Investigation Of Choice Research Articles

Comparison between Dasatinib-Blinatumomab Vs Ponatinib-Blinatumomab Chemo-Free Strategy for Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia Patients. Preliminary Results of the Gimema ALLL2820 Trial

Introduction. The outcome of Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) has dramatically improved in the last decade, due with the introduction in the clinical practice of tyrosine kinase inhibitors (TKIs). A further improvement has been obtained with the use of blinatumomab as a consolidation strategy in newly diagnosed patients. We previously designed an induction/consolidation chemotherapy-free frontline trial with dasatinib followed by blinatumomab (GIMEMA LAL2116, D-ALBA); the preliminary results showed that after 2 cycles of blinatumomab (primary endpoint), molecular responses were achieved in 60% of cases and that, with a median follow-up of 18 months, overall survival (OS) and disease (DFS) were 95% and 88% (Foà et al, NEJM 2020). An updated follow-up at 53 months (Foà et al, under revision and ASH 2023) confirmed the favorable long-term outcomes with OS and DFS of 75.8% and 80.7%, respectively. A total of 9 relapses occurred. The median time to relapse was 4.4 months (1.9-25.8); 4 were at the central nervous system (CNS). To further improve the outcome of these patients, we designed a phase III trial (GIMEMA ALL2820) in which in the experimental arm dasatinib was substituted with ponatinib, followed - in the consolidation phase - by at least 2 cycles of blinatumomab. The trial is currently enrolling. Aims. To compare the efficacy of the combination of ponatinib followed by blinatumomab with that reported with dasatinib followed by blinatumomab for the management of newly diagnosed adult Ph+ ALL patients. Patients and Methods. From September 2021 to July 2023, 74 patients have been enrolled in the experimental arm, based on ponatinib followed by at least 2 cycles of blinatumomab; the induction period has been reduced from 85 to 70 days and the dose of ponatinib was either 45 mg or 30 mg, according to patient's age. A dose reduction to 30 mg was foreseen by day 28 of induction, regardless of age, to avoid unacceptable toxicities. Furthermore, CNS prophylaxis was strengthened with a total of 15 medicated lumbar punctures and triple intrathecal therapy (methotrexate, aracytin and steroids) was administered. Finally, transplant allocation was not left to investigator's choice, but it was established according to biological features (minimal residual disease and presence of the IKZF1 plus genotype). Results. Median age was 57 years (range 20-80), with 31% of patients being older than 65 years; 51% were males, the median white blood count (WBC) was 12 x10 9/l (1-207 x10 9/l). The p190 fusion protein was detected in 75.6% of cases, the p210 in 21.6% and p190/p210 in 2.7%. The IKZF1 plus genotype was detected in 33% of cases. The median follow-up is 6.1 months (0 - 20.3). Of the 74 patients enrolled, 16 were still receiving induction treatment and have therefore been excluded from the present analysis, and 40 have received ≥2 cycles of blinatumomab. Regarding the induction phase, 55 of 58 patients (95%) achieved a complete hematologic remission (CHR), while 3 patients (5%) died in induction (a 77-year-old woman for unknown causes, a 68-year-old man for an intestinal occlusion and a 52-year-old man due to pneumonia). A molecular response (including both MRD negative and positive non-quantifiable (PNQ) cases) was obtained in 21/55 cases (38.2%). By the end of the consolidation phase, of the 40 evaluable patients 25 (62.5%). achieved a molecular response. So far, a single patient has relapsed (WBC at onset 121 x10 9/l and a IKZF1plus genotype) after 3 months from CHR: at relapse, this case harbored a T3151 mutation (Sanger sequencing and digital droplet PCR at diagnosis were wild type). At recurrence, CD19 expression was maintained. Conclusions. The preliminary analysis of the GIMEMA ALL2820 trial proved the feasibility of this ponatinib-blinatumomab induction consolidation strategy for newly diagnosed Ph+ ALL of all ages, with a 95% CHR rate. Molecular responses at the end of induction are slightly superior in the current trial (38.2% vs 29% in the D-ALBA study), whereas they are virtually equivalent after 2 cycles of blinatumomab (62.5% vs 60% in in the D-ALBA). So far, the benefit of the current protocol appears to rely on a lower relapse rate, with only 1 relapse being observed to date, while in the same time period 3 relapses were documented with the dasatinib-blinatumomab combination. Further details will be provided.

Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer

Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n= 49) and chemotherapy (n= 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value= 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial

PD-1 inhibitors combined with chemotherapy have shown efficacy in gastric or gastro-esophageal junction cancer. We compared the efficacy and safety of pembrolizumab plus chemotherapy with placebo plus chemotherapy in participants with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. KEYNOTE-859 is a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial, done at 207 medical centres across 33 countries. Eligible participants were aged 18 years and older with previously untreated histologically or cytologically confirmed locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to receive pembrolizumab or placebo 200 mg, administered intravenously every 3 weeks for up to 35 cycles. All participants received investigator's choice of fluorouracil (intravenous, 800 mg/m2 per day) administered continuously on days 1-5 of each 3-week cycle plus cisplatin (intravenous, 80 mg/m2) administered on day 1 of each 3-week cycle or capecitabine (oral, 1000 mg/m2) administered twice daily on days 1-14 of each 3-week cycle plus oxaliplatin (intravenous, 130 mg/m2) administered on day 1 of each 3-week cycle. Randomisation was done using a central interactive voice-response system and stratified by geographical region, PD-L1 status, and chemotherapy in permuted block sizes of four. The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population, and the populations with a PD-L1 combined positive score (CPS) of 1 or higher, and PD-L1 CPS of 10 or higher. Safety was assessed in the as-treated population, which included all randomly assigned participants who received at least one dose of study intervention. Here, we report the results of the interim analysis. This study is registered with ClinicalTrials.gov, NCT03675737, and recruitment is complete. Between Nov 8, 2018, and June 11, 2021, 1579 (66%) of 2409 screened participants were randomly assigned to receive pembrolizumab plus chemotherapy (pembrolizumab group; n=790) or placebo plus chemotherapy (placebo group; n=789). Most participants were male (527 [67%] of 790 participants in the pembrolizumab plus chemotherapy group; 544 [69%] of 789 participants in the placebo plus chemotherapy group) and White (426 [54%]; 435 [55%]). Median follow-up at the data cutoff was 31·0 months (IQR 23·0-38·3). Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population (12·9 months [95% CI 11·9-14·0] vs 11·5 months [10·6-12·1]; hazard ratio [HR] 0·78 [95% CI 0·70-0·87]; p<0·0001), in participants with a PD-L1 CPS of 1 or higher (13·0 months [11·6-14·2] vs 11·4 months [10·5-12·0]; 0·74 [0·65-0·84]; p<0·0001), and in participants with a PD-L1 CPS of 10 or higher (15·7 months [13·8-19·3] vs 11·8 months [10·3-12·7]; 0·65 [0·53-0·79]; p<0·0001). The most common grade 3-5 adverse events of any cause were anaemia (95 [12%] of 785 participants in the pembrolizumab group vs 76 [10%] of 787 participants in the placebo group) and decreased neutrophil count (77 [10%] vs 64 [8%]). Serious treatment-related adverse events occurred in 184 (23%) participants in the pembrolizumab group and 146 (19%) participants in the placebo group. Treatment-related deaths occurred in eight (1%) participants in the pembrolizumab group and 16 (2%) participants in the placebo group. No new safety signals were identified. Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma. Merck Sharp and Dohme.

Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma

BackgroundErdafitinib is a pan–fibroblast growth factor receptor (FGFR) inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2 alterations who have progression after platinum-containing chemotherapy. The effects of erdafitinib in patients with FGFR-altered metastatic urothelial carcinoma who have progression during or after treatment with checkpoint inhibitors (anti–programmed cell death protein 1 [PD-1] or anti–programmed death ligand 1 [PD-L1] agents) are unclear.MethodsWe conducted a global phase 3 trial of erdafitinib as compared with chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti–PD-1 or anti–PD-L1. Patients were randomly assigned in a 1:1 ratio to receive erdafitinib or the investigator’s choice of chemotherapy (docetaxel or vinflunine). The primary end point was overall survival.ResultsA total of 266 patients underwent randomization: 136 to the erdafitinib group and 130 to the chemotherapy group. The median follow-up was 15.9 months. The median overall survival was significantly longer with erdafitinib than with chemotherapy (12.1 months vs. 7.8 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.47 to 0.88; P=0.005). The median progression-free survival was also longer with erdafitinib than with chemotherapy (5.6 months vs. 2.7 months; hazard ratio for progression or death, 0.58; 95% CI, 0.44 to 0.78; P<0.001). The incidence of grade 3 or 4 treatment-related adverse events was similar in the two groups (45.9% in the erdafitinib group and 46.4% in the chemotherapy group). Treatment-related adverse events that led to death were less common with erdafitinib than with chemotherapy (in 0.7% vs. 5.4% of patients).ConclusionsErdafitinib therapy resulted in significantly longer overall survival than chemotherapy among patients with metastatic urothelial carcinoma and FGFR alterations after previous anti–PD-1 or anti–PD-L1 treatment. (Funded by Janssen Research and Development; THOR ClinicalTrials.gov number, NCT03390504.)

Therapeutic Potential of Tisotumab Vedotin in the Treatment of Recurrent or Metastatic Cervical Cancer: A Short Report on the Emerging Data.

Cervical cancer is the fourth most common type of cancer in women worldwide. It is associated with a high death rate, despite the fact that it is a nearly 100% preventable disease because of very effective primary and secondary preventive strategies. Advanced and recurrent disease is uncurable with a high relapse risk and the second-line therapies are limited with modest response rates and short durability. Investigating alternative mechanisms of action is crucial because of the high request for effective new therapies. Tisotumab vedotin (TV) is the first antibody-drug conjugated to target a cell surface-expressed tissue factor, and preliminary data in patients with metastatic and recurrentcervical cancer have been promising. In addition, the trials showed a favorable tolerability profile, with limited incidence of grade 3 or worse adverse events. According to the data of ENGOT-cx6/GOG-3023/innovaTV 204, the US Food and Drug Administration granted expedited approval of TV on September 20, 2021, for womenwith recurrent or metastatic cervical cancer. Actually, two other trials testing TV alone or in combination with other agents are ongoing. ENGOT-cx8/GOG-3024/innovaTV 205 is a Phase Ib/II trial of TV in combination with platinum or bevacizumab or pembrolizumab, in patients with recurrent or metastatic cervical cancer who have not received prior systemic therapy or who have progressed after no more than two prior systemic therapies. ENGOT-cx12/GOG-3057/InnovaTV 301 is a Phase 3 trial of TV vs investigator's choice chemotherapy in patients with advanced or recurrent cervical cancer who had received no more than 2 prior chemotherapy lines. The outcomes of these two trials will potentially confirm and reinforce the use of TV as a new standard of care in advanced or recurrent cervical cancer.

Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study

Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. Novocure.

Cost-effectiveness analysis of an orphan drug tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing.

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator's choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.

First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial

Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression. EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged ≥18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540. Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 26·1 months (95% CI 22·1-31·8; 149 [52%] of 284 died) versus 13·3 months (10·5-16·2; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 0·57, 95% CI 0·46-0·71; p<0·0001), median progression-free survival was 8·1 months (95% CI 6·2-8·8; 214 events occurred) in the cemiplimab group versus 5·3 months (4·3-6·1; 236 events occurred) in the chemotherapy group (HR 0·51, 95% CI 0·42-0·62; p<0·0001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 6·6 months (6·1-9·3) and overall survival of 15·1 months (11·3-18·7). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signals INTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer. Regeneron Pharmaceuticals and Sanofi.

Психологические особенности следователей с различными типами стратегий предварительного расследования уголовных дел

The article substantiates the original concept of the investigator's choice of a criminal investigation strategy based on the practical experience of the author's investigative work. According to the traditional approach in legal psychology, the investigator's activity is completely determined by the norms of the Criminal Procedure Code, and therefore does not represent the freedom of choice to the subject of the investigation. However, the author comes to the conclusion that such qualities of the subject as a tendency to risky behavior, the level of creativity, communicative and organizational abilities, tolerance to uncertainty and the type of behavior in conflict, influence the investigator's choice of a certain strategy for investigating a criminal case. The article attempts an empirical analysis of psychological resources to improve the effectiveness of the investigator.

TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6mg/kg iv. every 3weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator's choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression.

LBA5507 Background: Mirvetuximab soravtansine (MIRV), an antibody drug conjugate targeting FRα, demonstrated clinically meaningful antitumor activity in a single arm trial reported previously (Matulonis, JCO 2023). MIRASOL is a randomized phase 3 trial to confirm the efficacy of MIRV vs standard-of-care chemotherapy in patients (pts) with PROC. Methods: 453 PROC pts with high FRα expression (Roche FOLR1 Assay) with 1-3 priors were randomized 1:1 to MIRV 6 mg/kg, adjusted ideal body weight, Day 1 of a 21-day cycle or IC: paclitaxel, pegylated liposomal doxorubicin, or topotecan. The primary efficacy endpoint was progression-free survival (PFS) by investigator (INV) with key secondary endpoints ORR, overall survival (OS), and patient-reported outcomes in hierarchical order; other endpoints included safety and tolerability. Blinded independent central review (BICR) for PFS and ORR were sensitivity analyses. Results: With a data cutoff of March 6, 2023, 227 pts were randomized to the MIRV arm; 226 to the IC arm. Median follow-up was 13.1 months. Baseline characteristics were well balanced across arms; 14% of pts had one, 39% two, and 47% three prior lines of therapy; 62% received prior bev; and 55% received prior PARPi therapy. The study met its primary and key secondary endpoints with statistically significant results in PFS (INV), ORR (INV), and OS (Table). In the bev-pretreated subset (n=281), PFS HR was 0.64 (0.492, 0.842) and OS HR was 0.74 (0.535, 1.036); in the bev-naïve subset (n=172), PFS HR was 0.66 (0.459, 0.942) and OS HR was 0.51 (0.306, 0.860). The adverse event (AE) profile of MIRV was consistent with prior reports: predominantly low-grade ocular (MIRV vs IC all grade 56% vs 9%; grade 3+ 14% vs 0%) and gastrointestinal events (MIRV vs IC all grade 70% vs 66%; grade 3+ 13% vs 15%). Compared with IC, MIRV was associated with lower rates of grade 3+ treatment-emergent AEs (42% vs 54%), serious AEs (24% vs 33%), and discontinuations due to TEAEs (9% vs 16%). Fourteen percent of pts on the MIRV arm remained on study drug vs 3% on the IC arm. Conclusion: MIRV is the first treatment to demonstrate a PFS and OS benefit in PROC compared to IC. The efficacy data, along with the well-characterized safety profile, position MIRV as a new, standard of care for pts with FRα positive PROC. Clinical trial information: NCT04209855 .[Table: see text]

Efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in metastatic colorectal cancer: A multicenter, single-arm phase 2 trial.

3582 Background: Emerging evidence suggested that chemotherapy in combination with anti-angiogenic targeted agents can achieve higher response in multiple solid tumors. Fruquintinib is a highly selective small-molecule VEGFR inhibitor that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, we assessed the efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in pretreated advanced mCRC patients. Methods: In this prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280), patients with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3mg, D1-21, Q4w) and investigator's choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, Q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Results: As the data cutoff on February 10, 2023, 37 patients have been enrolled and treated, with 31 evaluable for efficacy. Median age was 63 years (range, 44-76) and 22 (59.5%) were male. The left colon cancer involved in 28 patients (75.7%). All patients were microsatellite-stable phenotype and 11 (29.7%) had mutations in KRAS gene. 16 (43.2%) patients received prior anti-VEGF therapy. 20 (54.1%) and 11 (29.7%) patients had liver and lung metastases respectively. At a median follow-up of 8.4 months, 28 patients are still on treatment. The ORR is 48.4%, with 15 partial response. The DCR is 90.3%. At data cutoff, median PFS has not yet reached. 23 patients (74.2%) remained progression free at 6 months. In terms of safety, the regimen was well tolerated, mainly grade 1/2 adverse events (AEs). Grade 3/4 AEs were neutropenia (21.6%), leukopenia (10.8%), thrombocytopenia (5.4%), proteinuria, diarrhea, hand-foot syndrome and hypertension accounted for 2.7% respectively. 5 pts received reduced doses of fruquintinib. No treatment-related deaths occurred. Conclusions: Fruquintinib combined with chemotherapy followed by fruquintinib maintenance shows promising efficacy and manageable safety profile for mCRC patients in second-line setting. Updated follow up data will be presented in the future. Clinical trial information: ChiCTR2200059280 .

A phase III study of lurbinectedin alone or in combination with irinotecan vs investigator's choice (topotecan or irinotecan) in patients with relapsed small cell lung cancer (SCLC; LAGOON trial).

TPS8613 Background: Lurbinectedin is a novel synthetic chemical entity that acts as an inhibitor of oncogenic transcription and is active in tumors addicted to transcription. A phase II Basket trial (NCT02454972) in patients with small cell lung cancer (SCLC) treated with lurbinectedin in the second-line setting showed overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months, with durable responses (43.0% ≥ 6 months). Based on these results, lurbinectedin was granted accelerated approval by the US FDA. An ongoing phase I/II trial (NCT02611024) is evaluating the lurbinectedin/irinotecan combination. Preliminary results showed ORR of 62% and median DoR of 5.7 months (2020 World Conference on Lung Cancer) warranting expansion to 100 patients. These results have supported the conduction of a phase III trial (LAGOON - NCT05153239). Methods: LAGOON is a randomized phase III clinical trial evaluating two experimental arms (lurbinectedin alone, 3.2 mg/m2 D1 q3wk, or lurbinectedin 2 mg/m2 D1 plus irinotecan D1, D8 q3wk) versus Investigator’s Choice (topotecan D1-5 q3wk or irinotecan D1 q3wk according to label) as control arm in relapsed SCLC patients. Approximately 705 patients will be enrolled. Central randomization will be implemented (1:1:1 ratio). Stratification will be done according to chemotherapy-free interval (CTFI) after first line (sensitive vs. resistant); prior anti-PD-(L)1; baseline central nervous system (CNS) involvement; lactate dehydrogenase value, and Investigator’s preference for the Control Arm. Main inclusion criteria include age ≥ 18 years, confirmed SCLC diagnosis, one prior line of platinum-containing chemotherapy with/without anti-PD-(L)1, and CTFI ≥ 30 days. Patients with CNS metastases can participate if pretreated and radiologically stable for at least 4 weeks. Main exclusion criteria include platinum-naïve patients, patients pretreated with more than one prior chemotherapy regimen (including platinum re-challenge), and prior treatment with lurbinectedin, trabectedin, PM14, or topoisomerase I inhibitors. An Independent Data Monitoring Committee will oversee the conduct of the study. An Independent Review Committee will provide the patient’s response at each tumor assessment endpoint to determine the best patient’s response and the date of objective response or progression/censoring according to RECIST v.1.1. Clinical trial information: NCT05153239 .

A phase 2/3 trial in progress on tebentafusp as monotherapy and in combination with pembrolizumab in HLA-A*02:01+ patients with previously treated advanced non-uveal melanoma (TEBE-AM).

TPS9594 Background: Tebentafusp is a bispecific (gp100 x CD3) ImmTAC that can redirect T cells to target gp100+ melanoma cells. In a Phase (Ph) 3 trial, tebentafusp demonstrated an overall survival (OS) benefit (HR 0.51) compared to investigator's choice (IC) in first line HLA-A*02:01+ patients with metastatic uveal melanoma (mUM). Gp100, which has limited expression in normal cells, is overexpressed in melanoma, including skin melanoma, supporting the investigation of tebentafusp in non-uveal melanoma. In a first-in-human trial, tebentafusp monotherapy demonstrated a promising 1-year OS (~74%) in anti-PD(L)1 naïve HLA-A*02:01+ patients with metastatic cutaneous melanoma (mCM). In a subsequent Ph1 trial, tebentafusp combined with anti-PDL1, with or without anti-CTLA4, demonstrated a 1-year OS of 75% in patients with mCM who progressed on prior anti-PD(L)1 therapy, which compares favorably with recent benchmarks (1-year OS 38%-57%) in similar patient populations.1-3 The promising activity of tebentafusp as monotherapy and in combination with anti-PD(L)1 agents in advanced melanoma (AM) provides the rationale to conduct a Ph2/3 trial of tebentafusp (TEBE-AM; NCT05549297) in patients who have progressed on standard of care therapies. In mUM trials, RECIST response underestimated the OS benefit of tebentafusp, whereas a strong association was shown between OS and early reduction in ctDNA levels relative to baseline.4 As an early measure of changes in tumor burden, ctDNA reduction is included as an innovative dual primary endpoint with OS for the Ph2 part of this study. Methods: TEBE-AM is a multicenter, open-label, seamless Ph2/3 study in HLA-A*02:01+ patients with non-uveal AM who have progressed on prior anti-PD(L)1, received prior ipilimumab, and a prior BRAF/MEK inhibitor regimen if actionable BRAF mutation is present. Patients are randomly assigned (1:1:1) to receive tebentafusp monotherapy, tebentafusp combined with pembrolizumab, or IC. In the IC arm, patients may enroll in clinical trials of investigational agents, receive local standard of care, or receive best supportive care, while being followed for key endpoints. Randomization into the Ph3 portion will commence immediately following completion of accrual into the Ph2 portion. Efficacy from the Ph2 portion may inform changes to the Ph3 design. Primary endpoints are ctDNA reduction relative to baseline and OS in Ph2 and OS in Ph3. Ph2 enrollment opened in Jan 2023 in the US and is expected to open in other countries mid-2023. Clinical trial registration: NCT05549297. 1. Zimmer L, et al. Eur J Cancer 75:47–55, 2017. 2. Silva IPD, et al. J Clin Oncol 38:10005–10005, 2020. 3. Arance AM, et al. J Clin Oncol 39:S9504, 2021. 4. Carvajal RD, et al. Nat Med 28:2364-2373, 2022. Clinical trial information: NCT05549297 .

APPROACH trial: Multimodal approach in patients with mHSPC: A pragmatic, randomized, phase 3 trial of androgen-deprivation therapy (ADT) plus apalutamide (APA) versus ADT plus apalutamide (APA) and local treatment—Meet-URO 29 study.

TPS5115 Background: it is reasonable to offer radiotherapy (RT) to improve outcomes for patients with newly diagnosed M1 prostate cancer with &lt; 5 bone metastases (HORRAD) or low volume disease (STAMPEDE) (Burdett, S et al., Eur. Urol. 2019). Data from clinical randomized trials evaluating feasibility and overall benefit of cytoreductive radical prostatectomy (cRP) in oligometastatic ormone sensitive patients are not available. The rationale for performing cytoreductive radical prostatectomy is to eliminate lethal clones ofcastration-resistant intraprostatic PCa, which can favor the process of metastasis (A Heidenreich et al. Current Opinion in Urology 2020), in order to improve OS and PFS and to prevent local progression and correlated events. Methods: APPROACH is an Italian multicenter study, which is enrolling ~566 pts with oligometastatic hormone sensitive prostate cancer who are candidates to receive treatment with apalutamide. After 6 months from the start of treatment, patients will be randomized 1:1 to receive local treatment or not in addition to apalutamide (investigator's choice between primary radiotherapy and cytoreductive prostatectomy). Primary end point: To determine whether treatment with apalutamide plus ADT for 6 months followed by locoregional treatment with radiotherapy or radical prostatectomy has better efficacy than treatment with apalutamide plus ADT alone in terms of radiographic progression-free survival (rPFS). Secondary end points: To evaluate tumor shrinkage after locoregional approach and to evaluate short and long-term side effects after locoregional surgery or RT, time to PSA progression, time to castration resistance, cancer specific survival, overall survival and quality of life according to EPIC-26 and EQ-5D-5L questionnaires. Clinical trial information: NCT05649943 .

Nivolumab (Nivo) plus ipilimumab (Ipi) 6-month treatment versus continuation in patients with advanced non-small-cell-lung cancer (aNSCLC): 3-year results of the IFCT-1701 DICIPLE phase 3 trial.

9068 Background: 1st-line immunotherapy (io) is a standard treatment for patients (pts) with advanced NSCLC devoid of targetable mutation. Classical 2-year io duration does not rely on indubitable evidence. We aimed to assess whether 6-month nivo/ipi was equivalent to continuation until progression or unacceptable toxicity in pts with disease control (DC). Methods: In this multicenter non-inferiority randomized phase 3 trial, eligible treatment-naive pts, age&gt;18, PS 0-1, had stage IV NSCLC and measurable disease. They received Nivo 3 mg/kg q2w plus Ipi 1 mg/kg q6w, until progression or unacceptable toxicity for a maximum of 6-month induction treatment. At 6 months, pts with DC and no severe TRAEs were randomized (1:1) into io continuation (arm A), and observation (arm B). At progression, arm A pts received an investigator's choice 2nd line platinum-based chemo, while arm B pts resumed double io. Primary endpoint was progression-free survival (PFS). 450 pts x 2 were to be randomized, to achieve 80% power, with 0.025 one-sided a error. Observing that European filing for the io combo was not submitted, the trial's steering committee recommended to stop the accrual on Jan. 2021. Results: From May. 2018 to Jan. 2021, 265 pts (70.6% male, 62.7yr median age, 59% stage IVB, 22.3% SCC, 9.9% PDL1≥50%, 12.2% PDL1&lt;1%) were accrued. 138 (72.6%) pts had disease progression before 6 months, 11 died (5.8%), 30 (15.8%) experienced TRAEs contra-indicating continuation, 11 (5.8%) were deemed ineligible for randomization. 71 pts with DC were randomized. With a median follow-up from randomization of 29.9 months, median PFS was 20.5 (7.4-36.7) months in arm A, 35.2 (21.4-NR) in arm B. 12-month PFS was 55.6% (38.0-69.9) and 81.2% (62.9-91.1), respectively (p=0.08). Adj.HR (arm B vs. arm A) was 0.66, 95%CI (0.28-1.31), p=0.23. OS data, yet immature, did not show any significant difference between both arms (adj.HR arm B vs. A: 0.54 95%CI (0.20-1.49), p=0.23). From randomization, 28.6% G3-5 TRAEs in arm A were observed vs. 2.9% in arm B (p=0.005). Conclusions: The 6-month i.o. interruption for NSCLC patients with DC did not yield significant PFS or OS differences in this prematurely halted trial. Updated OS with a 3-year follow-up, quality of life and biomarker data, will be presented at the meeting. Clinical trial information: NCT03469960 .

Aumolertinib with chemotherapy or alone compared with osimertinib in patients with EGFR-mutant non–small-cell lung cancer (TREBLE).

TPS9153 Background: Aumolertinib is a novel third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Safety and efficacy of aumolertinib have been demonstrated in patients with EGFR-mutated locally advanced or metastatic (LA/m) NSCLC. (Lu, 2021; Lu, 2022) A phase 3 study in these patients in the first-line setting showed a significant improvement in progression-free survival (PFS) for aumolertinib vs gefitinib (median 19.3 months versus 9.9 months; P &lt; 0.0001). Aumolertinib was generally well-tolerated. (Lu, 2022) Aumolertinib is approved in China for patients with LA/m NSCLC who have an EGFR T790M resistance mutation upon disease progression and for treatment naïve patients with EGFR-mutated NSCLC. Studies evaluating first-generation EGFR-TKI + chemotherapy (chemo) showed improved PFS in select patient populations. (Hosomi, 2019) It is unclear if the addition of chemo to a 3G EGFR-TKI will improve PFS in patients with EGFR-mutated LA/m NSCLC. As the addition of chemo to a 3G EGFR-TKI may prove warranted, there is a need to understand the relative efficacy and safety in the diversity of patients encountered in routine clinical practice. (Tanaka, 2021). Methods: This is a randomized, multi-regional, phase 3 clinical trial comparing aumolertinib + chemo or aumolertinib monotherapy with osimertinib monotherapy. Patients are eligible if they have stage IIIB, IVA, or IVB NSCLC; harbor ex19del or L858R EGFR mutations alone or with other EGFR mutations; and have an ECOG PS of ≤2. Patients are ineligible if they received prior systemic therapy for mNSCLC or are a candidate for curative intent therapy. Eligible patients will be randomized 2:2:1 and stratified by mutation status (ex19del or L858R), ECOG PS (0 vs 1/2), and race (White vs Asian vs other races combined). Anticipated enrollment is 500 patients; 200 to receive aumolertinib + chemo (110 mg PO QD aumolertinib + investigator's choice chemo), 200 to receive osimertinib (80 mg PO QD), and 100 to receive aumolertinib (110 mg PO QD). The primary endpoint is PFS, by blinded independent review committee (BICR) per RECIST 1.1, for aumolertinib + chemo vs osimertinib. Overall survival (OS) is a key secondary endpoint for aumolertinib + chemo vs osimertinib. Additional efficacy endpoints will be assessed for aumolertinib + chemo vs osimertinib and aumolertinib vs osimertinib, as well as safety and patient reported outcomes. Exploratory endpoints include characterizing mechanisms of acquired resistance across all arms, CNS efficacy, and exposure-response relationship. Enrollment began in July 2022. The study is currently recruiting and will include approximately 200 sites globally. The study design will provide a power of 80% at a 2-sided Type I error of 0.05 for the primary endpoint. If the primary endpoint is statistically significant, a sequential test method will be used to evaluate OS. Clinical trial information: NCT05493501 .

A randomized, open-label study of the efficacy and safety of galinpepimut-S (GPS) maintenance monotherapy compared to investigator's choice of best available therapy (BAT) in patients with acute myeloid leukemia (AML) who have achieved complete remission (CR) after second-line salvage therapy.

TPS7074 Background: Patients with relapse/refractory (r/r) AML have poor outcomes. Allogeneic stem cell transplantation (allo-SCT) can potentially cure some patients with r/r AML who achieve second CR (CR2). However, barriers to transplantation such as advanced age, poor functional status/comorbidities or lack of donor exist and not all patients are able to proceed to allo-SCT. Therefore, novel strategies to decrease relapse risk in these patients are urgently needed. A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. WT1 has emerged as an encouraging vaccine target in AML due to its overexpression in leukemic blasts. Maintenance therapy with Galinpepimut-S (GPS), a multivalent heteroclitic WT1 peptide vaccine, has shown promising activity in patients with AML by inducing a strong innate immune response (CD4+/CD8+) against the WT1 antigen and across a broad range of HLA types. Methods: This is an open-label, multicenter, randomized, phase III study of GPS vs. BAT in patients with AML in CR2/CRp2 (CR2 with incomplete platelet recovery). BAT may include observation, low dose cytarabine and hypomethylating agents +/- venetoclax. The primary endpoint of the study is overall survival (OS). Secondary endpoints include safety and tolerability of GPS and leukemia-free survival. Exploratory endpoints include WT1-specific immune response dynamics in blood and bone marrow. Approximately 125 - 140 patients will enroll, in a 1:1 ratio, to provide at least 90% power under an assumed hazard ratio of 0.52, based on median OS of 8.0 m (BAT) and 15.4m (GPS). Randomization will be stratified by duration of CR1 ( &lt; 12m vs. ≥12m), Cytogenetics (poor-risk vs. all other), CR2 vs. CRp2 and measurable residual disease (MRD) after CR2 (MRD- vs. MRD+). Inclusion criteria consists of willing subjects ≥18y with AML within 6m of achieving CR2/CRp2, ineligible for allo-SCT due to any reason, with ≥300 lymphocytes/ul and with adequate renal and hepatic function. Subjects with central nervous involvement, having received a live vaccine 30d prior to first dose of study drug, having a diagnosis of immunodeficiency, receiving ≥10mg daily of prednisone equivalent (or any other systemic immunosuppressant) for any indication 7d prior to first dose of study drug, hypersensitivity to study agent and with a history of solid organ transplant would be excluded. The clinical trial is actively enrolling, and the registry number is NCT04229979 . Clinical trial information: NCT04229979 .

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.