Terms Of Overall Response Rate Research Articles

Real world study of safety and efficacy of lorlatinib as second line and beyond in ALK-rearranged advanced non-small cell lung cancer patients in India - a multicentre chart review study (ROSELAND).

Lorlatinib, an anaplastic lymphoma kinase (ALK)-inhibitor, is approved as frontline as well as subsequent line of therapy in ALK-rearranged advanced non-small cell lung cancer (NSCLC). There is limited literature about safety and efficacy of lorlatinib in Indian patients. This was a retrospective multicentre study on patients with ALK-rearranged advanced NSCLC received lorlatinib as second line and beyond between May 2017 and December 2021. ALK was tested either by immunohistochemistry or fluorescent in-situ hybridisation. Clinicopathologic features, treatment details, toxicity and outcomes were analysed. A total of 38 patients were enrolled with a median age of 54 years (range: 30-72) and male: female ratio of 20:18. Fifteen (44%) patients had brain metastases at baseline. Lorlatinib use was - second line in 11 (29%), third line in 21 (55%) and fourth line in 4 (11%) of patients, respectively. The best radiologic response to lorlatinib was - complete response in 9 (24%), partial response in 17 (46%), stable disease in 9 (24%) and progressive disease in 2 (5%) of patients, respectively. After a median follow-up of 76.6 months (95% CI: 68.9-100), the median progression-free survival (PFS) of lorlatinib was not reached (95% CI: 24.3-not reached) and median overall survival (OS) of the whole cohort was 93.1 months (95% CI: 62-not reached). Both median PFS (p = 0.48) and median OS (p = 0.74) was similar between second line and later line use of lorlatinib. Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.

Effectiveness and tolerability of chlormethine gel for the management of mycosis fungoides: a multicenter real-life evaluation.

Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.

Results of Treatment Approaches in Myeloid Neoplasms According to TP53 Allelic Status (Multi-hit vs Monoallelic), a Real World Analysis

INTRODUCTION: Myeloid neoplasms with mutated TP53 (MN-TP53) represent a unique category in the 2022 International Consensus Classification (ICC) of Myeloid Neoplasms. This entity has an exceedingly poor prognosis with the available standard therapies, and clinical trials with novel drugs show limited benefits. Recently, it has been shown that TP53 multi-hit alterations may confer even worse prognosis, compared to the monoallelic status, in myelodysplastic syndromes. However, multi-hit status has not been analysed in all MN-TP53 subtypes. Elucidating this difference and its association with responses to treatment becomes essential from a clinical perspective. Therefore, our aim was to analyse whether the allelic status of TP53 in our cohort has an impact on therapeutic outcomes. METHODS: We retrospectively collected data from four institutions, between September 2011 and February 2023. Inclusion criteria were: 1) patients diagnosed with MN-TP53; 2) available information to categorize them into multi-hit or monoallelic group according to ICC 2022; and 3) eligible for treatment. The primary endpoint was to describe the outcomes, in terms of overall response rate (ORR) and overall survival (OS), of MN-TP53 according to TP53 status (multi-hit vs monoallelic) and treatment. RESULTS: A total of 105 patients diagnosed with MN-TP53 were identified. Eighty-seven were eligible for treatment and included in the analysis. Sixty-nine patients were identified as multi-hit, and 18 as monoallelic. Table 1 summarises patient's demographics and clinical characteristics. The median OS of the entire cohort was 7 months (range 0-141); while it was 6 months (0-141) for the multi-hit group and 8.5 months (0-44) for the monoallelic group; (p=0.23) (Figure 1). In both groups, most of the patients received non-intensive treatment as first line (1L) (40 patients [58%] in multi-hit group vs 14 [78%] in monoallelic), followed by intensive treatment (17 patients [25%] in multi-hit group vs 2 patients [11%] in monoallelic) and hypomethylating agent plus venetoclax (12 [17%] in multi-hit vs 2 [11%] in monoallelic). The overall response rate (ORR) was 43% for patients with multi-hit TP53 status and 67% for those with monoallelic status (p=0.38) . Correspondingly, 29% and 11% were not evaluated after 1L due to death or poor general condition. Progression after 1L of treatment was seen in 55% of patients with multi-hit TP53 status and in 43% of cases with monoallelic status (p=0.11). The subgroup analysis of the multi-hit cohort revealed no significant difference in response between intensive and non-intensive treatment (p=0.09). Nevertheless, there is a trend in favour of non-intensive treatment, including hypomethylating agents plus venetoclax (p=0.18). Allogeneic hematopoietic stem cell transplant was performed in 12 patients (17%) in the multi-hit group and in 2 patients (11%) in the monoallelic group. CONCLUSION: In this study, no difference in terms of OS was evidenced when comparing patients according to the type of TP53 status (multi-hit vs monoallelic). However, a trend to higher ORR and lower rate of progression was observed in the monoallelic group after 1L, which should be confirmed in further analysis. Concerning the TP53 multi-hit subgroup, we have not found any benefit on using intensive treatment in terms of ORR compared to non-intensive approach.

Evaluation of the Impact of Tocilizumab Use in Recipients of CAR T Cells for Non-Hodgkin Lymphoma

Introduction: CAR T has revolutionized the treatment of patients with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL). Treatment of the major toxicity of cytokine release syndrome (CRS) is tocilizumab (toci) and corticosteroids based on the ASTCT grade. Real-world experiences in the United States and Europe have reported a higher rate of tocilizumab use than in pivotal trials; however, the impact of single or multiple administrations on clinical outcomes is not clear. Methods: Patients diagnosed with diffuse (DLBCL), high grade (HGBCL) and primary mediastinal B cell lymphoma (PMBL) treated at our institution with commercial CAR T were retrospectively identified. The association between the number of doses received with best overall response by day 100, PFS, and OS was investigated through a Cox regression model using a 14-day landmark analysis. Late neutropenia was defined as an ANC <1000/mmc for two consecutive counts beyond day 30 post CAR-T infusion and a 30-day landmark analysis was performed in this case. Results: 230 patients with R/R DLBCL (80%), HGBCL (17%) and PMBL (3%) were included in the analysis. Axicabtagene ciloleucel (Axi-cel), tisagenlecleucel (Tisa-cel), and lisocabtagene maraleucel (Liso-cel) were administered in 62%, 29% and 9% of cases, respectively. Median age at time of CAR-T infusion was 65 years (range 20-86), with a male predominance (63%). The median number of prior treatment lines was 3 (range 1-12), and 21% underwent a prior autologous hematopoietic cell transplant. Disease burden prior to CAR-T infusion can be inferred by the following: bridging therapy was deemed necessary in 77% of patients, pre-lymphodepletion LDH was elevated in 40%, and bulky disease with largest mass diameter was > 10 cm in 10%. CRS and ICANS were grade 2 in 107 patients (46%) and 46 patients (20%), respectively. Median time to first administration of toci was 4 days (range 1-16) with patients receiving 0 (51%), 1 (27%), 2 (14%), or 3-4 (8%) doses. Best response by day 100 for the whole cohort was CR in 138 (60%) and PR in 36 (16%) patients. In univariable analysis, factors associated with a lower likelihood of response were the administration of Tisa-cel (p=0.014), bulky disease (p<0.001), administration of bridging therapy (p=0.009), and being refractory to the last treatment line (p=0.006). Number of doses of tocilizumab did not impact the likelihood of response (p=0.72). In a Cox regression model for survival, number of doses of tocilizumab was not associated with worse PFS (p=0.38, Figure 1) or OS (p=0.64), while other known negative predictors of response had impact on survival, such as bulky and refractory disease. By univariable analysis, tocilizumab administration was significantly associated with prolonged neutropenia (p<0.001). The likelihood to observe an ANC<1000/mmc beyond day 30 increased accordingly to the number of doses received (Figure 2). Other factors associated with late neutropenia were bulky disease (P=0.013), need of bridging therapy (p=0.004), and corticosteroids administration (p<0.001). Conclusion: The number of tocilizumab infusions did not impact CAR T efficacy in terms of overall response and long-term survival, a finding that is concordant with other real-world experiences. The cumulative incidence of late neutropenia events was impacted by the number of doses received. We speculate that a severe CRS driven systemic inflammatory response, requiring several tocilizumab and corticosteroids administrations, may hinder the bone marrow function and recovery.

Efficacy, safety, and cost-minimization analysis of axicabtagene ciloleucel and tisagenlecleucel CAR T-Cell therapies for treatment of relapsed or refractory follicular lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are chimeric antigen receptor (CAR) T-cell therapies used to treat adult patients with relapsed or refractory follicular lymphoma (rrFL) after two or more lines of systemic therapy. In the absence of head-to-head clinical trials, this study aimed to compare the efficacy, safety, and cost of axi-cel and tisa-cel in the treatment of rrFL after at least two lines of treatment. Overall response rate (ORR) and safety signals were compared using reporting odds ratios (RORs) with 95% confidence intervals (CIs) at p < 0.05. Progression-free survival (PFS), duration of response (DoR), and overall survival (OS) were compared using the Kaplan?Meier method with a log-rank test. Cost and cost-minimization analyses of drug acquisition, drug administration, serious adverse events (AEs), and relapsed management were calculated. Costs were extracted from the IBM-Micromedex Red Book, Centers for Medicare and Medicaid Services, and existing literature. Statistical analyses were conducted using Microsoft Excel and R version 4.0.5. No statistically significant differences were observed between axi-cel and tisa-cel in terms of ORR, DoR, and OS (p > 0.05). PFS was significantly better with tisa-cel (p < 0.05). Axi-cel was significantly associated with higher incidences of CRS, neurologic events, and grade 3-4 AEs than tisa-cel (ROR > 1, p < 0.05). Axi-cel and tisa-cel cost $512,021 and $450,885 per patient, respectively, resulting in savings of US$61,136 with tisa-cel over axi-cel. Tisa-cel appears to have a better safety profile, fewer serious AEs, lower mortality rate, and lower cost than axi-cel.

Clinical Utility of Mobocertinib in the Treatment of NSCLC - Patient Selection and Reported Outcomes.

Mobocertinib is an oral tyrosine kinase inhibitor (TKI) that selectively targets epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations. It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. This is accomplished via a carboxylated isopropyl ester moiety at the C5-position of mobocertinib's central pyrimidine core. In Phase 1/2 dose-escalation and dose-expansion studies, mobocertinib was found to have an investigator-confirmed overall response rate (ORR) of 56% (9/16; 95% CI: 30-80%) and 25% (3/12; 95% CI: 5-57%) in patients without and with baseline brain metastasis, respectively. Median investigator-assessed progression-free survival (mPFS) was 10.2 months (95% CI: 5.6 - not reached) and 3.7 months (95% CI: 1.8-15.9) in patients without and with baseline brain metastasis, respectively. A third phase evaluated patients who had received pre-treatment with platinum-based chemotherapy (PPP) and included an extension cohort (EXCLAIM cohort) which evaluated patients treated previously with 1 or 2 lines of therapy. An Independent Review Committee (IRC) found both cohorts to have similar outcomes in terms of ORR, median time to response, mPFS, and disease progression or death. The treatment-emergent adverse events (TEAE) related to mobocertinib are similar to other EGFR inhibitors and are predominately gastrointestinal (eg diarrhea, nausea, vomiting) and cutaneous (eg rash). In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.

FOLFIRI in advanced platinum-resistant/refractory small-cell lung cancer: a retrospective study

Background Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. Methods Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. Results Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0–5.2 months) and 5.3 months (95%CI, 3.5–8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. Conclusion FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen. HIGHLIGHTS FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response. FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients. FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.

Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.

TPS4184 Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .

Tracking plasticity along with proliferation and immune evasion using FOXC1, MKI67 and PDL1 for prediction of therapeutic response and risk for hyperprogressive disease with PD1/PDL1 inhibitors in advanced/metastatic cancers: Pan-tumor validation in clinical trial and real-world cohorts.

2627 Background: Accurate prediction of therapeutic response (TR) to treatment with immune checkpoint blockade (ICB) as well as any resultant durable clinical benefit in terms of improved progression-free survival (PFS) and overall survival (OS) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden (TMB). We hypothesized that a multi-marker predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1, respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD). Methods: Pre-treatment tumor RNA-Seq data obtained from training/validation clinical trial cohorts and real-world patients diagnosed with advanced/metastatic non-small cell lung cancer (NSCLC, n=82/28) and melanoma (n=154/121) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure &lt;=2 months post-treatment initiation. Optimized biomarker cutoff values based on model area-under-curve were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets. Results: ORR prediction accuracy was confirmed in validation datasets with high accuracy: NSCLC AUC=0.96, OR=9.63 (0.98-94.54, 95%CI) p=0.03 and melanoma AUC=0.91, OR=3.85 (1.73-8.58, 95%CI), p=0.0005. Predicted Responders consistently displayed superior PFS and OS compared to predicted Non-Responders: NSCLC PFS HR=0.51 (0.32-0.82, 95%CI) p=0.007, OS HR=0.44 (0.27-0.73, 95%CI) p=0.003; melanoma PFS HR=0.45 (0.30-0.68, 95%CI) p=0.002, OS HR=0.43 (0.26-0.71, 95%CI) p=0.002. Patients at risk for HPD were identified with high accuracy: NSCLC AUC=0.96, OR=9.67 (2.95-31.73) p&lt;0.0001; melanoma AUC=0.98, OR=44.36 (11.73-167.74, 95%CI) p&lt;0.0001. Conclusions: Tracking multiple dimensions of cancer biology including plasticity (using FOXC1), as opposed to tracking immune evasion alone, proved to be a superior and accurate pan-cancer, tissue-agnostic predictor of TR to ICB therapy in advanced/metastatic tumors in terms of ORR, PFS, OS as well as HPD risk prediction. This approach merits further testing in prospective clinical trials.

Abstract CT045: A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers

Abstract Background: Immune checkpoint inhibitors targeting the PD1/PD-L1 axis have made a breakthrough in advanced solid tumors, leading to improved overall survival (OS) in several cancer types. However, only a minority of patients experience durable responses, requiring further development of anti-tumoral immunotherapies to overcome tumor immune escape. We hypothesized that priming the immune system with TG4001, a vaccine using the highly attenuated Modified Vaccinia virus Ankara as vector expressing the HPV16 E6 and E7 proteins (rendered non-oncogenic) and interleukin-2, would increase the clinical benefit associated with PD-L1 blockade in HPV16+ cancer patients. In the single-arm part of the trial evaluating the combination of TG4001 and avelumab in terms of response rate, the overall response rate (ORR) was 22%. Presence of liver metastases had a profound impact on outcome in terms of ORR and Progression Free Survival (PFS). In patients (pts) without liver metastases an ORR of 32% was observed versus 0% in pts with liver metastases, warranting further development of this combination in this patient population (SITC 2020, Abstract ID 793). Methods: We have designed a randomized open-label two-arms trial evaluating the efficacy of the combination of TG4001 and avelumab versus avelumab alone (NCT03260023). Eligible pts have R/M HPV-16 positive anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers with no more than one prior line of chemotherapy for R/M disease and no previous exposure to cancer immunotherapy. HPV-16 positivity is determined in a central laboratory. Patients are randomly assigned 1:1 to receive either TG4001 plus avelumab or avelumab alone. Randomization is stratified by primary tumor type (cervical, anal, genital). TG4001 is administered subcutaneously (SC) at 5 × 107 plaque forming units (pfu) Q1w for 5 weeks, Q2w until month 6 and Q12w until progressive disease and avelumab intravenously (IV) at 800 mg Q2w until progressive disease. A total of up to 140 pts are currently being recruited into two cohorts (A and B) in France, Spain, and USA. For Cohort A, consisting of pts without liver metastases at Baseline (BL), a 2-stage sample size adjustment design is used with PFS by RECIST 1.1 as primary endpoint. Plans are to accrue 120 patients following Interim Analysis and Independent Data Monitoring Committee (IDMC) review. Cohort B recruits pts with liver metastases at BL. To be eligible, hepatic disease is restricted in terms of extent and number of lesions. A total of 20 pts will be recruited and analyzed for the percentage of early progressors. Secondary endpoints include overall survival, objective response rate according to RECIST1.1, duration of response, disease control rate. Exploratory endpoints comprise analyses of blood-based parameters and tumor-based proteins and RNA expression and their impact on clinical outcomes. Citation Format: Christophe Le Tourneau, Frédéric Rolland, Amaury Daste, Philippe Cassier, Sébastien Salas, Luis Manso Sánchez, Gerardo Colon-Otero, Lauriane Eberst, Olivier Lantz, Ana Lalanne, Annette Tavernaro, Hakim Makhloufi, Kaïdre Bendjama, Maud Brandely, Jean-Pierre Delord. A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT045.

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine+Rituximab in Low-grade Lymphomas.

Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine+rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N=51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N=92). Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P=.18), complete response rate (94% vs. 95%, P=.91), or 5 years progression-free survival (76% vs. 75%, P=.63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

Abstract OT3-11-02: SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL

Abstract Background The OlympiAD trial evaluated the PARP inhibitor (PARPi) olaparib versus a non-platinum standard chemotherapy in HER2-negative metastatic breast cancer (MBC) patients with a germline BRCA1/2 (gBRCA) mutation. Olaparib resulted in improved progression-free survival (PFS) and doubled the response rate vs chemotherapy. Nevertheless, the response rate to PARPi is 60% in the gBRCA1/2 population with MBC (current approval), suggesting a limited positive predictive value of gBRCA1/2 status. Moreover, patients with other relevant Homologous Recombination Repair defects (HRD) such as PALB2 or RAD51C/D mutation carriers, or HRD epigenetic silencing, are not captured with a gBRCA analysis. We have previoulsy shown that the functional HRD biomarker RAD51, tested in FFPE tumor samples using an optimized immunofluorescence-based assay, is associated with platinum response in early TNBC and PARPi response in preclinical BC models. We hypothesize that the RAD51 test would help to expand the clinical benefit of PARPi by predicting response to olaparib in MBC with germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation and beyond. Study design RADIOLA is an open-label, single-arm, multicentre phase II study evaluating treatment with olaparib in male or female ≥18 years patients with HER2-negative MBC with ≤ two prior chemotherapy lines in two cohorts: cohort 1 (N=41) with known germline/somatic BRCA1/2, PALB2 or RAD51C/D mutation; cohort 2 (N=25) with functional HRD, namely RAD51-low score (≤10%), in wild-type/unknown mutation status at study entry. All patients will receive olaparib 300mg po BID until progression or unacceptable toxicity. Primary objective will assess, in terms of overall response rate (ORR), the capacity of the RAD51 score to predict olaparib efficacy in cohort 1. Secondary objectives include PFS, clinical benefit rate, duration of response, safety in both cohorts and ORR in cohort 2. Recruitment Recruitment (11 sites) started in March 2022. As of July 2022, 7 patients have been enrolled in Spain. Funding This study is financially supported by AstraZeneca. Citation Format: Judith Balmaña, Tomás Pascual, Alba Llop-Guevara, Pablo Tolosa, Isabel Blancas, Maria-Eva Perez-Lopez, Barbara Adamo, Iris Teruel, Jose Ponce, Marta Gonzalez, Gemma Viñas, Laura Lema, Francisco Javier Salvador, Mª Teresa Martinez, Alejandra Espinosa, Aleix Prat, Violeta Serra. SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA TRIAL [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 OT3-11-02.

Primary tumour side as a driver for treatment choice in RAS wild-type metastatic colorectal cancer patients: a systematic review and pooled analysis of randomised trials

BackgroundRetrospective subgroup analyses of previous trials in the first-line therapy of RAS wt metastatic colorectal cancer (mCRC) suggested a predictive impact of primary tumour side on the efficacy of anti-epidermal growth factor receptor (EGFR) agents. Recently, new head-to-head trials of doublets/bevacizumab versus doublets/anti-EGFR, PARADIGM and CAIRO5 were presented. Patients and methodsWe searched for phase II and III trials comparing doublet chemotherapy plus an anti-EGFR or bevacizumab as the first-line treatment for RAS wt mCRC patients. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and radical resection rate result in the overall study populations and, according to the primary side, were pooled together in a two-stage analysis with random effects and fixed effect models. The interaction between sidedness and treatment effect was then analysed. ResultsWe identified five trials (PEAK, CALGB/SWOG 80405, FIRE-3, PARADIGM and CAIRO5), including 2739 patients, 77% left- and 23% right-sided. Among patients with left-sided mCRC, the use of anti-EGFRs was associated with higher ORR (74% versus 62%, OR = 1.77 [95% confidence interval {CI} 1.39–2.26–0.88], p < 0.0001), longer OS (hazard ratio [HR] = 0.77 [95% CI 0.68–0.88], p < 0.0001) and not significantly longer PFS (HR = 0.92, p = 0.19). Among patients with right-sided mCRC, the use of bevacizumab was associated with longer PFS (HR = 1.36 [95% CI 1.12–1.65], p = 0.002) and not significantly longer OS (HR = 1.17, p = 0.14). A subgroup analysis confirmed a significant interaction effect between the primary tumour side and treatment arm in terms of ORR (p = 0.02), PFS (p = 0.0004) and OS (p = 0.001). No differences in the radical resection rate were found according to treatment and sidedness. ConclusionsOur updated metanalysis corroborates the role of the primary tumour location in the choice of the upfront therapy for RAS wt mCRC patients, leading to strongly recommend anti-EGFRs in left-sided tumours and to prefer bevacizumab in the right-sided.

Determinants of activity and efficacy of anti-PD1/PD-L1 therapy in patients with advanced solid tumors recruited in a clinical trials unit: a longitudinal prospective biomarker-based study

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

BONSAI-2 study: Nivolumab as therapeutic option after cabozantinib failure in metastatic collecting duct carcinoma patients.

The BONSAI phase II trial recently demonstrated the activity of cabozantinib in metastatic collecting duct patients. The outcomes of patients in this setting treated with immunotherapy as second-line is unknown. The aim of the present report was to describe outcomes of patients enrolled in the BONSAI trial that received nivolumab as second-line treatment. We describe the oncological outcomes in terms of overall response rate, progression-free survival, overall survival and safety. We excluded patients that did not receive any second-line treatment or were treated with agents other than nivolumab. We identified five patients of whom one was excluded due to lack of data. Three patients obtained clinical benefit (one partial response, two stable disease); the second-line progression-free survival (nivolumab) ranged from 2.8 to 19.9 months to and second-line overall survival ranged from 5.1 to 26.5 months. No new safety signals were observed. Nivolumab may be considered as second-line therapy option after cabozantinib failure in selected metastatic collecting duct carcinoma patients.

Efficacy and Safety of Xelox in Comparison with Folfox in Metastatic Colorectal Cancer

Background: The study aimed to evaluate efficacy and safety of Xelox in comparison to Folfox chemotherapy for metastatic colorectal cancer. Methods: A quasi experimental study was undertaken at the Department of Oncology, Jinnah Postgraduate Medical Center between April 2022 to November 2022. All the patients coming to oncology department JPMC with confirmed diagnosis of metastatic colorectal cancer of age 18 years and above were included. All data were recorded in a predefined proforma by the researchers. Patients’ age, gender, and comorbidity, family history, and clinical characteristics were noted. The primary endpoints were the overall response rates and the frequency of adverse effects. Results: A total of 200 patients were enrolled with a mean age of 40 ± 14.38 years. There were 100 participants in the Xelox group while 100 participants in the Folfox group. About 45 (45%) in the Xelox group and 62 (62%) in the Folfox group reported adverse effects of the chemotherapy (p=0.015). The rate of neutropenia grade III/IV was greater in the Folfox category than the Xelox. Hand foot syndrome was significantly more frequently reported in the Xelox group than the Folfox group 22 (48.89%) and 18 (29.03%); p=0.036, respectively. Oral mucositis was also more frequently reported in patients taking Xelox than Folfox [20 (44.44%) vs. 15 (24.19%); p=0.023]. There was no significant statistical difference between Xelox and Folfox in terms of patient overall response rates. Conclusion: According to the study, there are no appreciable differences between Xelox and Folfox chemotherapy in terms of overall response rates among patients with colorectal cancer. However, overall, patients taking Folfox reported significantly higher rates of adverse effects with the exception of hand foot syndrome and oral mucositis which was more frequent in the Xelox group. Keywords: colorectal carcinoma, chemotherapy, xelox, folfox, Capecitabine, Oxaliplatin, fluorouracil

R-CHOP Versus R-EPOCH in Primary Mediastinal Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis

Introduction: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare B-cell lymphoma that is typically reported in young females. Although previously considered as a subtype of diffuse large B-cell lymphoma, PMBCL has unique clinical and molecular characteristics. The optimal treatment option for PMBCL remains to be elucidated. Two regimens that have been used as frontline therapy are rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisone (R-CHOP) and rituximab, etoposide phosphate, prednisone, vincristine, cyclophosphamide and doxorubicin hydrochloride (R-EPOCH). Our study compares the efficacy and safety of R-CHOP and R-EPOCH in PMBCL. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane and Clinicaltrials.gov using MeSH terms and relevant keywords for PMBCL, R-CHOP and R-EPOCH, including trade names and generic names, from inception to July 2022. The inclusion criteria were clinical trials and observational studies comparing the efficacy and safety of R-CHOP with R-EPOCH in PMBCL. Efficacy was assessed in terms of overall response rate (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS) and relapse. Safety was assessed in terms of risk of occurrence of neutropenia and febrile neutropenia. Estimates of risk ratio (RR) with 95% confidence intervals (95% CI) for dichotomous outcomes were pooled using the random effects model with the Mantel-Haenszel method. Forest plots were constructed to visualize the pooled results. Heterogeneity was estimated using the I2 statistic. All statistical analyses were performed in Review Manager software (RevMan, version 5.4.1). Results: The initial search revealed 347 articles. After exclusion of duplicates, reviews and non-relevant articles, we included six articles (one prospective cohort and five retrospective cohorts) which compared outcomes following R-CHOP versus R-EPOCH in PMBCL. A total of 469 patients were included; R-CHOP and R-EPOCH were evaluated in 213 and 256 patients, respectively. The median age ranged from 27 to 35 years, and 318 (67.8%) patients were female. The median follow-up ranged from 23 to 60 months. R-CHOP and R-EPOCH were associated with an ORR of 84.9% and 91.8%, respectively. The difference between ORR of the two regimens was not statistically significant (RR 0.93, 95% CI 0.85-1.02; p = 0.11; I2 = 13%). However, R-CHOP was associated with significantly worse CR compared to R-EPOCH (65.5% versus 80.1%, RR 0.84, 95% CI 0.72-0.99; p = 0.04; I2 = 23%). OS was significantly lower with R-CHOP therapy (RR 0.84, 95% CI 0.72-0.97; p = 0.02; I2 = 36%). The two regimens had comparable PFS (RR 0.76, 95% CI 0.57-1.02; p = 0.06; I2 = 71%), and relapse rate (RR 0.91, 95% CI 0.26-3.16; p = 0.89; I2 = 56%). R-CHOP was associated with a lower risk of neutropenia (RR 0.67, 95% CI 0.54-0.83; p = 0.0004; I2 = 0%) and febrile neutropenia (RR 0.59, 95% CI 0.39-0.90; p = 0.01; I2 = 13%). Conclusion: R-EPOCH demonstrates superior CR and OS compared to R-CHOP. However, ORR, PFS and relapse rate were comparable for both regimens. R-CHOP was also associated with a lower risk of neutropenia and febrile neutropenia. Larger prospective studies and randomized controlled trials are required to establish the standard of care in PMBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intense Immunosuppressive Therapy (anti-thymocyte globulin, alemtuzumab) As Salvage Therapy in Refractory T-Cell Large Granular Lymphocytic Leukemia and Pure Red Cell Aplasia

Background T-cell directed immunosuppression (IS: methotrexate, cyclosporine, and cyclophosphamide) is the main treatment modality applied for the therapy of immune single-lineage cytopenias including idiopathic neutropenia and pure red cell aplasia (PRCA). These two conditions are likely T-cell mediated and are often associated with T-cell large granular lymphocytic leukemia (T-LGL). The latter is thought to result from an originally polyclonal process evolving to a clonal proliferation of cytotoxic T-lymphocytes. Generally, response to 1st line therapies is about 30%, whereas rates as high as 80-90% can be achieved with 2nd, and 3rd lines. However, a significant fraction of patients remains refractory to multiple therapies and constitutes a management challenge. These patients remain transfusion dependent and/or have severely depressed neutrophil counts refractory to granulocyte-colony stimulating factor (G-CSF). In this scenario, intense IS with anti-thymocyte globulin (ATG) and alemtuzumab is often considered a salvage option, but no systematic experience exists and only a few controlled clinical trials have been conducted. Particularly, we previously reported an overall response rate (ORR) of 63% (n=23) with low dose alemtuzumab (10 mg sc q week x10) and 2/2 with ATG (40 mg/kg/d x 4 days) in patients with PRCA and/or LGL. Previous experience showed an ORR of 74% in a phase II study of 19 T-LGL patients treated with alemtuzumab, whereas a literature meta-analysis showed an ORR of 33% in 24 patients with PRCA treated with ATG. To better rationalize salvage therapy for refractory immune cytopenias, we explored the effectiveness of these agents at our tertiary referral center. Design and Methods We retrospectively examined treatment outcomes in 296 patients with LGL (113 had neutropenia and 73 anemia), and 78 patients with PRCA (+/- LGL). The study cohort had severe refractory cytopenia despite multiple treatment regimens and received salvage therapy with ATG and/or alemtuzumab. Complete response (CR) was defined as hemoglobin >10 g/dL, and absolute neutrophil count >1.0x109/L. Partial response (PR) was defined not meeting CR criteria. Response to therapy was evaluated while on therapy (alemtuzumab) and 4 months post-therapy (ATG). Overall response rate (ORR) was calculated as the percentage of patients with both CR and PR over the total number of patients who received the drug. The response rate was not available for 4 and 3 cases in the ATG and alemtuzumab cohorts respectively. Results A total of 62 patients who received salvage therapy with ATG (N=23) and alemtuzumab (N=39) for refractory cytopenia associated with LGL (N=38) and without LGL (N=24) were identified. Overall, the median age at disease onset was 58 years (IQR 45-69) with a 1.2 male to female ratio. On average, patients received 4 treatment modalities prior to ATG/alemtuzumab to which they did not respond or became refractory. CR rate (CRR) for patients treated with ATG was 42% (8/19) and ORR 89% (17/19). The CRR and ORR was 22% (8/36) and 81% (29/36), respectively in patients treated with alemtuzumab. No significant difference was observed in terms of ORR in patients treated with alemtuzumab compared to ATG (P = 0.45). In T-LGL cases, the presence of a STAT3 mutation did not impact an ORR to either alemtuzumab (31 vs 45% in STAT3 wild type) or ATG-treated cases (54 vs 38%). There was no significant difference in the LGL and PRCA (+/- LGL) cohorts treated with alemtuzumab (P = 0.89) and ATG (P = 0.13). Overall, no treatment-related death was registered, and toxicities were manageable. Alemtuzumab was held if absolute lymphocyte count was <200/µL. Of note, only one patient had CMV re-activation in our cohort. Conclusion Our data shows that alemtuzumab and ATG represent salvage IS regimens highly effective for the treatment of T-LGL and PRCA refractory to multiple lines of therapy with ORR higher if compared to historical data. This therapy resulted in a durable response in both T-LGL and PRCA (+/- LGL) with a good safety profile. The use of low dose alemtuzumab greatly decreases the complication rate and tolerability.

Addition of Brentuximab Vedotin to Gemcitabine in Relapsed or Refractory T-Cell Lymphoma: Final Analysis of a Lysa Multicenter, Phase II Study. "the TOTAL Trial"

Background : Outcome of relapse/refractory (R/R) peripheral T-cell lymphoma (PTCL) patients (pts) is usually poor. [Mak, 2013]. Brentuximab vedotin (Bv) monotherapy is approved for R/R anaplastic large cell-lymphoma (ALCL) with long term responders [Pro, 2017] and for 1st line in association with polychemotherapy [Horwitz, 2019] in all CD30+ PTCL (with no restriction related to expression cut-off). We designed a phase 2 study for R/R CD30+ PTCL combining gemcitabine (G) and Bv with the aim to increase the overall response rate (ORR) by 15%, compared to gemcitabine monotherapy (35%) [O'Connor, 2019] and among secondary endpoints to evaluate BV maintenance and the impact of both CD30 expression and soluble CD30 (sCD30) on response and survival. Patients and Methods: : Patients with confirmed CD30+ (≥5%) PTCL with measurable disease who failed or were refractory to 1-3 systemic therapy (excluding G and Bv) and ECOG performance status < 3 were eligible. Pts received 4 (28-days) cycles of G and Bv induction phase (GBvIP) (G : 1000mg/m² at D1 and D15 plus Bv: 1.8 mg/kg at D8) followed, in pts with complete (CR) or partial remission (PR) and non-eligible for SCT, by up to 12 (21-days) cycles of Bv (1.8 mg/kg) maintenance phase (BvMP). The primary endpoint was ORR (CR + PR) according to Lugano criteria (CT-scan-based). CD30 expression was semi-quantitatively assessed by immunohistochemistry (IHC) and serum sCD30 levels were determined by ELISA. (NCT03496779). Results: From April 2018 to October 2019, 71 pts with PTCL (47 males, 24 females) were enrolled. Central pathology review according to 2017 WHO criteria found nodal TFH-PTCL (34 ; 47.9%) [including AITL (27 ; 38%) and other nodal PTCL-TFH (7 ; 9.9%)] ; ALK- ALCL (14 ; 27%) ; PTCL-NOS (9 ; 13%) ; ALK+ ALCL (5 ; 7%), EATL (2 ; 2.8%) and other entities (7 ; 9.9%). Median age was 66 years (20-79), 65 pts (91.6%) were stage III-IV. ECOG status was ≥ 2 in 45 pts (63%). The number of prior lines were 1 (57), 2 (11) or 3 (3) and 28 pts (39.4%) had a refractory disease. In intention to treat analysis, the ORR after GBvIP was 46.5% including CR (14;19.7%), PR (19;26.8%). Among the 33 responders, 27 initiated BvMP as well as 1 non responding pt (with SD but a complete metabolic response). The median number of BvMP cycles was 9 (range 1-12). At least one G≥3 AE were recorded in 58/71 pts during GBvIP and 11/28 pts during BvMP. AE led to treatment discontinuation in 9/71 pts (GBvIP) and 14/28 pts (BvMP). Overall a polyneuropathy of G≥1 was recorded in 9/71 pts (GBvIP) and 14/28 pts (BvMP). After a median follow-up of 26.5 (0.5-42.1) months (mo), the median progression free survival (PFS) and overall survival (OS) were respectively 4.5 mo (95%CI [3.5 - 10]) (Figure 1A) and 12.9 mo (95%CI [8.6 - 25.5]). Among the 33 pts in PR/CR after GBvIP, the duration of response since inclusion (DOR) was 15.8 mo (95%CI [10.4 - (-)]) By univariate analysis, ORR was negatively influenced by high LDH (p=0.008) with borderline impact of ECOG (p=0.058), and both PFS and OS were reduced by refractory disease status at screening (p=0.031 and p=0.007) and non-ALCL histology (p=0.049 and p=0.041). CD30 expression was investigated on tumor samples collected either at screening (55.5%) or (if not available) at diagnosis (39,7%) or at previous relapse (4.8%). In pts with ALCL, CD30 expression was constant and high (>75% of tumor cells) along with a significant higher level of sCD30 compared to non ALCL pts. In non ALCL pts, the median % of CD30-positive tumor cells was 12.5% [0 - 12.5]. Focusing on non-ALCL pts we found a high impact of sCD30 level >120 ng/mL on both ORR, DOR, PFS and OS while CD30 expression on tumor cells did not appear to influence the results. (Figure 1B ; Table 1) Conclusion : According to our initial hypothesis, the addition of Bv to G is active in R/R CD30+ PTCLs both in terms of ORR, CR. In responding pts, the DOR exceeding 15 mo with very long responders suggests the value of Bv maintenance. Not surprisingly ALCL were associated with better results, but this treatment is also effective in non ALCL pts including a significant proportion of TFH lymphoma pts. Besides ALCL pts, biomarkers are needed to predict which pts could benefit the most of Bv based therapy. In line with a previous report [Horwitz, 2014], we did not find a clear impact of CD30 expression on tumor cells, however we demonstrate that baseline serum sCD30 at treatment initiation was strongly correlated with both response and outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of a bispecific antibody targeting PD-L1 and TIGIT with optimal cytotoxicity

Programmed death-ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two potential targets for cancer immunotherapy, early clinical studies showed the combination therapy of anti-PD-L1 and anti-TIGIT had synergistic efficacy both in the terms of overall response rate (ORR) and overall survival (OS). It is rational to construct bispecific antibodies targeting PD-L1 and TIGIT, besides retaining the efficacy of the combination therapy, bispecific antibodies (BsAbs) can provide a new mechanism of action, such as bridging between tumor cells and T/NK cells. Here, we developed an IgG1-type bispecific antibody with optimal cytotoxicity. In this study, we thoroughly investigated 16 IgG-VHH formats with variable orientations and linker lengths, the results demonstrated that (G4S)2 linker not only properly separated two binding domains but also had the highest protein yield. Moreover, VHH-HC orientation perfectly maintained the binding and cytotoxicity activity of the variable domain of the heavy chain of heavy‐chain‐only antibody (VHH) and immunoglobulin G (IgG). Following treatment with BiPT-23, tumor growth was significantly suppressed in vivo, with more cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells infiltration, and selective depletion of Regulatory T cells (Tregs). BiPT-23 represents novel immunotherapy engineered to prevent hyperprogression of cancer with PD-1 blockade, and preferentially killed PD-L1+ tumor cells, and TIGIT+ Tregs but maintained CD11b+F4/80+ immune cells within the tumor microenvironment (TME).