Complete Response Rate In Patients Research Articles

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas

IntroductionImmune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. Materials and MethodsWe included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. ResultsWe enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). ConclusionsThe resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. Patient SummaryIn recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .

Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study

Background. We previously reported pro-tumoral macrophages may be associated with resistance to lenalidomide and rituximab (R 2) treatment in follicular lymphoma (FL) ( Marques-Piubelli, Blood Adv 2022). As pre-clinical studies suggest that BTK inhibition can mitigate the crosstalk between monocyte/macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R 2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R 2 (aR 2) was shown to be safe and effective in patients with relapsed FL ( Strati P et al, ASH 2022). Here, we investigated the safety and efficacy of aR 2 in previously untreated FL patients and analyzed the biological effects of this combination on peripheral blood immune cells. Methods. This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 06/2023). Adult patients with previously untreated FL, grades 1 to 3A, stage 3-4, and meeting indication for treatment per GELF criteria were included. Treatment consisted of acalabrutinib lead-in at 100 mg PO twice a day for one 28-day cycle and continued for total of 13 cycles, lenalidomide 20 mg PO daily on days 1-21, during cycle 2-13, and rituximab 375 mg/m 2 IV weekly during cycle 2, and on day 1 of cycle 3-13. The primary endpoint was best complete response (CR) rate per Lugano 2014 criteria. Bulk RNA sequencing with deconvolution to characterize circulating immune cells was performed on peripheral blood collected at baseline, and on day 1 of cycles 2 and 6. Results. We enrolled and treated 24 patients. Baseline characteristics are shown in the Table. Median number of cycles was 13 (range, 6-13) and 15 (62.5%) patients experienced a cycle delay, due to COVID19 in 11 (46%) cases; 6 (25%) patients required dose reduction of lenalidomide, but none discontinued, and 2 (8%) required dose reduction of acalabrutinib and 1 discontinued. The most common (>5% of patients) grade 3-4 adverse events were neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). Best ORR was 100%, best CR rate was 92%, and median time to CR was 3 months ( Figure). After a median follow-up of 26.8 months (95% CI 24.6-29.6 months), 6 (25%) patients had disease progression, including 2 who transformed at 5 and 7 months. The 2-year PFS rate was 79.2% (95% CI, 64.5-97.2%). At data cutoff, 2 patients have died, 1 due to COVID19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months). The 2-year OS rate was 91.7% (95% CI, 81.3-100%). While the frequency of circulating immune cells were unchanged after single agent acalabrutinib, its use associated with a significant decrease in the expression of VMO1 (FDR 0.001), a gene encoding for a protein expressed on extra-cellular exosomes derived from non-classical monocytes, and a significant increase in gene signatures of monocyte proliferation (p=0.01), TNF response (p=0.01), anti-viral (p=0.006) and anti-tumoral activity (p=0.009), consistent with the expected effect of BTK inhibition in monocytes. After 5 cycles of aR 2, we observed a decrease in the frequency of circulating B cells (p=0.003) and regulatory NK cells (p=0.01), and an increase in the frequency of circulating naive T cells (p=0.004), CD4+ T cells (p=0.005) and classical monocytes (p=0.003). Conclusion. Our results indicate that the addition of acalabrutinib to R 2 is a safe and effective frontline non-chemotherapy regimen for FL patients, resulting in high CR rates, and induces favorable biological changes in multiple circulating immune cells. Since CRs occurred early, the study has been amended to include 26 additional patients who will be treated with only 6 cycles of aR2.

A systematic review and meta-analysis of pathologic complete response rates for patients with cholangiocarcinoma treated on liver transplant protocols.

We performed a systematic review through September 2022 of the PubMed, Embase, and Web of Science databases. A random-effect meta-analysis was conducted to pool data across studies with reported pCR rates. Heterogeneity between treatment protocols was assessed via subgroup analysis. The pCR and 1-, 3-, and 5-year recurrence-free survival (RFS) and overall survival (OS) rates were extracted as outcomes of interest. A total of 15 studies reported pCR rates and were grouped by use of the Mayo protocol (4/15), stereotactic body radiation therapy(2/15), and an Other category (9/15). The pooled pCR rate among all studies was 32%. Both radiation technique and duration of CHT showed no significant association with pCR (p = 0.05 and 0.13, respectively). Pooled 1-year RFS and OS after any neoadjuvant therapy and OLT was 80% (95% confidence interval [CI], 0.61-0.91), and 91% (95% CI, 0.87-0.94), respectively. There was no 1-year OS difference detected among the three groups. pCR was not associated with OS in the meta-regression. Pooled 3- and 5-year OS among all studies was 72% and 61%, respectively. The pooled incidence of pCR was 32%. Differences in radiation technique did not appear to influence pCR rates and upon meta-regression, pCR was not a surrogate marker for survival.

Avatrombopag Is Effective in First-Line Treatment of Severe Aplastic Anemia: Early Outcomes of a Prospective Study

Acquired severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease and its pathogenesis involves T cell-mediated autoimmunity. Antithymocyte globulin (ATG) and cyclosporine based immunosuppressive therapy (IST) is effective for patients not eligible for hematopoietic stem cell transplant, and the response rate is 60-70%. Complete hematological response (CR) predicts better survival of patients received IST treatment, but only a few patients achieve CR within 6 months (5% at 3 months and 12-17% at 6 months). Thrombopoietin receptor agonist (TPO-RA) eltrombopag improves the overall response (OR) rate and CR rate of SAA patients when combined with IST, but its hepatotoxicity is still worrying. Avatrombopag is another small-molecule TPO-RA without hepatic toxicity. We previously found that SAA patients received avatrombopag and IST as first-line treatment showed both higher CR rate and OR rate at 3 and 6 months. To validate our findings, a prospective, single-arm study of avatrombopag and IST for newly diagnosed SAA was carried out (NCT05720234). There were 25 patients enrolled in the study by June 31, 2023, including 21 SAA patients and 4 very severe aplastic anemia patients. Patients were diagnosed as AA within 6 months and received ATG, cyclosporine and avatrombopag as first-line treatment. Avatrombopag was administered at the first day of ATG initiation at dose of 60mg per day for patients weight ≥ 50kg and 40mg per day for patients weight < 50kg. ATG was given for 5 consecutive days. Cyclosporine was given orally at dose of 3.5-5mg/kg.d. There were 15 males and 10 males, at a median age of 37 years old. Eighteen patients achieved the end-point of 3 months and 10 patients achieved end-point of 6 months. There were 15 patients achieved hematologic response at 3 months (83.3%), including 5 complete responders (27.8%) and 10 partial responders. The overall response rate at 6 months was 80%, and CR rate was 60%. One patient evolved to hemolytic paroxysmal nocturnal hemoglobinuria at 3 months, with normal count of platelet and white blood cell. In conclusion, the addition of avatrombopag to IST as first-line treatment showed earlier hematologic response and higher complete response rate for patients with SAA.

The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11-specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10, and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.

Transjugular intrahepatic portosystemic shunt in patients with hepatocellular carcinoma: A systematic review.

Transjugular intrahepatic portosystemic shunts (TIPS) in patients with hepatocellular carcinoma (HCC) may improve access to curative therapies, treat portal hypertension (PH)-related complications without worsening liver function, and increase overall survival. Data on the efficacy and safety of TIPS to treat PH complications in HCC patients, as well as the HCC treatment response, were evaluated. Studies reporting efficacy in controlling bleeding/ascites or response to HCC therapy, safety, and survival in patients with HCC and TIPS were searched systematically on PubMed and Embase. An extraction of articles using predefined data fields and quality indicators was used. We selected 19 studies and found 937 patients treated for ascites/bleeding and 177 evaluating HCC treatment response. Over half were under 5cm and solitary lesions, and most studies included tumours with portal vein thrombosis. Regarding PH studies, TIPS resolved bleeding/ascites in >60% of patients, more effective for bleeding. There were no lethal complications reported and procedural bleeding occurred in <5%. Hepatic encephalopathy occurred in 15%-30% within three months. In the HCC treatment-response studies, major complication rates were low with no mortality. In the studies that evaluated the response to transarterial chemoembolization, complete response rate of patients with TIPS varied from 16% to 75%. Liver transplantation rate varied from 8% to 80%, with >40% rate in half of the studies. In the published studies, TIPS is effective in treating PH complications in patients with HCC. Prospective studies on TIPS placement in patients with HCC are urgently needed to evaluate the efficacy and safety of TIPS in this setting.

MCL-467 Glofitamab Monotherapy Induces High Complete Response Rates in Patients With Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

MCL-467 Glofitamab Monotherapy Induces High Complete Response Rates in Patients With Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

Complete response rates in rectal cancer: Temporal changes over a decade in a population-based nationwide cohort

IntroductionIn the past decade many changes in neoadjuvant treatment for patients with rectal cancer have taken place and are expected to impact complete response rates. The aim of this study was to investigate the impact on pathological, and overall, complete response rates in a nationwide population-based cohort, in relation to changes in neoadjuvant treatment and the start of a Watch & Wait (WoW) study. Materials and methodsA nationwide register study using prospectively collected data from the Swedish Colorectal Cancer Register between 2009 and 2020. Patients with rectal cancer stage I-III with a ypT0N0 in the resected specimen after neoadjuvant treatment and clinical complete responders from the yearly inclusion data of the national WoW study were included. Temporal changes in pathological and overall complete response rates were analysed, and differences in neoadjuvant treatment regimens over time and per region were studied. ResultsBetween 2009 and 2020 the pathological complete response rate for rectal cancer remained similar (Mann-Kendall tau of 0.091, p = 0.68) while the overall complete response rate increased significantly from 3.0% to 9.6% (Mann-Kendall tau of 0.818, p < 0.001). The pathological complete response rate for patients receiving short course radiotherapy followed by chemotherapy was reduced by 50% after the introduction of the WoW study. ConclusionsDuring the studied time period the overall complete response rate increased significantly presumably due to changes in national neoadjuvant treatment regimens. Since the start of the national WoW study clinical complete response seem to partly replace pathological complete response.

Safety of Targeted Axillary Dissection After Neoadjuvant Therapy in Patients With Node-Positive Breast Cancer

The increasing use of neoadjuvant systemic therapy (NST) has led to substantial pathological complete response rates in patients with initially node-positive, early breast cancer, thereby questioning the need for axillary lymph node dissection (ALND). Targeted axillary dissection (TAD) is feasible for axillary staging; however, data on oncological safety are scarce. To assess 3-year clinical outcomes in patients with node-positive breast cancer who underwent TAD alone or TAD with ALND. The SenTa study is a prospective registry study and was conducted between January 2017 and October 2018. The registry includes 50 study centers in Germany. Patients with clinically node-positive breast cancer underwent clipping of the most suspicious lymph node (LN) before NST. After NST, the marked LNs and sentinel LNs were excised (TAD) followed by ALND according to the clinician's choice. Patients who did not undergo TAD were excluded. Data analysis was performed in April 2022 after 43 months of follow-up. TAD alone vs TAD with ALND. Three-year clinical outcomes were evaluated. Of 199 female patients, the median (IQR) age was 52 (45-60) years. A total of 182 patients (91.5%) had 1 to 3 suspicious LNs; 119 received TAD alone and 80 received TAD with ALND. Unadjusted invasive disease-free survival was 82.4% (95% CI, 71.5-89.4) in the TAD with ALND group and 91.2% (95% CI, 84.2-95.1) in the TAD alone group (P = .04); axillary recurrence rates were 1.4% (95% CI, 0-54.8) and 1.8% (95% CI, 0-36.4), respectively (P = .56). Adjusted multivariate Cox regression indicated that TAD alone was not associated with an increased risk of recurrence (hazard ratio [HR], 0.83; 95% CI, 0.34-2.05; P = .69) or death (HR, 1.07; 95% CI, 0.31-3.70; P = .91). Similar results were obtained for 152 patients with clinically node-negative breast cancer after NST (invasive disease-free survival: HR, 1.26; 95% CI, 0.27-5.87; P = .77; overall survival: HR, 0.81; 95% CI, 0.15-3.83; P = .74). These results suggest that TAD alone in patients with mostly good clinical response to NST and at least 3 TAD LNs may confer survival outcomes and recurrence rates similar to TAD with ALND.

A systematic review of the efficacy of intravesical electromotive drug administration therapy for non-muscle invasive bladder cancer.

Non-muscle invasive bladder cancer (NMIBC) is characterized by a high rate of recurrence and progression, despite surgery and adjuvant therapies. To analyze the published results on the effectiveness of mitomycin C (MMC) applied with an electromotive drug administration device (EMDA) in the treatment of patients with non-muscle invasive bladder tumors. A systematic review was conducted using the PubMed and Google Scholar search platforms. We selected the studies that included the recurrence and/or progression rates or complete response rate in patients diagnosed with NMIBC according to their treatment and included MMC applied with EMDA. The last search was performed in November 2021. The search yielded 64 articles; 11 articles met the selection criteria. In two of the 11 selected articles, mitomycin C was applied with an EMDA device (MMC-EMDA) as an ablative treatment, avoiding surgery in 50% of the patients. In 1 of the 11 studies, the application of MMC-EMDA was used as an induction treatment using a single preoperative instillation with promising results. In the remaining 8 studies, adjuvant MMC was applied with the EMDA device; in 3 of these 8 cases, treatment with MMC-EMDA alone was applied initially. In another3 cases the same treatment was applied after nonresponse to bacillus Calmette Guerin (BCG), and in the last 2 studies, MMC-EMDA was applied in combination with the classic therapy (BCG). All the studies selected supported the efficacy and safety of MMC-EMDA in patients with intermediate and high- risk bladder cancer. In 3 studies, adjuvant therapy with MMC-EMDA was performed in nonresponders to BCG, finding that adjuvant therapy with MMC-EMDA applied to BCG nonresponders without CIS avoided or delayed surgery. The application of EMDA-enhanced MMC has been studied at different times of disease and with different administration protocols. It appears to delay bladder tumor recurrence and progression in certain populations. However, the methodological limitations of the published studies prevent definitive conclusions about its efficacy.

Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

Background: New treatment options are needed for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. In a retrospective cohort study of 114 patients with MCL who had PD while receiving ibrutinib, median OS upon ending ibrutinib treatment was 2.9 months (95% CI: 1.6-4.9; Martin et al. Blood 2016). The CD20xCD3 T-cell-engaging bispecific monoclonal antibody, glofitamab, has a novel 2:1 (CD20:CD3) configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Obinutuzumab pretreatment (Gpt) is given 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS). Phase I/II (NCT03075696) data for glofitamab monotherapy with step-up dosing (SUD) and Gpt (1000mg or 2000mg) have shown high response rates and manageable, mostly low-grade CRS in patients with R/R MCL, most of whom had prior BTKi therapy (Phillips et al. ASH 2021). Here, we report on the durability of response with glofitamab SUD in a larger cohort with additional follow up. Methods: All patients received Gpt 7 days before the first dose of glofitamab. Intravenous glofitamab SUD was given on Days (D) 8 (2.5mg) and 15 (10mg) of Cycle (C) 1, then at the target dose (16mg or 30mg after 1000mg Gpt; 30mg after 2000mg Gpt) from C2D1, every 3 weeks for up to 12 cycles. Response rates were assessed by Lugano criteria (Cheson et al. JCO 2014). Results: As of March 14, 2022, 37 patients had received glofitamab SUD after Gpt (1000mg Gpt, n=16; 2000mg Gpt, n=21). Median age was 72.0 years (range: 41-84), 73.0% of patients were male, 91.9% had Ann Arbor Stage III/IV disease and 32.4% had MCL IPI score ≥6 at study entry. Median prior lines of therapy was three (range: 1-5); 24 (64.9%) patients had prior BTKi therapy and seven (18.9%) had prior lenalidomide therapy. The majority of patients were refractory to their first line of therapy (62.2%; n=23) and/or their last prior therapy (73.0%; n=27). Median time since last therapy was 1.9 months (range: 0.1-107.5). After a median follow up of 8 months (range: 0-19), overall response rate (ORR) and complete response (CR) rates were 83.8% (31/37) and 73.0% (27/37), respectively, across both Gpt cohorts. In the 2000mg Gpt cohort, ORR and CR rates were 90.5% (19/21) and 81.0% (17/21), respectively. In the 1000mg Gpt cohort, ORR and CR rates were 75.0% (12/16) and 62.5% (10/16), respectively. Across both Gpt cohorts, median time to CR was 51 days. The majority of CRs (20/27; 74.1%) were ongoing at the data cut-off and an estimated 71.6% of patients with a CR remained in response at 9 months. Median duration of response was 12.6 months (95% CI: 10.0-NE) and median duration of CR was 10.0 months (95% CI: 4.9-NE). The two deaths that occurred after 10 months were due to COVID-19 (Figure). In safety-evaluable patients (n=37), the most common adverse events (AEs) were CRS (75.7%; by ASTCT criteria) and neutropenia (40.5%). CRS rates were lower in the 2000mg Gpt (14/21; 66.7%) vs the 1000mg Gpt (14/16; 87.5%) cohort. CRS events in the 2000mg Gpt cohort were all Grade (Gr) 1-3 (Gr 1, 33.3%; Gr 2, 23.8%; Gr 3, 9.5%), whereas there were two Gr 4 CRS events in the 1000mg Gpt cohort (Gr 1, 25.0%; Gr 2, 37.5%; Gr 3, 12.5%; Gr 4, 12.5%). All CRS events were manageable (17 patients received tocilizumab to manage CRS) and most resolved by data cut-off (one patient had ongoing CRS at the time of analysis). Neurologic AEs (NAEs) occurred in 19 patients (51.4%); all were Gr 1/2 except for one Gr 3 subdural hematoma in the 2000mg Gpt cohort. NAEs consistent with immune effector cell-associated neurotoxicity syndrome following glofitamab administration occurred in five patients (13.5%, all Gr 1/2 and nonserious). Tumor flare events occurred in five patients (13.5%, all Gr 1/2). No patients discontinued treatment due to AEs. Ten deaths were reported and considered unrelated to study treatment: PD, n=5; AEs, n=5 (COVID-19/pneumonia, n=4; cardiac arrest, n=1). Conclusions: Fixed-duration glofitamab monotherapy after Gpt (1000mg or 2000mg) induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior BTKi therapy and thus a particularly poor prognosis. CRS events were manageable and mostly low grade. This is one of the largest datasets and longest follow-ups reported with a CD20xCD3 bispecific monoclonal antibody for patients with R/R MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CD19 4-1BBL (RO7227166) a Novel Costimulatory Bispecific Antibody Can be Safely Combined with the T-Cell-Engaging Bispecific Antibody Glofitamab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background RO7227166 is a bispecific monoclonal antibody that simultaneously targets CD19 on B-cells and 4-1BB on T-cells and other immune cells. In the presence of a T-cell receptor signal and strictly dependent on CD19 crosslinking, RO7227166 provides a strong co-stimulation to T-cells via 4-1BB agonism. RO7227166 is therefore not exhibiting single-agent activity. Our preclinical and clinical data demonstrated 4-1BB upregulation on immune cells by glofitamab and in our in vivo humanized lymphoma xenograft mouse models the combination of glofitamab plus RO7227166 showed increased anti-tumor efficacy mediated by increased infiltration of activated CD8 T-cells within the tumor. We therefore hypothesized that RO7227166 would boost the anti-tumor activity of glofitamab in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL). Methods We report data from the first-in-human study BP41072 (NCT04077723), a multicenter open label Phase 1 trial investigating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary antitumor activity of RO7227166 in combination with glofitamab (part II of the study) in relapsed/refractory (R/R) B-NHL pts. Pts received 1000mg obinutuzumab 7 days prior to first glofitamab administration to mitigate cytokine release syndrome (CRS). Glofitamab was then dosed following a step-up regimen in cycle 1 (C1), from cycle 2 day 1 (C2D1) on, every 3 weeks (Q3W) for up to 12 cycles. First RO7227166 dose was given on C2D8 and from C3 onwards on the same day as glofitamab. RO7227166 dose escalation was guided by an mCRM EWOC model with overdose control. Response rates were reported based on the Lugano criteria. Results As of June 7, 2022, a total of 46 pts with R/R aggressive B-NHL (diffuse-large B-cell lymphoma [DLBCL]) and 24 pts with R/R indolent B-NHL (23 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]) received RO7227166 doses ranging from 360µg up to 33mg. So far the dose level with the expected maximum efficacy is not yet reached. Pts had a median age of 66 years, 44.3% were female, with ECOG of 0 (62.9%) or 1 (37.1%). Approximately half of pts had Stage IV disease (44.3%), 18.6% pts had bulky disease (at least one lesion > 6cm), 27.1% had prior CAR-T therapy. Median prior lines of therapy was 3 (range 1-7), with 40% refractory to last prior therapy, 21.4% primary refractory and 12.9% refractory to CAR-T. Across 70 safety evaluable pts, 67 (95.7%) had adverse events (84.3% pts grade 1, 64.3% pts grade 2, 44.3% pts grade 3, 8.6% pts grade 4 and 4.3% pts grade 5). Grade 5 events were pneumocystis jirovecii pneumonia which qualified as dose-limiting toxicity (n=1) and septic shock (n=1) and COVID-19 infection (n=1) which were both assessed as not related to study medications. The most frequent adverse event was CRS with 63 events occurring in 38 (54.3%) pts (maximum grade 1 in 37,1% pts, and maximum grade 2 in 17,1% pts, according to ASTCT score). Of all 63 events (including multiple events for some pts), 55 were related to glofitamab alone (87,3%), 5 events to glofitamab and RO7227166 (8%, all grade 1) and 3 events related to RO7227166 alone (4.8%, all grade 1). Overall the safety profile was mainly driven by glofitamab (Hutchings, et al. 2021) and we are yet to detect an additive safety signal from RO7227166 when combined with glofitamab. RO7227166 exposure increased dose-dependently across the investigated doses. Furthermore, preliminary pharmacodynamic analysis showed further expansion of primed and activated CD8, and effector memory T-cells in the periphery, which supports the expected mode of action of RO7227166 in combination with glofitamab. Of the 56 response-evaluated subjects, pts with DLBCL achieved a best overall response rate (BORR) of 67% and a complete response rate (CRR) of 39%, while the BORR and CRR for patients with FL was 91% and 73%. Summary This is the first study demonstrating that glofitamab can be safely combined with a costimulatory bispecific antibody (RO7227166) in R/R B-NHL. No new safety signals or signs of increased immune-related AEs were detected and the overall safety profile was consistent with that reported from single-agent glofitamab. At doses explored, combination therapy maintains efficacy similar to glofitamab single-agent, and dose escalation continues with additive benefit of the combination expected at higher doses.

Predictive value of the systemic immune-inflammation index for the efficacy of neoadjuvant chemotherapy and prognosis in patients with stage III ovarian cancer-a retrospective cohort study.

The systemic immune-inflammation index (SII) has been proven to be related to the prognoses of multiple malignant tumors. However, there are still few studies on the relationship between the SII and the effect of neoadjuvant chemotherapy in patients with ovarian cancer. It is of great significance to predict the efficacy of neoadjuvant chemotherapy in patients with ovarian cancer. Our study was aimed at determining the predictive value of the SII for the efficacy of neoadjuvant chemotherapy and prognosis in patients with stage III ovarian cancer. A total of 102 patients with stage III ovarian cancer treated in Tongji Hospital of Tongji University from January 2017 to January 2019 were retrospectively collected. According to the level of the SII before neoadjuvant chemotherapy, patients were divided into the high SII group and low SII group. We compared the effect of neoadjuvant chemotherapy between the 2 groups, and observed the progression-free survival and mortality of patients in the 2 groups after 3 years follow-up. Compared with patients in the low SII group, the complete response rate of patients in the high SII group decreased significantly after neoadjuvant chemotherapy (13.73% vs. 45.10%, P=0.001), and the progressive disease rate increased (19.61% vs. 1.96%, P=0.011). The SII had certain value in predicting the inefficacy of neoadjuvant chemotherapy in patients with stage III ovarian cancer, and the area under the curve was 0.655 (95% CI: 0.548-0.762, P=0.007). The progression-free survival of patients in the high SII group was shorter than that of patients in the low SII group (P<0.001), and the overall survival rate of patients in the high SII group was lower (47.06% vs. 70.59%, P=0.016). The SII had predicting value for the postoperative death of ovarian cancer patients after neoadjuvant chemotherapy, and the area under the curve was 0.646 (95% CI: 0.537-0.756, P=0.012). Multivariate regression analysis showed that higher SII was a risk factor for death in ovarian cancer patients after neoadjuvant chemotherapy (OR: 2.700, P=0.017). A high SII was a predictor of inefficacy of neoadjuvant chemotherapy in patients with stage III ovarian cancer and was related to poor prognosis.

137. THE COMPARISON OF SHORT-TERM OUTCOMES BETWEEN NEOADJUVANT CHEMOTHERAPY COMBINED WITH IMMUNOTHERAPY AND NEOADJUVANT CHEMORADIOTHERAPY FOR ESOPHAGEAL SQUAMOUS CANCER

Abstract To evaluate the short-term outcomes of neoadjuvant chemotherapy combined with immunotherapy followed by esophagectomy for locally advanced esophageal squamous cell carcinoma. Patients receiving neoadjuvant chemotherapy combined with immunotherapy (NACI group) or chemoradiotherapy (NACR group) at our center between September 2019 and September 2021 were identified. The primary outcomes were tumor regression score (TRS), pathological complete regression (pCR), overall survival (OS), progression-free survival (PFS) and pathological downstaging. Secondary outcomes were toxic effects and postoperative complications. The propensity score matching for enrolled patients was performed. Data of 149 patients were analyzed. All included patients received minimally invasive esophagectomy, with only 3 conversion to open surgery. With regard toTRS, 25 (45.5%), 61 (64.9%) patients were scored 0 and 1 in the NACI and NACR groups, respectively (p = 0.020). Of note, 17 (30.9%) patients in the NACI group achieved pCR (ypT0N0), while 48 (51.1%) patients in NACR group achieved pCR (P = 0.026). Neoadjuvant chemoradiotherapy was associated with higher risk of postoperative pneumonia (p = 0.034). The 1-year cumulative progression-free survival rate was 85.4% and 75.4% in the NACI and NACR groups respectively (p = 0.147). We found that neoadjuvant immunotherapy combined with chemotherapy compared with neoadjuvant chemoradiotherapy was associated with lower pneumonia rate and was safe and feasible for locally advanced ESCC. However, the tumor regression score and the pathological complete response rate of patients treated with neoadjuvant immunotherapy was lower than those of patients treated with neoadjuvant chemoradiotherapy. The short-term follow-up results were comparable between two treatment modalities.

Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: a single-arm, phase 2 trial

TGF-β is an immunosuppressive cytokine that is upregulated in colorectal cancer. TGF-β blockade improved response to chemoradiotherapy in preclinical models of colorectal adenocarcinoma. We aimed to test the hypothesis that adding the TGF-β type I receptor kinase inhibitor galunisertib to neoadjuvant chemoradiotherapy would improve pathological complete response rates in patients with locally advanced rectal cancer. This was an investigator-initiated, single-arm, phase 2 study done in two medical centres in Portland (OR, USA). Eligible patients had previously untreated, locally advanced, rectal adenocarcinoma, stage IIA-IIIC or IV as per the American Joint Committee on Cancer; Eastern Cooperative Oncology Group status 0-2; and were aged 18 years or older. Participants completed two 14-day courses of oral galunisertib 150 mg twice daily, before and during fluorouracil-based chemoradiotherapy (intravenous fluorouracil 225 mg/m2 over 24 h daily 7 days per week during radiotherapy or oral capecitabine 825 mg/m2 twice per day 5 days per week during radiotherapy; radiotherapy consisted of 50·4-54·0 Gy in 28-30 fractions). 5-9 weeks later, patients underwent response assessment. Patients with a complete response could opt for non-operative management and proceed to modified FOLFOX6 (intravenous leucovorin 400 mg/m2 on day 1, intravenous fluorouracil 400 mg/m2 on day 1 then 2400 mg/m2 over 46 h, and intravenous oxaliplatin 85 mg/m2 on day 1 delivered every 2 weeks for eight cycles) or CAPEOX (intravenous oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks for four cycles). Patients with less than complete response underwent surgical resection. The primary endpoint was complete response rate, which was a composite of pathological complete response in patients who proceeded to surgery, or clinical complete response maintained at 1 year after last therapy in patients with non-operative management. Safety was a coprimary endpoint. Both endpoints were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02688712, and is active but not recruiting. Between Oct 19, 2016, and Aug 31, 2020, 38 participants were enrolled. 25 (71%) of the 35 patients who completed chemoradiotherapy proceeded to total mesorectal excision surgery, five (20%) of whom had pathological complete responses. Ten (29%) patients had non-operative management, three (30%) of whom ultimately chose to have total mesorectal excision. Two (67%) of those three patients had pathological complete responses. Of the remaining seven patients in the non-operative management group, five (71%) had clinical complete responses at 1 year after their last modified FOLFOX6 infusion. In total, 12 (32% [one-sided 95% CI ≥19%]) of 38 patients had a complete response. Common grade 3 adverse events during treatment included diarrhoea in six (16%) of 38 patients, and haematological toxicity in seven (18%) patients. Two (5%) patients had grade 4 adverse events, one related to chemoradiotherapy-induced diarrhoea and dehydration, and the other an intraoperative ischaemic event. No treatment-related deaths occurred. The addition of galunisertib to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer improved the complete response rate to 32%, was well tolerated, and warrants further assessment in randomised trials. Eli Lilly via ExIST program, The Providence Foundation.

Neoadjuvant therapy gains FDA approval in non-small cell lung cancer

SummaryForde et al.1 reported on a randomized clinical trial (CheckMate 816) and showed that neoadjuvant therapy with nivolumab plus chemotherapy led to improved event-free survival and pathological complete response rate in patients with resectable non-small cell lung cancer (NSCLC).

Abstract 3603: Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma

Abstract Autologous T cells genetically engineered to express a chimeric antigen receptor targeting CD19 (CD19-CAR) have achieved high complete response rates in patients with hematologic malignancies, but &amp;gt;50% of patients progress following therapy. Here, we sought to understand key T-cell intrinsic factors impacting efficacy, namely CAR T-cell expansion, persistence, and homing to the tumor. Using an approach called reverse fate mapping, we followed individual T-cell clones at the single-cell level from pre-manufacture apheresis to the infusion product, tumor-involved lymph node, and blood at peak and late expansion in 12 adult patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel, an FDA-approved CD19-CAR T-cell immunotherapy. The resulting CAR T-cell atlas comprises matched transcriptome (scRNA-seq) and surface protein expression (CITE-seq) for 322,028 cells from 44 samples, with 119,397 unique T-cell receptor (TCR) clonotypes identified. This atlas enabled us to ask questions like: “What were the phenotypes of the most successful CAR T-cell clones at the time of infusion or pre-manufacture apheresis?” We found that T-cell clonotypes with juvenile features at apheresis, including IL7R expression, were the most successful at expansion to higher frequencies in the infusion product, while clones with effector gene expression programs, such as those encoding perforin and granzymes, contracted between apheresis and product. Conversely, it was GZMK-expressing T cells in pre-manufacture apheresis that were dominant in the tumor early following CAR T-cell infusion. Further, T-cell clonotypes with active effector programs at infusion dominated at peak expansion. Finally, we defined active expression modules and pathways in the infusion product for CAR T-cell clones that homed to the tumor or became dominant at late expansion. These analyses pinpoint the molecular mechanisms that could be modulated to rationally steer CAR T-cell differentiation trajectories at the genetic or pharmacological level. This work was supported in part by the Parker Institute for Cancer Immunotherapy, California Institute for Regenerative Medicine, Kite Pharma, and Stanford Cancer Institute. Citation Format: Zinaida Good, Mark P. Hamilton, Jay Y. Spiegel, Sreevidya Kurra, Moksha Desai, Snehit Prabhu, Eric Yang, Michael G. Ozawa, Paul J. Hanson, Fang Wu, Matthew J. Frank, John H. Baird, Lori Muffly, Gursharan K. Claire, Juliana Craig, Katherine A. Kong, Dhananjay Wagh, John Coller, Sylvia K. Plevritis, Bita Sahaf, David B. Miklos, Crystal L. Mackall. Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma [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 3603.

Effect and clinical significance of zoledronic acid combined with radiotherapy in the treatment of bone pain caused by bone metastasis in non-small cell lung cancer patients

Objective: To investigate the effect of zoledronic acid on the remission of bone pain in patients with non-small cell lung cancer (NSCLC) during and after radiotherapy. Materials and Methods: A total of 197 NSCLC patients who received radiotherapy for osteopathy with complete recorded visual analog scale (VAS) scores were enrolled. Of these, 79 patients were treated with radiotherapy alone (radiotherapy group), and 118 patients were treated with radiotherapy combined with zoledronic acid (zoledronic acid group). The differences in VAS scores between the two groups were compared. Logistic regression was used to determine the odds ratio (OR) of the complete response rate for osteodynia between the zoledronic acid group and the radiotherapy group. Univariate and multivariate Cox regression analyses were used to evaluate the independent prognostic factors for overall survival (OS). Results: The complete response rate in patients in the zoledronic acid group was significantly higher than that in patients in the radiotherapy group (odds ratio [OR] = 3.201, 95% confidence interval [CI]: 1.559-6.575, P = 0.002). Except for the baseline VAS score, all VAS scores in the zoledronic acid group at different time points during radiotherapy, at the end of radiotherapy, and 1 month after radiotherapy were significantly lower than those in the radiotherapy group (all P &lt; 0.01). Grade 3 constipation was observed in only one patient in the zoledronic acid group. There were no other Grade 3 adverse events. Multivariate Cox regression analysis showed that only the treatment group (zoledronic acid group vs. radiotherapy group, hazard ratio [HR] = 0.720, 95% CI: 0.530-0.978, P = 0.036) and manner of bone destruction (mixture vs. osteolytic, HR = 0.596, 95% CI: 0.424-0.837, P = 0.003) were independent prognostic factors for OS. Conclusion: Zoledronic acid combined with radiotherapy can not only accelerate bone pain control but also prolong survival in NSCLC patients with bone metastases.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non–muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. Patient summaryThis study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non–muscle-invasive bladder cancer. Prospective assessment of serum anti–human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.