BACKGROUND:Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS:GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION:This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.
Background ORCHARD (NCT03944772) was a biomarker-directed, phase II, platform study conducted to characterise resistance mechanisms and evaluate novel treatment combinations in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) following progression on first-line osimertinib. We report results from the module evaluating osimertinib plus platinum-based chemotherapy. Methods Patients received osimertinib (80 mg once daily) plus ≤ 4 cycles of platinum-based doublet chemotherapy (pemetrexed 500 mg/m2 plus carboplatin AUC5) on day 1 of every 21-day cycle, followed by pemetrexed maintenance until disease progression, unacceptable toxicity, or another discontinuation criterion. The primary endpoint was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Results Thirty-one patients received study treatment. Eight patients had a confirmed partial response (ORR 26 %; 80 % CI, 16–39). Median DoR was 7.6 months (95 % CI, 4.2–not calculable). Median PFS was 5.6 months (95 % CI, 4.0–7.5); PFS events were reported in 29 (94 %) patients. Median OS was 10.9 months (95 % CI, 8.5–15.0); 20 (65 %) patients had died at data cut-off. Grade ≥ 3 adverse events (AEs) occurred in 20 (65 %) patients; AEs leading to discontinuation of any treatment occurred in seven (23 %) patients. Conclusion In patients with EGFR-mutated advanced NSCLC who had progressed on first-line osimertinib, osimertinib plus platinum-based chemotherapy demonstrated a modest clinical benefit and manageable safety profile, consistent with the individual drug profiles.
Background Immune checkpoint blockade provides durable benefit in a subset of patients with advanced non-small cell lung cancer (NSCLC), but response rates remain limited after progression on standard systemic therapy. Stereotactic body radiotherapy (SBRT) may enhance tumor-antigen release and systemic immune activation, thereby improving the efficacy of PD-1 blockade. This multicenter, single-arm, phase II study evaluated the efficacy and safety of SBRT plus nivolumab in previously treated advanced NSCLC. Methods Eighty-three patients who had experienced disease progression after at least one line of standard systemic therapy were enrolled across nine centers. Patients received SBRT to the primary lung lesion or, in selected cases without a visible primary tumor, to an involved nodal lesion, followed by nivolumab. Patients with symptomatic bone metastases could receive prior bone radiotherapy. The primary endpoint was objective response rate (ORR) according to RECIST version 1.1. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Bone radiotherapy and biomarker analyses were exploratory. Results The ORR was 39.7% (95% confidence interval [CI], 29.4-51.1%), including complete responses in 10.8%, and the disease control rate was 61.4%. The median duration of response was 27.0 months. Median PFS and OS were 11.1 months and 25.9 months, respectively. Among the 36 patients with bone metastases, the exploratory ORR was 57.2% in those who received bone radiotherapy and 13.6% in those who did not. Elevated baseline alkaline phosphatase and urea levels were associated with poorer survival in exploratory analyses. Treatment-related adverse events occurred in 63.9% of patients, with grade 3-4 events in 4.8% and no treatment-related deaths. Conclusions SBRT plus nivolumab demonstrated encouraging and durable antitumor activity with manageable toxicity in previously treated advanced NSCLC. The findings concerning bone radiotherapy and serum biomarkers are exploratory and hypothesis-generating and require validation in prospective randomized studies.
Purpose The study compared outcomes of anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer (mNSCLC) patients treated with first-line (1L) tyrosine kinase inhibitors (TKIs) as monotherapy. Methods This retrospective cohort study (January 2016-June 2024) used Komodo Healthcare Map claims to analyze ALK+ mNSCLC patients treated with 1L ALK TKIs by presence of brain metastasis (BM). Multivariable and propensity score (PS)-weighted Cox proportional hazards regressions compared 1L ALK TKI cohorts for treatment discontinuation (TTD), time to next treatment (TTNT), and overall survival (OS): alectinib, brigatinib, lorlatinib vs crizotinib; brigatinib vs alectinib; brigatinib vs lorlatinib. Patterns of full-prescribing dose achievement and dose reduction were examined descriptively. Results 1,623 patients received 1L alectinib (n=1,100), brigatinib (n=58), crizotinib (n=384) or lorlatinib (n=81). Alectinib, brigatinib, and lorlatinib all had significant adjusted hazard ratios (HRs) for TTD and TTNT vs crizotinib, overall and within BM subgroups. PS-weighted HRs for 1L brigatinib vs alectinib/1L brigatinib vs lorlatinib were: TTD: 0.85 (0.56-1.28)/0.93 (0.49-1.76); TTNT: 0.94 (0.60-1.48)/1.46 (0.64-3.32); OS: 0.86 (0.44-1.70)/1.41 (0.41-4.84). Full prescribing dose was achieved by 97% of alectinib, 89% of brigatinib, and 70% of lorlatinib patients (p<0.001); 79%, 78%, 65%, respectively, were still on full prescribing dose by 12 months of treatment (p=0.01). Conclusions There was no statistically significant difference in TTD, TTNT, OS for brigatinib vs alectinib and lorlatinib; however, the small brigatinib and lorlatinib samples limit statistical power. More patients on 1L alectinib or brigatinib achieved full prescribing dose and stayed on it for longer compared to those on 1L lorlatinib.
INTRODUCTION:Targeted fixed duration (FD) therapies have emerged as new treatment options that have been shown to be highly effective for patients with chronic lymphocytic leukemia (CLL). To date, there is limited Canadian data on the uptake and outcomes of CLL treatment following the approval of FD therapy. PATIENTS AND METHODS:This study was conducted to evaluate the clinical and demographic characteristics, treatment outcomes, and healthcare resource utilization (HCRU) of CLL patients treated with FD treatments in the 1L setting between 01 January 2010 and 31 December 2023 in Alberta, Canada. RESULTS:In total, 589 patients received therapy for CLL during this time period, and venetoclax plus obinutuzumab (VO) represented the most common therapy from 2021 to 2023. Additionally, patients receiving VO showed the highest survival rates at 12 months (95% confidence interval [CI]) at 97.6% (94.5, 100.0), followed by fludarabine, cyclophosphamide, and rituximab (FCR) at 96.6% (94.0, 99.3). CONCLUSION:These results highlight the shift in the treatment landscape for CLL with the potential for improved patient outcomes.
Background Given the potential benefit of MET-tyrosine kinase inhibitors (TKIs) after progression on osimertinib in EGFR-mutated advanced NSCLC, evaluating real-world biomarker testing and treatment sequencing is important. We report findings from a global, direct-to-physician, survey-based chart review. Patients and Methods Physicians treating NSCLC were surveyed regarding re-biopsy and MET testing practices and awareness of MET overexpression and/or amplification (OverExp/Amp) cutoff levels. Biomarker testing, MET OverExp/Amp quantification and treatment sequencing were assessed in patients with EGFR-mutated advanced NSCLC with acquired MET OverExp/Amp after progression on first-line osimertinib, who received second-line treatment between January 2018-December 2023 (data cutoff: April 8, 2025). Results Among 280 physicians, re-biopsy practices varied; the most commonly reported MET testing method was NGS (78%), followed by IHC (11%) and FISH (11%). Understanding of MET OverExp/Amp cutoff levels varied, with 35-47% of physicians unaware of appropriate cutoffs. Among 367 patients (94% with MET Amp), MET alterations were mostly detected through tissue-based (58%) versus liquid-based tests (31%) or both (11%). MET alterations were detected using NGS (77%), then PCR (10%), IHC (10%) and FISH (4%). In 257 patients with MET cutoff data available, most MET Amp had gene copy numbers ≥6 (88%). MET-TKIs (29%) and EGFR-TKIs (24%) were the most common second-line treatments, followed by chemotherapy (20%). Of 193 patients with high MET levels, most received targeted treatments (MET-TKI 35%, EGFR-TKI 23%). Conclusion Re-biopsy practices and knowledge of MET OverExp/Amp cutoffs varied among physicians. IHC/FISH were underutilized; however, their use should be encouraged for optimal patient identification and treatment selection. MicroAbstract Should describe: Area and reason for the study; Approach taken including sample size aspects; Overall result; General significance of the findings. All information should be accessible to a non-expert audience. 3–4 sentences (59/60 words). Real-world biomarker testing and treatment sequencing was evaluated in 367 patients with EGFR-mutated advanced NSCLC post-progression on osimertinib. MET overexpression and/or amplification (OverExp/Amp) were most commonly identified by NGS; IHC/FISH were underutilized. Patients with high OverExp/Amp most commonly received second-line EGFR- and MET-TKI-based treatments. Tissue-based re-biopsy and IHC/FISH should be encouraged to identify MET-driven progression post-osimertinib to improve outcomes.
Background Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly(ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. Methods GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central pre-screening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. Discussion This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.
INTRODUCTION/BACKGROUND:T-cell-engaging bispecific antibodies (BsAbs) are effective for relapsed/refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). Radiation therapy (RT) is increasingly used for palliation or bridging/cytoreduction in patients receiving BsAbs, but data on the safety of RT delivered in close temporal proximity to BsAbs are limited. We report the largest series to date evaluating RT and BsAbs in B-NHL. PATIENTS AND METHODS:We retrospectively identified patients with B-NHL who received RT ≤ 3 months before, during, or ≤ 3 months after BsAb at a single institution between 2018 and 2024. Timing was categorized as pre-, peri-, or post-BsAb. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria; other toxicities per CTCAE v5.0. In-field responses were assessed per Lugano criteria. RESULTS:Twenty-nine patients underwent 31 BsAb courses and received RT to 52 sites (50% pre-, 13% peri-, 37% post-BsAb). Common histologies included DLBCL (52%), follicular lymphoma (FL) (26%), and transformed FL (16%). All RT-related toxicities were grade 1 to 2, with no RT-related hospitalizations. CRS occurred in 7 BsAb courses and ICANS in 4, with no apparent relationship to RT timing or dose. Early post-RT lymphopenia was common across groups, but its frequency and severity did not differ by RT timing. Among 44 evaluable lesions, the in-field overall response rate was 84% (CR 45%, PR 39%). CONCLUSION:RT before, during, or after BsAb was well tolerated, without apparent additive toxicity, and achieved high in-field response rates, supporting the safe integration of RT with BsAbs for R/R B-NHL.
INTRODUCTION:Trastuzumab deruxtecan (T-DXd) was approved in China in October 2024 for previously treated human epidermal growth factor receptor 2 (HER2)-mutant (HER2m) unresectable/metastatic non-small cell lung cancer (NSCLC), based on DESTINY-Lung02 and DESTINY-Lung05 primary results. Here, we report the DESTINY-Lung05 final analysis. METHODS:DESTINY-Lung05 (NCT05246514), an open-label, single-arm, multicenter, phase 2 study, investigated T-DXd (5.4 mg/kg once every 3 weeks) in patients from China with HER2m (locally or centrally confirmed activating HER2 exon 19/20 mutation) metastatic NSCLC with disease progression on/after ≥ 1 prior anticancer therapy. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 by independent central review (ICR). Secondary endpoints included progression-free survival (PFS) by ICR, overall survival (OS), and safety. RESULTS:As of November 4, 2024, 72 patients with HER2m NSCLC had received T-DXd 5.4 mg/kg; the median duration of follow-up was 20.2 months (range, 2-27). Confirmed ORR (ICR) was 56.9% (95% confidence interval [CI] 44.7-68.6). Median PFS (ICR) and OS were 9.9 months (95% CI 7.1-16.5) and 21.0 months (95% CI 17.5-not calculable), respectively. Grade ≥ 3 drug-related adverse events occurred in 40 (55.6%) patients. Adjudicated drug-related interstitial lung disease/pneumonitis events were observed in 9 (12.5%) patients (n = 8 grade 1/2; n = 1 grade 3). CONCLUSIONS:With extended follow-up, T-DXd continued to demonstrate clinically meaningful and durable antitumor activity in patients from China with pretreated HER2m metastatic NSCLC, with no new safety signals. Results affirm the use of T-DXd as a treatment option in China for this patient population.
BACKGROUND:Next-generation Sequencing (NGS) is critical for providing treatment recommendations across multiple stages of non-small cell lung cancer (NSCLC). However, a substantial proportion of patients do not undergo testing. This study evaluated the completion rates and timeliness of NGS in patients with stage II to IV NSCLC at a single academic institution with a reflex NGS testing protocol. METHODS:Patients with stage II to IV nonsquamous NSCLC (ns-NSCLC) diagnosed between 2015 and 2022 were identified retrospectively. A reflex, tissue-based testing protocol was initiated in 2015 using in-house NGS. Pyrosequencing was performed if NGS failed. RESULTS:501 patients were included: 75 (15.0%) with stage II, 82 (16.4%) with stage III, and 344 (68.6%) with stage IV ns-NSCLC. Tissue NGS was completed in 380 (75.8%) patients and 465 (92.8%) completed some tissue-based genomic testing when including pyrosequencing. Median time from biopsy to NGS was 17.0 days (range, 6-61 days). 61.0% of patients had NGS results prior to a first treatment of any type and 88.4% had tissue NGS results prior to systemic therapy. Among stage IV patients with completed NGS, median overall survival was 2.27 years for patients with NGS results prior to first treatment compared to 1.08 years for patients without NGS results prior to treatment initiation (P = .04). CONCLUSIONS:Implementation of an in-house, reflex NGS testing protocol enabled rapid genomic profiling in a high proportion of patients with stage II to IV ns-NSCLC. NGS completion prior to receiving first-line therapy was associated with improved survival compared to completion after first line treatment in stage IV patients.
Background Promoting early detection of lung cancer is essential to improve survival and reduce treatment intensity. Incidental pulmonary nodules (IPN) detected on routine chest CT scans represent an opportunity for early diagnosis but are frequently missed or not managed appropriately. Computer-assisted detection (CAD) software and patient tracking through virtual nodule clinics (VNCs) may improve IPN detection and promote appropriate clinical management. Research question Is implementation of CAD combined with VNCs feasible and effective for improving IPN detection and management in routine clinical practice? Study design and methods A dedicated IPN program integrating CAD for analysis of all chest CT scans and a navigator-supervised VNC was implemented across 6 European hospitals. Aggregated clinical and radiological data were collected from the VNC application. Feasibility outcomes including CAD failure rate, nodule detection rate, patient flagging in the VNC, lung cancer diagnosis, and site-level adoption and continued software use, were evaluated using descriptive statistics. Results Data were collected from program initiation until January 2025, with a mean duration of 14 months (range 8-25). 65,344 patients were included. CAD software successfully analyzed 99.5% of scans (range 99.1–99.6%) and detected abnormalities in 62.7% (40,954) of scanned patients. Radiologists flagged 619 patients with IPN for management in the VNC, ten of which (1.6%) were diagnosed with lung cancer. All lung cancers were early-stage. CAD use was maintained in all sites, with radiologists reporting increased diagnostic confidence. The VNC was perceived as a valuable safety-net, although insufficient resources and workflow disruptions limited consistent use. Interpretation This pilot demonstrates feasibility of CAD and VNCs in routine workflows and informs future efficacy studies. CAD showed promising technical reliability and detection performance, and its sustained use suggests clinical acceptability. VNC uptake could be further optimized by supporting the navigator role with dedicated resources and improving ease of use.
The treatment landscape of multiple myeloma (MM) is evolving rapidly, driven by the approval of new therapies and the increasing integration of advanced response-assessment tools, including measurable residual disease (MRD). These developments have made treatment algorithms increasingly complex. Furthermore, access to novel therapies is often delayed and varies from 1 country to another, necessitating national-level treatment guidelines. Under the auspices of the Turkish Society of Hematology, we have been publishing national treatment guidelines. The first national myeloma guideline was published in 2020 and subsequently updated in 2024. Building on recently published registrational data and the 2025 EHA-EMN guidelines, we present the second update of the Turkish Myeloma Treatment Guidelines. We aim to include all currently approved therapies as well as emerging therapies likely to be approved in the near future. This approach guides Turkish hematologists in daily routine practice when needed. This guidance aligns with internationally accepted standards and explicitly considers reimbursement protocols and their impact on local implementation. This effort aims to support new drug approvals and facilitate the implementation of diagnostic and response-assessment tools in routine clinical practice in Türkiye. Our objective is to promote consistent, equitable, and adaptable myeloma care across Türkiye.
BACKGROUND:Chimeric antigen receptor (CAR) T-cell therapies offer substantial survival benefits for relapsed and/or refractory multiple myeloma (RRMM). However, access remains limited across the US. We examined geographic variation in MM burden and key drivers of CAR T access disparities to inform targeted strategies to close these gaps. PATIENTS AND METHODS:Patients with MM and CAR T recipients from January 2021-August 2024 were identified from the Komodo Patient-Level Analytics and Insights Derivative claims database. MM prevalence at the ZIP-3 level came from the US Cancer Statistics database. Drive-times to the nearest authorized treatment center (ATC) for patients with MM and to ATCs for CAR T recipients were calculated and compared nationally and by region. RESULTS:There were 106,593 prevalent patients over the study period. The South had the second highest MM burden (66.1/100,000 people) but the lowest proportion of patients within 1 hour of an ATC (55.7%). CAR T recipients in the South also traveled the longest to their ATC (median, 1.5 hours). Multivariable analysis with socio-economic and demographic covariates indicated that ≥ 2 hour potential drive-time to nearest ATC versus < 1 hour (adjusted odds ratio [or] = 0.43; 95% confidence interval (CI), 0.27-0.69), household income < $50k versus ≥ $100k (or = 0.19; 95% CI, 0.05-0.69), and residence in nonmetropolitan areas versus metropolitan (or = 0.41; 95% CI, 0.28-0.60) were significantly associated with reduced odds of CAR T use. CONCLUSIONS:There were substantial geographic and socioeconomic disparities in CAR T access, with long drive‑times, lower household income, and non‑metro residence limiting uptake and underscoring the need for targeted ATC expansion.
INTRODUCTION:Azacitidine-venetoclax (AZA-VEN) has become a standard treatment in older or chemotherapy-ineligible AML patients. While the registration trial showed a median overall survival (OS) of 14.7 months, most real-world studies have not reproduced this result. PATIENTS AND METHODS:We analyzed treatment patterns, adverse events, responses and outcomes in 199 patients treated with AZA-VEN in the DATAML registry. RESULTS:The median age was 75.6 years, 48.7% had secondary AML (11% post-MPN); 11.7% had another cancer, and 9% had received AZA for prior myelodysplastic syndrome. Cytogenetic risk was intermediate (55.8%) or adverse (43.7%). The most frequent gene mutations were ASXL1 (33%), TET2 (27%), TP53 (26%), RUNX1 (24%) and SRSF2 (24%). The first cycle was performed on an outpatient basis in 39.4% of patients. The median number of cycles was 4 and 37% received > 6 cycles. Beyond cycle 6, reductions in treatment dose or duration were attributed to VEN in 55% of patients and to AZA for 43%. The complete remission (CR) plus CR with incomplete hematologic recovery (CRi) rate was 58.5%, and day-30 death rate was 3%. Median OS was 8.9 months. mPRS and refined-ELN2024 classifications were significantly associated with response and OS. In CR/CRi patients, G-CSF use was significantly and independently associated with improved OS (median, 10.1 months without versus 20.3 with G-CSF; P = .001). In an external cohort, G-CSF was also associated with a trend towards improved OS. CONCLUSION:In real-world clinical practice, patients with more severe characteristics are typically selected for AZA-VEN, which could explain suboptimal outcomes. G-CSF should be prospectively explored in AZA-VEN treated patients.
Myelofibrosis (MF) is a biologically heterogeneous myeloproliferative neoplasm characterized by constitutive activation of the JAK-STAT pathway, progressive marrow fibrosis, cytopenias, splenomegaly, and systemic inflammation. Ruxolitinib, a JAK1/JAK2 inhibitor, remains the standard frontline therapy for intermediate- and high-risk MF, providing significant improvements in splenomegaly, constitutional symptoms, and survival. However, responses are highly variable, and a substantial proportion of patients experience suboptimal benefit, early discontinuation, or disease progression, underscoring the need for reliable predictors of treatment outcome. This review summarizes current evidence on clinical, molecular, cytogenetic, and dynamic predictors of ruxolitinib response in MF. Clinical variables, including cytopenic phenotype, peripheral blasts, baseline spleen size, symptom burden, prognostic risk category, timing of treatment initiation, and dose intensity, consistently influence treatment efficacy and durability. Notably, inadequate dose intensity emerges as the most relevant modifiable determinant of response. Molecular profiling further refines risk stratification: high-molecular-risk mutations, increased mutational burden, RAS/CBL pathway alterations, and adverse cytogenetics are associated with inferior outcomes, while driver mutation status alone has limited predictive value. The emergence of dynamic prognostic models such as RR6, iRR6, and STR-PM has enabled the integration of early treatment-related variables, including spleen response, transfusion dependence, and dose intensity, to identify patients at higher risk of treatment failure. These tools represent a shift from static baseline prognostication toward adaptive, response-oriented management. Emerging approaches integrating multi-omics profiling, circulating biomarkers, and artificial intelligence are warranted to further improve individualized decision-making among the expanding JAK inhibitor-based strategies in MF.
BACKGROUND:Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS:HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION:to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.
