoes a comprehensive review of its health policies and public spending between 2024 and 2025, it is an opportune time to prioritize ensuring that patients can access the advancements offered by technology and science.

Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST).

Current evaluation of treatment response in solid tumors depends on dynamic changes in tumor diameters as measured by imaging. However, these changes can only be detected when there are enough macroscopic changes in tumor volume, which limits the usability of radiological response criteria in evaluating earlier stages of disease response and necessitates much time to lapse for gross changes to be notable. One promising approach is to incorporate dynamic changes in circulating tumor DNA (ctDNA), which occur early in the course of therapy and can predict tumor responses weeks before gross size changes manifest. However, several issues need to be addressed before recommending the implementation of ctDNA response criteria in daily clinical practice such as clinical, biological, and regulatory challenges and, most importantly, the need to standardize/harmonize detection methods and ways to define ctDNA response and/or progression for precision oncology. Herein, we review the use of liquid biopsy (LB) to evaluate response in solid tumors and propose a plan toward standardization of LB-RECIST.

Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

HER2-low expression in patients with advanced or metastatic solid tumors.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples. PATIENTS AND METHODS: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples. RESULTS: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC. CONCLUSION: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies.

Sodium fluoride (Na18F) PET Response Criteria in Solid Tumors (NAFCIST): a framework for response assessment in bone tumors.

The current Response Evaluation Criteria in Solid Tumors for measuring tumor response in osteosarcoma may be sub-optimal, as even responsive bone tumors may show limited change in tumor diameters. This limits the use of traditional imaging assessment tools. Therefore, discerning osteosarcoma response to therapy on magnetic resonance imaging before surgery is often difficult, and it is typically evaluated after surgery by assessing the amount of necrosis in resected surgical specimens. To address these challenges, sodium fluoride (Na18F) positron emission tomography/computed tomography (PET/CT) scans can be utilized to better image bone response to therapy, as, fluoride is avidly taken up by bone. Na18F Response Criteria in Solid Tumors (NAFCIST) has been developed as a novel method to evaluate treatment response using Na18F PET/CT. Current evidence supporting NAFCIST comes from a pilot study that evaluated alpha particle radium-223 in patients with osteosarcoma. In this review, practical guidance for utilizing NAFCIST in the context of bone tumors is illustrated to aid future studies.

Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy.

BRAF activation occurs as part of the mitogen-activated protein kinase (MAPK) cellular signaling pathway which leads to increased cellular proliferation and survival. Mutations in BRAF can result in unbridled activation of downstream kinases with subsequent uncontrolled cellular growth that formulate the basis for oncogenesis in multiple tumor types. Targeting BRAF by selective inhibitors has been one of the early successes in precision oncology. Agents have been explored either as monotherapy or in combination with MEK inhibition in BRAF V600-mutant pan-cancers and with EGFR inhibition in colorectal cancer. Spectrum of BRAF inhibition has evolved from being melanoma-specific to being a pan-cancer target. In this article, we review BRAF and MEK inhibitor drug development journey from tissue-specific melanoma, non-small-cell lung cancer, and anaplastic thyroid cancer to tissue-agnostic approvals.

Cancer: slaying the nine-headed Hydra.

Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.

Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.

BACKGROUND: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.

Lurbinectedin, a selective inhibitor of oncogenic transcription, in patients with pretreated germline BRCA1/2 metastatic breast cancer: results from a phase II basket study.

BACKGROUND: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer. PATIENTS AND METHODS: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Confirmed partial response (PR) was observed in six patients [ORR = 28.6%; 95% confidence interval (CI) 11.3% to 52.2%] who had received a median of two prior advanced chemotherapy lines. Lurbinectedin was active in both BRCA mutations: four PRs in 11 patients (36.4%) with BRCA2 and two PRs in 10 patients (20.0%) with BRCA1. Median DoR was 8.6 months, median PFS was 4.1 months and median OS was 16.1 months. Stable disease (SD) was observed in 10 patients (47.6%), including 3 with unconfirmed response in a subsequent tumor assessment [ORR unconfirmed = 42.9% (95% CI 21.8% to 66.0%)]. Clinical benefit rate (PR + SD ≥ 4 months) was 76.2% (95% CI 52.8% to 91.8%). No objective response was observed among patients who had received prior poly (ADP-ribose) polymerase inhibitors. The most common treatment-related adverse events (AEs) were nausea (61.9%), fatigue (38.1%) and vomiting (23.8%). These AEs were mostly grade 1/2. The most common grade 3/4 toxicity was neutropenia (42.9%: grade 4, 23.8%: with no febrile neutropenia). CONCLUSIONS: This phase II study met its primary endpoint and showed activity of lurbinectedin in germline BRCA1/2 breast cancer. Lurbinectedin showed a predictable and manageable safety profile. Considering the exploratory aim of this trial as well as previous results in other phase II studies, further development of lurbinectedin in this indication is warranted.

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies.

BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.

Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.

BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers.

INTRODUCTION: Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker. METHODS: Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded. RESULTS: MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy. CONCLUSION: This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.