One-sided Alternatives Research Articles

Lenvatinib and pembrolizumab in patients with metastatic papillary renal cell carcinoma: A phase 2 pilot study.

109 Background: Traditionally, metastatic papillary renal cell carcinoma (papillary mRCC) has been treated with tyrosine kinase inhibitors, resulting in a 23% objective response rate and a progression-free survival of 9 months (SWOG 1500 trial). Combinations of immunotargeted therapy have shown improved outcomes in clear-cell mRCC. This prospective pilot study aimed to evaluate the preliminary efficacy of combining lenvatinib with pembrolizumab in patients with papillary mRCC. Methods: At study entry in August 2021, patients with papillary mRCC types 1 or 2, multiple measurable lesions per RECIST 1.1 criteria, and no prior therapy for advanced disease were included. The primary endpoint was the objective response rate. The study employed Simon's two-stage design (Simon, 1989) to test the null hypothesis that the true response rate is 23% against a one-sided alternative. In the first stage, 5 patients were enrolled. If there were 1 or fewer responses among these initial 5 patients, the study would be halted. The null hypothesis would be rejected if 6 or more responses were observed in the entire cohort of 12 patients. This design yields a type I error rate of 0.05 and power of 0.8 when the true response rate is 63%. Results: As planned, 5 patients were enrolled in the stage 1. The median age was 57.4 years. Among them, 4 patients were diagnosed with papillary RCC type 2, and 3 patients had an unresected primary tumor. Additionally, 1 patient presented with brain metastases. The objective response rate was 100%, of which there was 1 complete and 4 partial responses. As of the last follow-up, the status of patients on therapy was as follows: i) three patients remained on therapy for more than 12 months; ii) one patient experienced disease progression after 14.3 months of treatment; iii) one patient who initially had an ongoing response developed grade 3 uncontrolled diarrhea after 5.5 months from the start of therapy. Despite the positive outcomes observed in stage 1 of the study, the enrollment was stopped. This decision was influenced by emerging results from the large phase 2 trial KEYNOTE-B61, as reported by Chung-Han Lee et al. (ASCO 2023). Conclusions: All patients responded to lenvatinib and pembrolizumab therapy. These results suggest promising efficacy of the combination in metastatic papillary RCC. Clinical trial information: KCRB01012021 .

Enfortumab vedotin (EV) as monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of stage I of a phase 2 trial.

152 Background: EV is an antibody-drug conjugate consisting of a fully human antibody directed against the extracellular domain of Nectin-4, which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. In animal models of prostate cancer, metastatic lesions showed high membranous Nectin-4 expression (PMID: 30767361). We aimed to investigate EV in pts with mCRPC. Methods: This IRB-approved, investigator-initiated, single-arm, single-center, phase 2 study administered EV at 1.25 mg/kg IV on days 1, 8, and 15 of 28 days cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, performance status ≤ 1, adequate organ function, prior treatment (Rx) with ≥3 cycles of docetaxel and at least one androgen-receptor pathway inhibitor, received/refused all therapies shown to improve overall survival except cabazitaxel which is exclusionary. Primary objective: To assess antitumor activity of EV as determined by one of the following: 1) objective response by RECIST 1.1 in those with measurable disease, 2) confirmed conversion of circulating tumor cell count (CTC) to <5/7.5 mL blood, 3) PSA decline of ≥ 50%, and 4) stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design was used. The null hypothesis (H0) that true response rate (RR) is 25% is tested against a one-sided alternative. In stage I if ≤3 responses were observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts (type I error rate 0.046, power 0.854 when true RR is 50%). Results: Herein, we present results of 11 pts treated on stage I of study. All pts were non-Hispanic white with median age of 72 years (range 43-78). Median number of prior systemic therapies in addition to castration: 5 (range 3-8). Median follow-up of the cohort was 9 months (range 1-13). 4/11 had RECIST measurable disease and 7/11 had CTC ≥5 at baseline. Overall 7/11 (64%) pts had protocol-defined response (5/11 PSA 50% responses, 3/4 objective response, 4/7 confirmed CTC response and 2/11 ≥ 6 months on Rx). Of the 9 pts who discontinued Rx, 8 discontinued due to disease progression (1 withdrew consent). Median number of completed cycles were 6 (range: 2-12) and median radiographic progression-free survival was 5.5 months (95% CI 5.3-not reached). Most common grade 3/4 treatment-related adverse events (TRAEs) were anemia, AST increase, dry skin, fatigue, hyperglycemia, rash, leucopenia (1 pt each) and nausea and decrease in neutrophil (2 pts each). 8 pts had dose interruptions and dose reductions. No Grade 5 TRAEs. Conclusions: EV showed promising efficacy and an acceptable safety profile in pts with heavily treated refractory mCRPC. Further enrollment in stage 2 of the trial is ongoing. Clinical trial information: NCT04754191 .

Guiding adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient-derived organoids.

TPS711 Background: Recurrence rates in intermediate risk non-muscle invasive bladder cancer (NMIBC) are high and therefore, clinical guidelines recommend adjuvant instillations. However, the exact regimen with an exact number of instillations and the chemotherapeutic agent to be used are not clearly defined. During the last years we have established a standardized pipeline to generate patient-derived organoids (PDO) from cold cup biopsies of NMIBC. We showed that the subsequent organoids maintain key features of the parental tumor and share the molecular landscape. Moreover, our pipeline allows to investigate drug response to different agents in a standardized manner. Methods: In this ongoing, open-label, single center phase II trial, we aim to use drug screens in PDO of patients with intermediate risk NMIBC to guide drug selection for intravesical instillation. Patients with diagnosis of intermediate-risk NMIBC are enrolled. PDO are generated from biopsies prior transurethral resection of the bladder tumor. On the generated PDO drug response is determined to four chemotherapeutic agents that have already been used for bladder instillations in the literature (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). The most effective drug is selected for adjuvant instillation into the bladder once weekly for 6 instillations. The follow-up thereafter is performed according to European guidelines. The primary endpoint of the study is to determine the proportion of patients for which a specific selection of chemotherapeutic agent for intravesical instillation can be determined by using drug screens in PDOs. Secondary endpoints are recurrence- and, progression free survival, quality of life and translational studies. The null hypothesis, that a drug prediction will only be possible in 65% of patients, will be tested against a one-sided alternative. Assuming that the real proportion is 85%, 31 participants should show a statistically significant result at 5% significance and 80% power (exact binomial test). Due to early termination of 10%, a total number of 34 patients will be included. We are successfully conducting a trial to implement drug screens in PDO into daily routine and to guide patient treatment. This is a novel concept to precise treatment selection in patients with intermediate-risk NMIBC. When the primary endpoint is met, a modification of the trial with larger sample size, novel compounds and a focus oncological outcomes is foreseen. Clinical trial information: NCT05024734 .

A nonparametric test for comparing survival functions based on restricted distance correlation

Abstract In this article, we propose an omnibus test for comparing two survival functions under non-proportional hazards. The test statistic is based on a product-limit estimate of the restricted distance correlation, which is closely related to the L 2 {L}_{2} distance between survival curves. The strong consistency is established under mild regularity conditions. Our simulation studies show that the new test has satisfactory power under proportional hazard and various non-proportional hazards settings including delayed treatment effect, diminishing effect, and crossing survival curves; therefore, it can be a competitive alternative to the existing omnibus tests such as Kolmogorov-Smirnov test, Cramer-von Mises test, two-stage test, and the maxCombo test based on weighted log-rank statistics. Two extensions of the new test to one-sided alternatives and a Gaussian kernel are also discussed.

Total neoadjuvant treatment without surgery for locally advanced rectal cancer: Prospective study to assess tumor response, circulating genetic, and epigenetic biomarkers, and stromal transcriptome to interpret clinical outcome (NO-CUT trial).

TPS3633 Background: Total neoadjuvant therapy (TNT) has recently become a standard therapy for locally advanced rectal cancer (LARC). All nonsurgical interventions, including chemotherapy and concurrent chemoradiotherapy (CRT), are administered before either surgical resection of the rectum or non-operative management (NOM), depending on response to TNT. In the case of NOM, the impact of distant relapse on survival remains to be elucidated and circulating tumor DNA (ctDNA) monitoring has been proposed as a tool for early detection of relapse. Furthermore, predictive biomarkers of response to TNT are warranted for the early identification of patient candidates for NOM. In this regard, stromal contribution to sensitivity to pre-operative CRT is investigated by a transcriptomic signature on baseline tumor samples, as previously proposed by Isella C et al., Nature Genet, 2015. Methods: NO-CUT is a multicenter one-stage phase II trial aimed at assessing if a TNT approach with CAPOX followed by CRT can safely spare demolitive surgery in patients with LARC achieving a clinical complete response without increasing the risk of distant metastatic relapse. A Brookmeyer and Crowley approach was chosen to test the null hypothesis that the true distant relapse-free survival at 2.5 years rate is ≤75% against a one-sided alternative. The NOM cohort of the trial needs to accrue 44 evaluable patients and to be followed for at least 2.5 years. Such design yields a type I error rate of 10% and power of 80% when the true 2.5 years distant RFS proportion is 87%. Since it is assumed that the proportion of patients entering in the NOM cohort of the trial is at least 25%, a total of 180 patients are to be enrolled in NO-CUT study. Patients with medium-low LARC undergo TNT (4 cycles of CAPOX: capecitabine 1000 mg/m2 bid days 1-14 q 3 weeks; oxaliplatin 130 mg/m2 day 1 q 3 weeks) and 5 weeks of standard pelvic CT-RT, then restaging with imaging (MRI, CT-scan, and ultrasound endoscopy), and tumor biopsy. According to an algorithm defined for assessing tumor response, patients enter either NOM or surgery cohorts. During the follow-up phase of the trial, the NOM cohort is followed with intensive pelvic imaging and periodic blood samplings for 5 years. Tumor samples and ctDNA are studied at baseline, after TNT, and during follow-up. As of January 2023, 161 of planned 180 patients in 4 centers have been enrolled. Supported by grants from Associazione Italiana Ricerca Cancro (AIRC IG 2017-20685) and Fondazione Oncologia Niguarda. Clinical trial information: EudraCT 2017-003671-60 .

CRI-CCTG-0003/IND.240: An immunotherapy platform study in platinum-resistant high grade serous ovarian cancer (IPROC).

TPS5617 Background: Identifying new treatments for patients with platinum-resistant high grade serous ovarian cancer (HGSC) is a priority. Although several biological features of HGSC suggest inherent immunogenicity, immunotherapy has had limited efficacy to date. IPROC is an adaptive platform trial designed to evaluate multiple immunotherapy combinations selected and informed by an expert panel. IPROC accommodates both biomarker-agnostic and biomarker-directed combinations. Protocol and sub study specific translational studies are conducted on archived diagnostic tissue and serial prospective blood and tumor sample collection. Methods: IPROC is an open-label, multi center, phase II platform trial. Eligibility includes HGSC histology; progression within 6 months of the last platinum regimen; <1 prior line of chemotherapy for platinum resistant disease (unlimited prior lines for platinum sensitive); prior treatment with immunotherapy allowed (provided not discontinued for toxicity), ECOG 0/1. Patients must be willing and able to undergo study procedures. The primary endpoint is ORR (RECIST1.1). Secondary endpoints include iRECIST ORR, RECIST/iRECIST progression free and overall survival and safety. Exploratory objectives include whole exome sequencing and immune profiling of tumor and blood samples to identify biomarkers and new immunotherapy strategies/combinations for future evaluation. Tumor biopsy occurs at baseline, cycle 2 and progression (voluntary) with blood and plasma collected at each cycle and on progression. All sub studies use Simon 2-stage design with 10 patients (pts) enrolled in each stage. At the end of stage 1, in the absence of response, a modified cohort based on biomarker selection may be created through protocol amendment. In each substudy a null hypothesis that the objective response rate (ORR) is ≤5% is tested against a one-sided alternative that the ORR is ≥ 25%. A combination would be accepted as active if ≥4/20 pts respond with α=0.02 and power of 0.76. As of January 19, 2023, 2 sub studies are open and 12 patients have accrued. Sub study A is evaluating the combination of durvalumab and BA3011, a conditionally active anti-AXL humanized monoclonal antibody (IgG1) conjugated to monomethyl auristatin E (MMAE) in AXL overexpressing HGSC. Sub study B is evaluating durvalumab plus BA3021, a CAB anti-receptor tyrosine kinase orphan receptor 2 (ROR2) humanized monoclonal antibody (IgG1) conjugated to MMAE in ROR2 overexpressing HGSC. Further sub studies are planned (NCT04918186). Clinical trial information: NCT04918186 .

Phase II study of niraparib in patients with advanced melanoma with genetic homologous recombination (HR) mutation/alteration.

TPS9596 Background: There are a limited number of therapeutic options available for metastatic melanoma patients progressing on the checkpoint inhibitor(s) and BRAF-targeting drugs. PARP inhibitors have been approved in the setting of BRCA1/2 germline mutations, and have demonstrated activity in the setting of HR deficiency in other cancers. Documentation of PARP inhibitors in melanoma would have clear clinical impact. We have previously shown that 21-34% of metastatic melanomas harbor at least 1 molecular aberration in the HR pathway, considered pathogenic, and likely leading to HR deficiency. Previously, we demonstrated dramatic regression of tumors harboring HR mutation(s) with PARP inhibitor treatment in a PDX model. These findings provide a strong rationale to evaluate the clinical efficacy of a PARP inhibitor in patients with advanced melanoma with HR deficiency. Methods: This is a single arm, open-label, multi-center phase II trial. The primary objective of the study is: To evaluate the clinical efficacy of niraparib in advanced melanoma patients with HR deficiency. The secondary objectives is to evaluate PFS, OS, and safety profile of niraparib. The key eligibility criteria: Advanced melanoma patients with mutation in any of the following: ARID1A/B, ARID2, ATM, ATR, ATRX, BARD1, BRCA1/2, BAP1, BRIP1, CHEK2, FANCD2, MRN11A, RAD50, RAD51, RAD54B, PALB2 (requires a genetic analysis result performed at any CLIA-certified laboratory) disease progression on PD1-antibody therapy and if BRAF mutant, BRAF/MEK inhibitors ≥ 18 years of age; ECOG PS ≤ 1; prior systemic cytotoxic therapy ≤1 regimen; no limit on number of prior immunotherapy or targeted therapy regimens. No symptomatic brain metastasis; active brain lesions ≥6 mm size, or requiring steroid treatment Patients will be treated with oral niraparib once daily (28-day cycle); the dose will be 300 mg (if weight ≥77 kg and platelet counts of ≥150,000 µL); otherwise 200 mg RECIST 1.1 will be used to evaluate clinical response every 8 weeks. Adverse events will be recorded according to CTCAE version 4.03. The primary study endpoint is overall response rate. Simon’s optimal 2-stage design is proposed. With significance level of5% and 80% power, our null hypothesis that the true response rate is 0.10 will be tested against a one-sided alternative: H0: p ≤ 10%, a response rate of no real interest VS H1: p ≥ 30%, a response rate that would be of considerable interest 10 patients will be analyzed for a response evaluation in the first stage of the study, and 19 in the second stage, for a total of 29 patients. If the response rate is 10% (1/10) or less at the end of the first stage, further accrual will be terminated. With 2 or more responses in the first stage, accrual will continue to a total of 29 patients for this cohort. The null hypothesis will be rejected if ≥6 responses are observed in a cohort of 29 subjects. Clinical trial information: NCT03925350 .

Early results from CASCARA: A phase 2 study of cabazitaxel/carboplatin plus abiraterone in high-volume metastatic castrate-sensitive prostate cancer (mCSPC).

5071 Background: Best treatment of mCSPC involves doublet therapy (ADT + novel hormonal agent) or triplet therapy (ADT + novel hormone + docetaxel); however, opportunity remains for further improvement. Studies show that homologous recombination repair (HRR) gene mutations are enriched in metastatic prostate cancer, and may portend resistance to docetaxel. CASCARA tested quadruplet therapy (ADT + cabazitaxel/carboplatin + abiraterone) in high-volume mCSPC, aiming to enhance PSA responses and decrease progression at 1 year. Methods: This phase 2 study enrolled 61 mCSPC patients with high-volume disease who received ADT plus cabazitaxel (20 mg/m2 q21d x 6) and carboplatin (AUC=4 q21d x 6) followed by abiraterone (1000 mg, plus prednisone 5 mg). Primary endpoint was freedom from PSA/radiographic progression at 1 year. Other endpoints included PSA50 response, freedom from PSA progression, and safety. Archival biopsies were retrospectively evaluated for HRR ( BRCA1/2, ATM, CHEK2, CDK12, BRIP1, RAD51B) mutations at a CLIA-certified lab. A sample size of 61 was determined using a Simon two-stage design (stage 1: 32 men, stage 2: 29 men) with a null hypothesis of a 1-year PSA/radiographic progression-free rate of 0.80 against a one-sided alternative of 0.92. Results: From 11/2019 to 06/2022, 61 men enrolled at 7 sites. Median age was 64 (range, 45–76) years; 21% were African American. Median baseline PSA was 8.9 (range, 0.1–1021) ng/mL. 44% of men had ECOG=1. 91% had Gleason sum 8–10. Prevalence of DNA alterations (50 evaluable pts) was 18% for HRR mutations, 38% for TP53 muts, 22% for ERG fusions, 10% for SPOP muts. Freedom from PSA/radiographic progression at 1 year was 77% (95% CI, 63–87%), and freedom from PSA progression at 1 year was 81% (95% CI, 67–90%). The PSA50 rate response was 97%. PSA ≤0.2 ng/mL at month-7, a surrogate for survival in other mCSPC studies, was 61%; PSA ≤4 ng/mL at month-7 was 82%. Outcomes according to mutation status are shown. AEs included 7% grade (Gr)-3/4 myelosuppression, 8% Gr-3/4 infections, 10% Gr-3 GI disorders, and 3% Gr-3 fatigue. There were 4 treatment-related discontinuations. Conclusions: Quadruplet therapy with ADT + cabazitaxel/carboplatin + abiraterone was well tolerated. At 1 year, 77% of pts were progression-free. PSA ≤0.2 ng/mL at month-7 was 61%, exceeding the historical month-7 PSA ≤0.2 ng/mL rate of 45% in CHAARTED–docetaxel arm. Further exploration of this quadruplet strategy in randomized phase III studies is warranted. Clinical trial information: NCT03934840 . [Table: see text]

A phase II multi-cohort single-arm study of tiragolumab with atezolizumab plus bevacizumab in previously treated advanced non-squamous non–small-cell lung cancer.

TPS9152 Background: Checkpoint inhibitor immunotherapy (CPI) offers durable, immune-mediated, anti-tumor responses to a subset of patients (pts) with advanced non-small cell lung cancer (NSCLC), but not all derive meaningful benefit. Two clinical unmet needs where CPI has fallen short include EGFR-mutated NSCLC, where CPI is minimally effective, and NSCLC with intrinsic or acquired resistance to currently available CPI. Novel combination strategies have shown promise. Two agents that have demonstrated synergy with the anti-PD-L1 CPI atezolizumab in NSCLC are bevacizumab, a vascular endothelial growth factor (VEGF)-blocking antibody, and tiragolumab, a T-cell immunoglobulin and ITIM domain (TIGIT) immune checkpoint-blocking antibody. This multi-cohort phase II trial seeks to evaluate the efficacy of tiragolumab with atezolizumab plus bevacizumab in 2 CPI-resistant cohorts - EGFR-wild type, CPI-refractory advanced NSCLC (cohort A) and EGFR-mutated, CPI-naïve advanced NSCLC (cohort B) - incorporating novel genomic and immunologic analyses to deliver mechanistic insight into the biology of CPI-resistance in NSCLC. Methods: This open-label, phase II study has two cohorts. Cohort A includes pts with advanced PD-L1+ (TPS ≥ 1%), EGFR/ALK/ROS1 wild type NSCLC with progression on prior anti-PD(L)1-based CPI therapy. Cohort B includes pts with targeted therapy-refractory EGFR-mutated NSCLC who are CPI-naïve. Pts must have measurable disease and those with symptomatic and/or untreated brain metastases are excluded. Pts in both arms will receive tiragolumab 600mg IV with atezolizumab 1200mg IV and bevacizumab 15mg/kg IV every 3 weeks until progressive disease or unacceptable toxicity. The primary efficacy endpoint will be assessed separately in each cohort by investigator-assessed objective response rate (ORR) according to RECIST v1.1. Each cohort utilizes a Simon 2-stage design in which a null ORR of 4% is tested against a one-sided alternative of 20%. A sample size of 21 pts/cohort provides 80% power with a one-sided type 1 error rate of 5% to determine a true ORR of 20%. Secondary efficacy endpoints include: duration of response, progression-free survival (PFS), 6-month PFS, overall survival. Blood and tumor specimens will be acquired pre- and on-treatment. Correlative analyses to illuminate the biology of CPI resistance will include multiplex imaging mass cytometry of tumor tissue. In addition, whole exome sequencing, T-cell receptor sequencing, and MANAFEST neoantigen prediction will be used to identify neoantigen-specific T-cells and track these temporally (during/post treatment) and spatially (across biologic compartments). The study is activated and both cohorts are accruing simultaneously with enrollment ongoing. Clinical trial information: NCT04958811 .

Abstract OT2-10-03: HCRN BRE 19-433: A Multi-institutional Phase II Study to Evaluate Efficacy and Safety of TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 negative Patients with PD-L1+ Metastatic Triple Negative Breast Cancer (TARA)

Abstract Background Although immunotherapy (IO) in combination with chemotherapy has improved progression free and overall survival in patients with PD-L1+ metastatic triple negative breast cancer (mTNBC), prognosis remains poor. A potential therapeutic strategy to restore sensitivity to IO in patients with progressive disease is to introduce agents that re-sensitize the immune system to IO leading to a more tumor-specific and less toxic treatment in the second-line setting or beyond. Both talazoparib, a PARP inhibitor, and radiation (XRT) independently increase PD-L1 expression on the tumor cell surface resulting in heightened sensitivity to IO agents like atezolizumab, a PD-L1 inhibitor. Although a local treatment, XRT has the ability to produce an abscopal effect resulting in systemic shrinkage of non-irradiated tumors outside/distant to the XRT field, a phenomenon observed in patients receiving concurrent IO. While talazoparib is standard treatment in patients with gBRCA1 and 2 mutations, it is also a potent radiosensitizing agent that suppresses homologous recombination and PARP-1-dependent nonhomologous end joining (NHEJ) repair while promoting error-prone alt-NHEJ. When combined with IO, talazoparib can amplify immune responses by generating immunogenic neo-antigens independent of gBRCA1/2 status. We, therefore, hypothesize that the combination of talazoparib, XRT, and atezolizumab will re-sensitize mTNBC tumors to IO and promote a durable tumor-specific response that spares patients from toxicities associated with traditional chemotherapy regimens. Methods This is a Phase II multi-institutional study designed to assess efficacy and safety of talazoparib, high dose XRT, and atezolizumab given in the second-, third-, or fourth-line settings to patients with mTNBC that is PD-L1 positive. A total of 23 patients with mTNBC who do not carry gBRCA pathogenic variants will be enrolled. All patients will be treated with induction talazoparib of 1mg PO daily starting Day 1 of a 28-day cycle. Patients will then receive 8 Gy x 3 fractions to 1-4 metastatic lesions QOD beginning Day 12, 13, or 14. Atezolizumab will be given intravenously (840 mg)) on Day 15 of the 1st cycle and then on Day 1 and Day 15 of the subsequent cycles. Talazoparib and atezolizumab treatment will continue until progression or severe toxicity. The primary endpoint is objective response rate (ORR) in non-irradiated lesions 8 weeks after the first dose of atezolizumab. Key inclusion criteria include biopsy proven mTNBC (ER< 10%, PR< 10%, Her2-) with at least 2 extracranial metastatic lesions. Patients must have at least 1 extracranial metastatic lesion amenable to high dose radiotherapy and at least one additional extracranial lesion of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) that will not receive radiotherapy. Tumors must be PD-L1 positive as defined as >1% on IHC using the SP142 Ventana Assay. Key exclusion criteria include patients with germline BRCA pathogenic variants, more than three previous lines of chemotherapy treatment in the advanced setting with or without IO, and breast cancer progression within the first 3 months of previous IO treatment for non-metastatic or metastatic breast cancer. Sample size was determined using Simon’s 2-stage Minimax design to detect a 20% increase in ORR. The null hypothesis that the true response rate among gBRCA1/2 negative patients of 10% will be tested against a one-sided alternative. Inflammatory cytokines, circulating B cells, and ctDNA will be collected for correlative analysis. Enrollment began in April 2021. The study is managed by the Hoosier Cancer Research Network and is open to accrual at Emory University and University of Alabama at Birmingham. Clinical trial information: NCT04690855 Citation Format: Mylin A. Torres, Kevin Kalinsky, Erica Stringer-Reasor, Ahmed Elkhanany, Jolinta Lin, David M. Schuster, Sarah Friend, Jeffrey Switchenko, Manali Bhave. HCRN BRE 19-433: A Multi-institutional Phase II Study to Evaluate Efficacy and Safety of TAlazoparib, Radiotherapy and Atezolizumab in gBRCA 1/2 negative Patients with PD-L1+ Metastatic Triple Negative Breast Cancer (TARA) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-03.

ENCORE: A phase 2 trial of enfortumab vedotin (EV) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

TPS294 Background: EV, an antibody-drug conjugate (ADC), consists of a fully human antibody directed against the extracellular domain of Nectin-4 (N4), which is conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), by a protease-cleavable linker. MMAE disrupts tubulin polymerization leading to mitotic arrest and apoptosis. N4 RNA is expressed in prostate tissue, but its expression levels in mCRPC are currently unknown. In animal models of prostate, metastatic lesions showed a very high (++++) membranous N4 expression and correlated with advanced disease (PMID: 30767361). In prostate cancer cell lines engineered to express N4 (PC3-Nectin-4), the hybridoma version of EV: AGS-22M6E, demonstrated potent dose-dependent cytotoxicity (PMID: 27013195). MMAE destabilizes microtubules in contrast to stabilization by taxanes and has shown anti-tumor activity in taxane refractory cell lines and in mCRPC pts with prior taxane therapy (PMID: 31742767). We initiated a phase 2 trial of EV in pts with mCRPC. Methods: This IRB approved, investigator-initiated, single-arm, single-center, non-randomized, open-label study will enroll 34 pts. EV will be administered at 1.25 mg/kg IV on days 1, 8, and 15 of 28- day cycle. Key eligibility criteria: ≥18 years age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, ECOG performance status ≤ 1, adequate organ function, prior treatment with ≥3 cycles of docetaxel, at least one androgen-receptor axis targeting agent, received/refused all therapies shown to improve overall survival (OS) except cabazitaxel which is exclusionary. Primary objective: To assess the antitumor activity of EV as determined by one of the following: objective response by RECIST 1.1, confirmed conversion of circulating tumor cell count (CTC) to <5/7.5 mL blood, PSA decline of ≥ 50% (per PCWG3) and stable disease for ≥ 6 months per PCWG3 modified RECIST 1.1. Simon’s two-stage design will be used. The null hypothesis (H0) that true response rate (RR) is 25% will be tested against a one-sided alternative. In first stage if ≤3 responses are observed of 11 pts, the study will be stopped. Otherwise, 23 additional pts will be accrued (total 34). H0 will be rejected if ≥13 responses are observed in 34 pts. This design yields type I error rate of 0.046 and power of 0.854 when true RR is 50%. Secondary endpoints: safety, tolerability, progression-free survival (radiological, clinical and PSA), OS, duration of PSA50% response, CTC conversion rate from ≥5/7.5 ml at baseline to <5/7.5 ml, PSA% change from baseline to 12 weeks and maximum PSA% decline from week 12 until treatment discontinuation. 3 patients have been enrolled. Clinical trial information: NCT04754191 .

Treatment Free Remission after Combination Therapy with Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed after a Prior Attempt at TKI Discontinuation-H Jean Khoury Cure CML Consortium Study

Successful tyrosine kinase inhibitor (TKI) discontinuation is currently one of the main goals of CML therapy. Patients who are in sustained deep molecular remission can attempt TKI discontinuation; approximately 50% of such patients will achieve a successful treatment free remission (TFR) and the other 50% will have molecular recurrence , warranting reinitiation of TKI therapy. Molecular recurrence is defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) . With a goal to increase the ultimate fraction of successful TFR, inquiry has begun into the rate and optimal approach to TFR after a second attempt at TKI discontinuation in patients with molecular recurrence after their first attempt. Molecular recurrence, is suspected to be driven by CML progenitor element(s) capable of, permitted to, and/or signaled to proliferate; different approaches to eradicate such a compartment have been proposed. One such potential means may be through alternative and synergistic BCR::ABL1 inhibition with the allosteric inhibitor asciminib in combination with approved TKIs for CML. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. The activity of asciminib is a result of its ability to bind a vacant pocket on the kinase domain that is normally occupied by the myristoylated N-terminus of ABL, a negative regulatory element lost upon the fusion of ABL to BCR. Asciminib has an excellent selectivity profile, is several-fold more potent than current approved TKIs such as nilotinib, and in vitro was active in the low nanomolar range against a spectrum of clinically observed ATP site mutations. Asciminib demonstrated efficacy in phase I studies in resistant/intolerant chronic and accelerated phase CML, including T315I mutation positive and ponatinib pretreated patients. In a phase III trial, asciminib was more active than bosutinib in a phase III trial in patients who had received 2 prior TKIs Our primary objective in this study is to determine the 1-year TFR rate after 12 months of combination therapy with imatinib plus asciminib, followed by treatment cessation, in subjects who have previously had molecular recurrence first TFR attempt. This is a single arm phase II study that will enroll a maximum of 51 patients (NCT04838041). All subjects will have a confirmed diagnosis of CML-CP. Each subject must have previously attempted to discontinue imatinib, and were restarted on imatinib at the time of molecular recurrence in order to be eligible for this trial. This trial will use asciminib 40 mg PO daily plus imatinib at a maximum dose of 400 mg PO once daily in the combination treatment phase of this trial. All eligible subjects will be treated with asciminib and imatinib on cycle 1 day 1 of the combination therapy phase. Patients will remain on imatinib for 12 cycles. RQ-PCR to measure BCR::ABL1 transcripts in the peripheral blood at screening and at specific time points during the first 12 cycles on trial (combination therapy phase). At the end of 12 cycles, asciminib and imatinib will be discontinued in any subject who has continued in stable deep remission and thus meets criteria for TFR. This study will assess a wide range of PROs before and after stopping imatinib. These will be done in conjunction with RQ-PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. The alternative hypothesis of relapse rate after second discontinuation of TKI combination treatment is 35% will be tested against a one-sided alternative of historical control of 55% relapse rate. Simon's two-stage admissible design will be used. The null hypothesis that the true TFR rate (no loss of MMR) is 45% will be tested against a one-sided alternative. In the first stage 29 patients will be accrued. If there are 15 patients or fewer who maintain TFR in these 29 patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 47. The null hypothesis will be rejected if 27 or more patients maintain TFR in 47 patients. This design yields a type I error rate of 5% and power of 85% when the true TFR rate is 65%. To account for a potential dropout rate of 8% due to adverse events or loss of response, 51 patients will be enrolled to achieve the 47 patients needed.

Phase II Study of Tagraxofusp in Newly Diagnosed Secondary Acute Myeloid Leukemia (S-AML) after Previous Exposure to Hypomethylating Agents (TAGALONG Study)

Background: S-AML patients with prior exposure to hypomethylating agents (p-HMAs) have dismal clinical outcomes and are unfortunately excluded from many clinical trials. Thus, there is no standard-of-care for this high-risk patient population. Tagraxofusp (TAG; SL-401) is a CD123-directed targeted therapy that carries a truncated diphtheria toxin leading to irreversible inhibition of protein synthesis and apoptosis. TAG is FDA-approved for the treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm. There is high CD123 expression in AML and leukemic stem cells (Jordan, Leukemia 2000); thus, TAG represents a promising investigational therapeutic option. Recent data from the Children's Oncology Group AAML1031 Phase III study revealed that high CD123 expression was associated with high-risk genomic abnormalities and worse clinical outcomes (Lamble, J Clin Oncol 2022). An ongoing study of TAG + azacitidine (AZA) +/- venetoclax demonstrated no dose-limiting toxicities of TAG in newly diagnosed and relapsed/refractory AML/MDS (Lane et al, Blood [Abstract] 2021). Pre-clinical data suggests that down-regulation of DPH1, a gene responsible for synthesizing diphthamide (the target of the diphtheria toxin), is associated with TAG-resistance. Treatment with AZA hypomethylates CpG motifs in the promoter region of DPH1 which can restore sensitivity to TAG. The combination of TAG and AZA led to prolonged time to progression and overall survival than either agent alone in mouse models (Togami et al, J Clin Invest 2019). However, the optimal administration of TAG and AZA is unknown. Objectives: The primary objective of this study is to estimate the rate of complete remission (CR) in patients with newly diagnosed S-AML after p-HMAs receiving TAG +/- AZA. Secondary objectives are to describe toxicity, estimate the overall response rate, overall survival, disease free survival, progression free survival, event free survival, and the rate of allogeneic stem cell transplant. Correlative objectives include identifying genomic and single-cell transcriptomic predictors of response, serial assessment of response and MRD with digital PCR, and assessing CD123 expression in responders versus non-responders. Study Design: Key inclusion criteria are that subjects must be ≥18 years old with newly diagnosed, untreated AML. All subjects must have CD123 expression on leukemia cells by a centralized flow cytometry assay, a documented diagnosis of prior MDS, CMML, MPN, or MDS/MPN overlap syndrome, and have received at least 2 cycles of a HMA. An ECOG performance status of 0-2 and adequate organ function is required (ejection fraction >45%), including an albumin ≥ 3.2 g/dL to mitigate capillary leak syndrome. Key exclusion criteria are subjects who are suitable for and are willing to receive intensive chemotherapy, acute promyelocytic leukemia, and known CNS involvement. Cycles 1 and 2 will consist of TAG administered at 12 mcg/kg IV daily for 5 consecutive days every 21 days. Subjects who achieve a marrow CR (CR, CRi, CRh, MLFS) after Cycle 2 will continue TAG for up to 1 year at 12 mcg/kg IV for 5 days every 28 days. Subjects without a marrow CR after 2 cycles of treatment will be treated with TAG 12 mcg/kg IV for 3 days + AZA 75 mg/m2 SQ or IV on Days 1-7 every 28 days. Patients without an overall response to TAG + AZA after 4 cycles will be discontinued from study treatment. Statistical Design: A Simon's two-stage design will be utilized to test the hypothesis that TAG +/- AZA leads to an improved CR rate compared with historical controls. The null hypothesis that the true CR rate is 15% will be tested against one-sided alternative. In the first stage, 23 patients will be accrued. If there are 3 or fewer patients who achieve CR by cycle 6 of therapy, accrual to the study will be stopped to determine the outcome of the study. Otherwise, the study will move on to Stage 2 and 25 additional patients will be accrued for a total of 48 subjects. The null hypothesis will be rejected if 12 or more CR's are observed in 48 patients. This design yields a type 1 error rate of 0.05 and power of 80% when the true CR rate is 30%. Continuous monitoring for toxicity will be performed and the study will be stopped if there is unacceptable toxicity. The trial will begin recruitment as a multi-center investigator-initiated study in the last quarter of 2022 (NCT05442216). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT106: Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study

Abstract Background: Some patients with primary renal cell carcinoma (RCC) are unable to have surgery for different reasons (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.). We hypothesize that combination of nivolumab and ipilimumab could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) or with preference to have no surgery or intervention for any reason received combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint was complete response rate. Simon's two-stage design was used. The null hypothesis that the true complete response rate was 11% and was tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). The null hypothesis should be rejected if 3 or more responses are observed in 8 patients. Results: Between February 2020 and June 2021, 8 patients were included. Median age was 77.9 years (range 73-89). Patients were Caucasian (100%), predominantly male (75%), 62.5% had centrally located RCC, 25% had ECOG PS 1, and 6 of 8 patients had moderate and severe comorbidities. Median follow-up was 12.7 months (95% CI 5.2-16.5). All patients received immunotherapy during 4 months without grade ≥2 adverse events. No complete responses were observed. Partial responses were found in 2 patients (25%). Median size of the primary tumor at RCC diagnosis and after immunotherapy was 3.11 cm (range 2.2-3.9) and 2.86 cm (range 1.5-4.0), respectively. Any shrinkage of the primary tumor was reported in 4 (50%) patients (change in median sum of diameters -18%). Only one patient had tumor enlargement (+0.5 cm (+13%) after 9 months. SBRT was used in this patient. All other patients are under active surveillance. Next secondary end-point of 3-year progression-free survival will be reported. Conclusions: The activity of immunotherapy against primary tumor was limited in patients with T1aN0M0 RCC ineligible for surgical treatment. Duration of stable disease will be studied with long-term follow-up of these patients. Treatment with nivolumab and ipilimumab was safe in patients with moderate and severe comorbidities. Citation Format: Ilya Tsimafeyeu, Maria Volkova, Rustem Gafanov, Igor Myslevtsev, Andrey Andrianov, Axel Bex. Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT106.

Phase II study of KN046 in patients with thymic carcinoma who failed immune checkpoint inhibitors.

TPS8607 Background: Thymic carcinomas are the most aggressive form of thymic epithelial tumors. They are often not operable and are more resistant to chemotherapy than thymomas. Thymic carcinoma is sensitive to pembrolizumab. However, most patients who respond to pembrolizumab eventually recur. Recently, molecules that combine PD(L)1 and CTLA-4 have been developed for solid tumor patients, with the hope that targeted therapy will be more effective than standard of care. KN046 is a bi-specific antibody against PD-L1 and CTLA-4 with a much higher affinity of the anti-PD-L1 portion and a weaker affinity for anti-CTLA-4, potentially leading to less autoimmune disorders and toxicities. We developed a Phase II study to test the hypothesis that dual PD-L1 and CTLA-4 inhibition with KN046 may represent a safe and tolerable option for patients with advanced thymic carcinoma who have progressed on prior treatment with immune checkpoint inhibitors. Methods: Key eligibility criteria include thymic carcinoma with progression after treatment with an immune checkpoint inhibitor with no limit to prior lines of therapy, adequate organ function and performance status. History of prior or current autoimmune disorders are not allowed and history of baseline positive anti-acetylcholine receptor (AChR) autoantibody are not allowed. KN046 will be administered intravenously at 5 mg/kg every 2 weeks until progression or excessive toxicity for up to 2 years. A cycle is defined as 2 treatments (28 days). The primary objective is to evaluate the antitumor activity of KN046 in patients with thymic carcinoma as measured by overall response rate defined by RECIST 1.1 criteria. The secondary objectives are to assess the safety and tolerability of KN046 including safety as measured by the number of adverse events (CTCAE 5.0), duration of response (RECIST 1.1) from first documented response to the date of first documented disease progression, progression-free survival, and overall survival. Exploratory objectives include the association of biomarkers (PD-L1 expression, tumor immune microenvironment determined by multiplex IHC, tumor mutational burden, T-cell inflamed gene expression profile) and clinical efficacy parameters. We will also characterize the safety laboratory results (AChR autoantibodies and creatinine kinase) and the occurrence of adverse events of interest. Simon’s two-stage design will be used. The null hypothesis that the true response rate is 5% will be tested against a one-sided alternative of target response rate ≥20%. In the first stage, 10 patients will be accrued. If there are no responses in the first stage, then the study will be stopped. Otherwise, 19 additional patients will be accrued for a total of 29 patients. The null hypothesis will be rejected if ≥4 responses are observed in 29 patients, with a type 1 error rate of 0.05 and power of 80%. The study was activated at Weill Cornell Medicine in December 2021. Clinical trial information: NCT04925947.

A phase II study investigating biological effects of maintenance usage of hydroxychloroquine on Par-4 levels in patients with resected tumors.

3085 Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.

Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

Calculating Sample Size for Follmann’s Simple Multivariate Test for One-Sided Alternatives

ABSTRACT Follmann developed a multivariate test, when , to test H 0 versus where and . Follmann provided strict lower bounds on the power function when an orthogonal mapping requirement was satisfied, the use of which requires knowledge about the unknown population covariance matrix. In this article, we show that the orthogonal mapping requirement for his theorem is equivalent to and can be replaced with , which does not require knowledge about the population covariance matrix. Using the lower bound on power, we are able to develop conservative sample sizes for this test. The conservative sample sizes are upper bounds on the actual sample size needed to achieve at least the desired power. Results from a simulation study are provided illustrating that the sample sizes are indeed upper bounds. Also, a simple R program to calculate sample size is provided.

Randomized phase II trial of avelumab alone or with cetuximab for unresectable, locally advanced or metastatic squamous cell anal carcinoma progressed to at least one line of treatment: The CARACAS study.

4051 Background: Advanced squamous cell anal carcinoma (advSCAC) is a rare disease with poor prognosis. No standard therapies beyond first line are currently available, yet a promising activity was documented for the anti-EGFR cetuximab (CET) and for anti-PD-1 agents in previous retrospective case series and phase I-II studies, respectively. In experimental models combination of EGFR and PD-L1 blockade was synergistic as PD-L1 blockade led to NK cells activation enhancing cetuximab ADCC. In this trial we aimed to evaluate safety and activity of the anti-PD-L1 avelumab (AVE) alone or in combination with CET in pretreated advSCAC. Methods: This was an open-label, prospective, multicenter randomized phase 2 trial (NCT03944252). Patients (pts) with advSCAC progressed after at least 1 line of treatment were randomized 1:1 to receive either AVE 10 mg/kg (arm A) or AVE + CET 500 mg/sqm (arm B) as bi-weekly regimens. A Simon’s two-stage Mini-Max design was used. The null hypothesis of a true response rate 5% was tested against the one-sided alternative of a true response rate 20% in each arm. Setting type I error at 0.05 and power at 80%, 30 pts per arm had to be randomized. No formal comparison between the two arms was planned. Primary endpoint was overall response rate (ORR); secondary endpoints were Progression-Free Survival (PFS), Overall Survival (OS) and safety. Results: Sixty pts were enrolled, 30 in each arm. All baseline characteristics were well balanced between the two arms. Median age was 63 years; M/F was 19/41; 12 out of 30 pts in each arm had distant metastases; 7 in arm A and 10 in arm B received > 1 previous lines of treatment. At a median follow up of 8.7 months, 3 out of 30 pts in each arm obtained PR (ORR 10%); SD was observed in 12 pts in arm A (40%) and 14 in arm B (47%). Disease control rate was thus 50% in arm A and 57% in arm B. Duration of disease control was 6.1 (95%CI 3.7–11.0) and 6.1 (95%CI 4.1–9.6) months in arm A and B, respectively. Median PFS was 2.1 (95%CI 1.8–4.0) in arm A and 3.9 months (95%CI 2.1–5.6) in arm B. Grade 3-4 adverse events were 13.3% in arm A and 33.3% in arm B: anemia 10% vs 13.3%, fatigue 0 vs 6.7%, skin toxicity 0 vs 6.7%. Treatment interruption due to AE occurred in 3 pts, 1 in arm A and 2 in arm B. Translational analyses will be performed on tissue and blood samples for exploratory purpose. Conclusions: The CARACAS trial was the first clinical study to test dual EGFR and PD-L1 blockade in advSCAC. Both AVE monotherapy and AVE-CET showed promising activity with manageable safety profile. Clinical trial information: NCT03944252 .

Cough Reflex Sensitivity in Asthmatic Children.

New knowledge about the neural aspects of cough has revealed a complex network of pathways that initiate cough. The effect of inflammation on cough neural processing occurs at multiple peripheral and central sites within the nervous system. Evidence exists that direct or indirect neuroimmune interaction induces a complex response, which can be altered by mediators released by the sensory or parasympathetic neurons and vice versa. The aim of this study was to clarify changes of cough reflex sensitivity - the activity of airway afferent nerve endings - in asthmatic children.25 children with asthma and 15 controls were submitted to cough reflex sensitivity measurement - capsaicin aerosol in doubling concentrations (from 0.61 to 1250 µmol/l) was inhaled by a single breath method. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Asthmatic children' (11 boys and 14 girls, mean age 9 ± 1 yrs) cough reflex sensitivity (geometric mean, with the 95 % CI) for C2 was 4.25 (2.25-8.03) µmol/l vs. control C2 (6 boys and 9 girls, mean age 8 ± 1 yrs) was 10.61 (5.28-21.32) µmol/l (p=0.024). Asthmatic children' C5 was 100.27 (49.30-203.93) µmol/l vs. control C5 56.53 (19.69-162.35) µmol/l (p=0.348). There was a statistically significant decrease of C2 (cough threshold) in the asthmatic patients relative to controls (p-value for the two-sample t-test of log(C2) for the one-sided alternative, p-value = 0.024). The 95 % confidence interval for the difference of the mean C2 in asthma vs. control, [1.004, 6.207]. For C5, the difference was not statistically significant (p-value = 0.348). There was a statistically significant decrease of cough reflex sensitivity (the activity of airway afferent nerve endings) - C2 value in the asthmatic children relative to controls.