Platinum-based Systemic Chemotherapy Research Articles

Selective adjuvant radiation therapy for distant lymph node metastasis in patients with stage 4B epithelial ovarian cancer: a case series

Although the efficacy of surgery followed by taxane- and platinum-based systemic chemotherapy has been clearly demonstrated in the standard first-line treatment of epithelial ovarian cancer, the role of radiation therapy for distant lymph node metastasis in patients with epithelial ovarian cancer is not well-established due to a lack of reported studies. We identified four patients who underwent selective adjuvant radiation therapy for neck and para-aortic lymph node lesions after primary debulking surgery between 2020 and 2022, followed by platinum-based chemotherapy for stage 4B high-grade serous ovarian cancer. Through a retrospective review of medical records, we analyzed patient clinicopathologic features, treatment course, and imaging findings. The median age was 49.25 years (range, 46–54 years). All patients had the International Federation of Gynecology and Obstetrics stage 4B disease. Following primary debulking surgery, all patients received weekly paclitaxel-carboplatin chemotherapy and maintenance treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. All patients received selective adjuvant radiation therapy for neck and para-aortic lymph node metastasis before PARP inhibitor maintenance. The median follow-up time was 36.75 months (range, 19–45 months). All patients achieved a complete response. None of the patients experienced disease recurrence or died during the follow-up period. The management of distant lymph node metastasis in patients with epithelial ovarian cancer remains a matter of debate. Selective adjuvant radiation therapy in first-line treatment for ovarian cancer appears to be a feasible approach with maintenance therapy for stage 4B epithelial ovarian cancer.

Systemic treatment of advanced and metastatic urothelial cancer: The landscape in Australia.

The 5-year survival rate of metastatic urothelial carcinoma (mUC) is estimated to be as low as 5%. Currently, systemic platinum-based chemotherapy followed by avelumab maintenance therapy is the only first-line treatment for mUC that has an overall survival benefit. Cisplatin-based chemotherapy (usually in combination with gemcitabine) is the preferred treatment but carboplatin is substituted where contraindications to cisplatin exist. Treatment with immune checkpoint inhibitors, antibody-drug conjugates, and kinase inhibitors has not yet demonstrated superiority to chemotherapy as first-line therapy and remains investigational in this setting. A recent media release indicates that chemotherapy plus nivolumab gives an OS advantage as first-line treatment but results of this study have not yet been made public. Pembrolizumab remains an option in those having primary progression on first-line chemotherapy or within 12 months of neoadjuvant chemotherapy. The antibody-drug conjugate, enfortumab vedotin has TGA approval for patients whose cancer has progressed following chemotherapy and immunotherapy and has just received a positive Pharmaceutical Benefits Scheme recommendation. The use of molecular screens for somatic genetic mutations, gene amplifications, and protein expression is expanding as drugs that target such abnormalities show promise. However, despite these advances, a substantial proportion of patients with mUC have significant barriers to receiving any treatment, including advancing age, frailty, and comorbidities, and less toxic, effective therapies are needed.

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. AK112 is the first-in-class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. This study aimed to evaluate the efficacy and safety of AK112 combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). This open-label, multicenter, phase II clinical trial was conducted in 11 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, and an estimated life expectancy of at least 3 months. The participants were categorized into three cohorts based on prior therapy and functional genomic alterations. Patients in cohort 1 were previously untreated advanced NSCLC, had no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene modifications, and received AK112 combined with pemetrexed (500mg/m2) for non-squamous (non-sq)-NSCLC or paclitaxel (175mg/m2) for sq-NSCLC plus carboplatin (area under the curve of 5mg/mL per min) for four cycles, followed by AK112 with pemetrexed for non-sq-NSCLC and AK112 alone for sq-NSCLC as maintenance therapy. The participants in cohort 2 had advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy, and received pemetrexed plus AK112 and carboplatin for four cycles, followed by pemetrexed plus AK112 as maintenance therapy. The participants in cohort 3 had advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/programmed death-ligand 1 (PD-L1) treatments and received AK112 plus docetaxel (75mg/m2). Two dosages of AK112 (10 or 20mg/kg) were examined in each cohort, and the drug was administered intravenously on day 1 of each 3-week treatment cycle. The primary endpoints were the investigator-assessed objective response rate (ORR) and safety. This study was registered with ClinicalTrials.gov (NCT04736823). Eighty-three patients were enrolled from February 2021 to August 2022 and received the study treatment. Cohorts 1, 2, and 3 had 44, 19, and 20 patients, respectively. The confirmed ORR was 53.5% (23/43) [95% CI, 36.9-67.1], 68.4% (13/19) [95% CI, 43.4-87.4], and 40.0% (8/20) [95% CI, 19.1-63.9] in cohorts 1, 2, and 3, respectively. In cohort 1, the median PFS was not reached, and the 12-month PFS rate was 59.1%. In cohorts 2 and 3, the median PFS were 8.5 [95% CI, 5.5-NE] and 7.5 [95% CI, 2.3-NE] months, and the 12-month PFS rates were 35.5% and 44.5%, respectively. The most common grade ≥3 treatment-related adverse events were decreased white blood cell count [7 (8.4%)], neutropenia [5 (6.0%)], thrombocytopenia [2 (2.4%)], anemia [4 (4.8%)], and myelosuppression [2 (2.4%)]. AK112 plus platinum-doublet showed promising antitumor activity and safety not only in first-line treatment of advanced NSCLC patients without driver mutation but also in patients with EGFR-functional mutation who failed previous EGFR-TKI therapy and advanced NSCLC patients who failed prior systemic platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatments, suggesting a valuable potential new treatment option for this patient population. Akeso Biopharma, Inc., Zhongshan, China, and National Natural Science Foundation of China.

HIPEC in Ovarian Cancer Is the Future… and Always Will Be? Results from a Spanish Multicentric Survey.

Ovarian cancer is the leading cause of death due to gynecological tumors in the female population. Despite optimal first-line treatment, including cytoreduction and platinum-based systemic chemotherapy, recurrences are frequent. The use of hyperthermic intraperitoneal chemotherapy (HIPEC) has been criticized, especially because of the lack of randomized controlled trials (RCTs) with convincing results to support the use of HIPEC in patients with ovarian cancer with peritoneal dissemination. In 2018, the clinical trial published by Van Driel et al. reported improved outcomes in favor of HIPEC treatment with cisplatin. In this study, we conducted a national survey within the Spanish group of peritoneal surgical oncology (Grupo Español de Cirugía Oncológica Peritoneal, GECOP) to explore the impact of the results of this RCT on clinical practice. A total of 33 groups completed the survey. Routine clinical practice was not changed in 28 of the 33 groups (85%) based on the results of the Van Driel trial. Despite the results of this RCT, most groups considered that more RCTs are needed and that, in the future, HIPEC may become the standard of care. In conclusion, the results from RCTs evaluating HIPEC treatment in patients with ovarian cancer has not been transferred to clinical practice.

Phase 2 study of HDAC inhibitor tucidinostat in combination with anti-PD-1 antibody in patients with locally advanced or metastatic urothelial carcinoma.

e16563 Background: Tucidinostat (also known as chidamide), a novel histone deacetylase (HDAC) inhibitor, has been approved for treatment of patients (pts) with relapsed or refractory peripheral T-cell lymphoma and advanced hormone receptor-positive breast cancer in China. Tislelizumab (a PD-1 checkpoint inhibitor) is currently approved for pts with PD-L1-high locally advanced or metastatic urothelial carcinoma (UC) who progressed during/following platinum-containing therapy in China. However, the response rate of tislelizumab as monotherapy is limited in UC. The aim of this study was to evaluate the efficacy and safety of tucidinostat combined with tislelizumab in pts with locally advanced or metastatic UC. Methods: This study is an open-label, single-center, phase Ⅱ trial. Patients who previously failed systemic platinum-based chemotherapy with UC were included, regardless of PD-L1 status. Eligible pts received 30 mg oral tucidinostat twice weekly (BIW) in combination with 200 mg tislelizumab by intravenous drip every three weeks (Q3W). This is a Simon's two-stage design. All pts were treated until progression or unacceptable toxicity in two years. The primary endpoint was objective response rate (ORR). The secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), the safety and tolerability. Results: From Jan. 2021 to Sep. 2022, 26 pts were enrolled (median age 62 y, range 31-74y), of whom 24 were evaluable for response per RECIST 1.1 criteria. One pt was lost to follow-up and one withdrew the group due to sudden cerebral infarction. Complete response (CR) was observed in 2 pts, while partial response (PR) was observed in 8 pts, with an ORR of 41.7% (10/24). The DCR was 62.5%. The median PFS was 4.6 months. Most adverse events (AEs) were grade 1 or 2. The most common grade 3 AEs were neutropenia 11.5%, thrombocytopenia 11.5%, leukopenia 7.7%, anemia 7.7%, anorexia 7.7%, creatinine increased 3.8%. One pt experienced grade 4 immuno-pneumonia was permanently discontinued. One pt was on maintenance therapy of tucidinostat without immunotherapy because of interstitial pneumonia. Conclusions: The preliminary data indicate that tucidinostat combined with tislelizumab might be a potentially effective regimen with a manageable safety profile in UC. The study remains ongoing and updated results will be presented later. Clinical trial information: NCT04562311 .

The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers.

Survival outcomes for patients with advanced ovarian cancer remain poor despite advances in chemotherapy and surgery. Platinum-based systemic chemotherapy can result in a response rate of up to 80%, but most patients will have recurrence and die from the disease. Recently, the DNA-repair-directed precision oncology strategy has generated hope for patients. The clinical use of poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA germ-line-deficient and/or platinum-sensitive epithelial ovarian cancers has improved survival. However, the emergence of resistance is an ongoing clinical challenge. Here, we review the current clinical state of PARP inhibitors and other clinically viable targeted approaches in epithelial ovarian cancers.

SunRISe-4: TAR-200 plus cetrelimab or cetrelimab alone as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or refuse neoadjuvant platinum-based chemotherapy.

TPS584 Background: Standard of care for patients (pts) with MIBC is radical cystectomy (RC) with neoadjuvant systemic platinum-based chemotherapy (PBC); however, systemic chemotherapy is associated with significant toxicity. TAR-200 is an intravesical drug delivery system that provides local continuous gemcitabine release within the bladder. SunRISe-4 (NCT04919512) is an open-label, multicenter, randomized phase 2 study designed to assess the efficacy and safety of neoadjuvant TAR-200 + systemic cetrelimab (CET [anti–programmed death-1 antibody]) vs neoadjuvant CET alone in pts with MIBC scheduled for RC who are ineligible for or refuse neoadjuvant PBC. Methods: Eligibility criteria: age ≥18 years, Eastern Cooperative Oncology Group performance status of 0 or 1, histologically confirmed cT2-T4a MIBC with absence of nodal or metastatic disease at screening, and residual intravesical tumor volume of ≤3 cm prior to randomization. Pts will be stratified by completeness of transurethral resection of bladder tumor (TURBT; visibly complete vs incomplete and ≤3 cm) and tumor stage (cT2 vs cT3-4a) at initial diagnosis. Pts (N≈160) will be randomized 5:3 to receive TAR-200 + CET (Cohort 1, n≈100) or CET alone (Cohort 2, n≈60). In Cohort 1, TAR-200 (225 mg gemcitabine) will be placed intravesically at the initial treatment visit; TAR-200 will be removed and replaced over a 12-week period. In both cohorts, CET will be serially dosed intravenously over the same timeframe. Primary disease assessments include axial imaging (at screening and Week 6), centralized review of TURBT (initial diagnostic TURBT or debulking TURBT for pts with lesions >3 cm after initial TURBT) as well as RC and nodal tissue specimens. After RC, all pts will have follow-up visits from Weeks 4 to 108 post RC (end of study). The primary outcome measure is the pathologic complete response rate at time of RC. Secondary outcome measures include safety, tolerability, and recurrence-free survival (per Response Evaluation Criteria in Solid Tumors 1.1 or histologic evidence). Exploratory outcome measures include patient-reported cancer-related quality of life (Functional Assessment of Cancer Therapy–Bladder questionnaire) and pathologic overall response rate at RC. Overall survival and time to symptomatic progression, pharmacokinetics, biomarker analysis, and immunogenicity will also be evaluated. As of September 12, 2022, 2 of 160 planned pts have been enrolled and randomized, and recruitment is ongoing at ≈95 sites. Clinical trial information: NCT04919512 .

Tissue Distribution of Cisplatin by Intra-arterial Infusion Route in Comparison to Systemic Route: Implication to Therapy for Node-positive Bladder Cancer.

In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intravenous (IV) route. Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.

Sintilimab combined with chemotherapy successfully treated a patient with advanced submandibular gland tumor.

Primary submandibular gland tumors arerelatively rare. Due to its low incidence and broad spectrum phenotypic, biologicaland clinical heterogeneity types, a wide range of options have been developed to treat this tumor. To date, however, efficacious standard treatment regimens are lacking. Here, the authors present a case ofa patient withan advanced submandibular gland tumor. Histological and imaging results diagnosed the case as stage IV submandibular gland adenocarcinoma with multiple metastases. The patient was subjected to systemic platinum-based chemotherapy combined with sintilimab. Aprimary lesion complete responsewas observed after six cycles of treatment. This case affirms theefficacy of thePD-1inhibitor sintilimab combined with platinum-based chemotherapy as a first-line treatment for advanced submandibular gland tumors.

Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management

HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence.

A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

Mutation Landscape of Homologous Recombination Repair Genes in Epithelial Ovarian Cancer in China and Its Relationship With Clinicopathlological Characteristics.

ObjectiveThe status of homologous recombination repair (HRR) gene mutations and their impact on the survival of patients with Chinese epithelial ovarian cancer (EOC) are still unclear. In this study, we retrospectively analyzed the mutations of HRR genes in tumor tissues and evaluated their values for predicting the survival of Chinese EOC patients.MethodsA total of 273 primary EOC patients from five different hospitals between 2015 and 2016 were recruited. All patients received staging surgeries or debulking surgeries combined with systemic platinum-based chemotherapy. DNA was extracted from formalin-fixed, paraffin-embedded sections and analyzed for mutations using a 21-gene panel (including 13 well-known HRR genes) by next-generation sequencing.ResultsHigh-grade serous carcinoma (HGSOC) accounted for 76.2% of the cohort. A total of 34.1% (93/273) cases had 99 deleterious mutations in 9 HRR genes, namely, BRCA1 (56/273, 20.5%), BRCA2 (20/273, 7.3%), ATM (5/273, 1.8%), RAD51C (5/273, 1.8%), RAD51D (5/273, 1.8%), BRIP1 (2/273, 1.8%), CHEK2 (2/273, 0.7%), FANCI (2/273, 0.7%), and RAD54L (1/273, 0.4%). There is a strong mutual exclusion between HRR genes. The mutation landscape revealed several unappreciated deleterious variants in BRCA1/2 and other HRR genes reported previously. Estimated according to the mutation allele frequency, about 4.8% of the patients had potential somatic HRR gene mutations, which might be underestimated. Moreover, HRR mutations mainly exist in HGSOC (83/208, 39.9%), clear cell (2/30, 6.7%), and endometroid subtypes (8/20, 40%), but not seen in other rare subtypes. BRCA1 mutations tend to be present in younger patients with family history or multiple primary foci. Patients with BRCA1/2 mutations tend to have a longer progression-free survival and overall survival, while other HRR mutation carriers tend to have a shorter progression-free survival, but no significant difference in overall survival.ConclusionThis study revealed the distribution of HRR gene mutations in Chinese EOC tissues. BRCA1/2 account for the majority of HRR gene mutations and predict long prognosis in HGSOC. Non-BRCA HRR mutations also account for a very important proportion and might be associated with poor prognosis in HGSOC. It is suggested that HRR gene mutations need to be detected in EOC tissues and germline status be further clarified in clinical algorithm for potential targeted therapy, genetic screening, and prognosis prediction.

Multicenter retrospective study of ramucirumab-containing chemotherapy for gastrointestinal neuroendocrine carcinoma patients previously treated with platinum-based chemotherapy: RAM-NEC study (WJOG13420G).

511 Background: Platinum-based systemic chemotherapy (CTx) is recommended for poorly differentiated advanced gastrointestinal neuroendocrine carcinoma (GI-NEC). As second-line CTx various regimens are adopted according to the guidelines of GI adenocarcinoma or small cell lung cancer in daily practice. Recently, some clinical and preclinical reports suggest that vascular endothelial growth factor (VEGF) inhibitors are effective against NEC. In this study, we evaluated the efficacy of ramucirumab (RAM, anti-VEGF receptor 2 antibody)-containing CTx. Methods: We retrospectively evaluated gastric (G-) or colorectal (C-) NEC patients previously treated with first-line platinum-based CTx followed by second-line CTx between March 2015 and June 2020 (G-NEC) or between May 2016 and June 2020 (C-NEC). The main inclusion criteria were ECOG performance status (PS) of 0–2, pathologically diagnosed as G or C- NEC or mixed adenoneuroendocrine carcinoma. We compared the efficacy of RAM-containing CTx as second- or later-line treatment (Group A) with that of CTx without RAM as second-line treatment (Group B). A Cox proportional hazard model and inverse probability weighting of propensity scores were used to adjust the background factors between the two groups. Results: From 25 facilities, 139 patients were included in this study. Group A and B contained 50 (G/C, 43/7 patients) and 89 (G/C, 58/31 patients) patients, respectively. Patient characteristics were as follows (Group A/Group B): median age (range), 70 (28–83)/68 (39–86); ECOG PS 1–2, 66/69%, more than two prior regimens, 46/0%; response to previous platinum-based CTx, 46/38%. The regimen in combination with RAM in Group A was paclitaxel/nab-paclitaxel/FOLFIRI (62/26/12%). Second-line CTx in Group B were commonly amrubicin (58%) and irinotecan (11%). The efficacy (Group A/Group B) after a median follow-up time of 7.5/5.5 months were as follows: median overall survival (mOS), 8.6/5.8 months (HR, 0.68; 95% CI, 0.45–1.01; p = 0.058); median progression-free survival, 4.3/1.9 months (HR, 0.57; 95% CI, 0.39–0.84; p = 0.004); objective response rate, 50/8% ( p < 0.0001); disease control rate, 70/24% ( p < 0.0001); mOS in G-NEC, 8.6/5.3 months (HR, 0.62; 95% CI, 0.39–0.99; p = 0.047); and mOS in C-NEC, 5.4/6.8 months (HR, 0.66; 95% CI, 0.26–1.66; p = 0.378). The most common grade 3 or higher treatment-related adverse event that occurred in more than 5% of patients in Group A was neutropenia (32%). Conclusions: This study suggests that RAM-containing CTx as second- or later-line treatment is effective for GI-NEC patients, especially for G-NEC. Central pathological review and biomarker analyses using pretreated tissue specimens are ongoing. We will present updated data in the congress. Clinical trial information: UMIN000043200.

Current status and future perspectives of immunotherapy against urothelial and kidney cancer.

Much attention has been paid to immune checkpoint inhibitors to various cancer treatments. In urothelial cancer, pembrolizumab was initially approved for patients who either recurred or progressed following platinum-based chemotherapy. For the platinum-fit population, although the standard first-line treatment is still platinum-based systemic chemotherapy, avelumab has been recently approved as a maintenance therapy for patients who have not had disease progression with four to sixcycles of first-line chemotherapy. In addition, adjuvant nivolumab has just prolonged disease-free survival (DFS) by ~10months, compared with placebo in patients with muscle-invasive bladder urothelial cancer or upper tract urothelial cancer at high-risk of recurrence after radical surgical resection. On the other hand, in kidney cancer, nivolumab was initially approved for advanced renal cell carcinoma patients after one or two prior anti-angiogenic therapies. Next, combinations of two immune checkpoint inhibitors (nivolumab + ipilimumab) and immune checkpoint inhibitor+tyrosine kinase inhibitors (pembrolizumab + axitinib and avelumab + axitinib) were approved for the first-line treatment for patients with advanced renal cell carcinoma. Recently, new generation tyrosine kinase inhibitors, such as cabozantinib and lenvatinib have been combined with immune checkpoint inhibitors. Both nivolumab + cabozantinib and pembrolizumab + lenvatinib have demonstrated superior progression-free survival and objective response rate, compared with sunitinib. So far, no prospective trials have demonstrated the duration of immune checkpoint inhibitor treatments. We are now doing the Japan Clinical Oncology Group 1905 trial, where patients with advanced renal cell carcinoma who have received an immune checkpoint inhibitor for 24weeks are divided into two groups: those who continue immune checkpoint inhibitor treatment and those who discontinue immune checkpoint inhibitor treatment.

A phase II study of sintilimab plus anlotinib for Chinese patients (pts) with persistent, recurrent or metastatic cervical cancer (CC)

<h3>Objectives:</h3> There are limited effective therapies for CC pts who have previously received multiple lines of chemotherapy. The combination of immune checkpoint inhibitors (ICIs) plus angiogenesis inhibitors has demonstrated significant anti-tumor activity in certain cancer. The goal of this study was to evaluate the efficacy and safety of sintilimab (a human programmed death-1 ICI) plus anlotinib (a multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling) in persistent, recurrent or metastatic CC pts. <h3>Methods:</h3> Patients who have received at least once platinum-based systemic chemotherapy, recurrence or metastasis advanced cervical cancer (including squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma), more than 1% PD-L1 expression, ECOG 0-1 were considered eligible for enrollment. Sintilimab was administered intravenously (200mg once every 3weeks), and anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. <h3>Results:</h3> From September 2019 to August 2020, 25 patients with FIGO stage I (8%), II (36%), III (44%), IV (4%) and undiagnosed (8%) were enrolled with a median age of 52 years old (range: 36-67). Among these patients, 17 patients were evaluable. The therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 11.8%, 58.8%, 29.4% and 0% respectively, yielding the ORR of 70.6% (95% CI: 44.0%-89.7%) and the DCR of 100% (95% CI: 80.5%-100.00%). The median PFS was not reached. Most of the occurring adverse events were grade 1 or 2, and >10% Grade 1 AEs included hyperlipemia (40.0%), hypothyroidism (20.0%), hypertension (16.0%), >10% Grade 2 AEs included hand-foot syndrome (12.0%). Intolerance was only observed in 1 patient. <h3>Conclusions:</h3> Sintilimab plus anlotinib showed a promising efficacy with a favorable toxicity profile for patients with persistent, recurrent or metastatic cervical cancer. We will report more data in the future.

Anlotinib plus sintilimab in patients with recurrent advanced endometrial cancer: A prospective open-label, single-arm, phase II clinical trial.

5583 Background: Endometrial cancer is one of the most common gynecologic malignancies in the world. however, the effects of systemic chemotherapy are limited. The combination of targeted therapy with immunotherapy is a new research field in the treatment of malignant tumors. Anlotinib is a novel tyrosine kinase inhibitor with highly selective inhibition effects on multi-targets, especially on vascular endothelial growth factor receptor, Platelet-derived growth factor receptor and Fibroblast growth factor receptor. Sintilimab is a highly selective, fully humanized, monoclonal antibody, which blocks the interaction between Programmed death 1 and its ligands. This research aimed to evaluate the efficacy and safety of the combination of anotinib and sintilimab in patients with recurrent advanced endometrial cancer. Methods: Patients who received at least one platinum-based systemic chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1 were considered eligible for enrollment. Sintilimab was administered intravenously (200mg，q3w); anlotinib was taken orally (12mg qd, d1-14, 21 days per cycle). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included duration of response, disease control rate (DCR), progression-free survival (PFS), overall survival and safety. Results: From November 2019 to to September 2020, 23 patients with a median age of 56 years (range: 37-70), FIGO stage IA (21.7%), IB (8.7%), II (4.4%), IIIA (13.1%)，IIIC (30.4%), IVB (21.7%) were enrolled. Among these participants, 22 patients were evaluable. The therapeutic evaluation showed the incidence of complete response, partial response, stable disease and progression disease was 13.6%, 63.7%, 13.6% and 9.1% respectively, yielding the ORR of 77.3% (95%CI: 58.3%-96.3%) and the DCR of 91.7% (95%CI: 79.8%-100%). ≥1 and ＜1 Combined Positive Score of PD-L1 expression were observed in 66.7% (14/21) and 33.3% (7/21) patients respectively, and the ORR was 92.9% (95%CI: 77.4%-100%) and 57.1% (95%CI: 18.4%-90.1%) in the two groups. The median time of the first response was 1.5 months (range, 0.7-12.8). The median PFS was not reached. Most of the occurring adverse events (AEs) were grade 1 or 2. Grade 3 AEs included ileus (4.3%), immune myocarditis (4.3%) immune peritonitis (4.3%), hand-foot syndrome (8.7%), neutropenia (4.3%), neutrophils decrease (4.3%), and hypertension (4.3%); Grade 4 AE was lymphocytosis (4.3%). Neither unexpected safety signals nor treatment-related death occurred. Conclusions: Anlotinib plus sintilimab showed a promising antitumor activity with a favorable toxicity profile for patients with recurrent advanced endometrial cancer. We will report more data in the future. Clinical trial information: NCT04157491.

Penpulimab plus anlotinib as second-line treatment for the small cell lung cancer after failure of platinum-based systemic chemotherapy.

8568 Background: Combined therapy of an immune checkpoint inhibitor with a targeted anti-angiogenic agent had been proved to be effective for lung cancer. Penpulimab (AK105) was engineered to eliminate FcγR binding and antibody-dependent cell-mediated cytotoxicity (ADCC)/ antibody-dependent celluar phagocytosis (ADCP) completely, where ADCC/ADCP effects could induce T-cell apoptosis and clearance and therefore compromise anti-tumor activity. Penpulimab demonstrated a slower programmed death-1(PD-1) antigen binding off-rate, which resulted in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1. These structural differentiations enhance the anti-tumor activity of penpulimab and improve its safety. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Anlotinib has been approved by National Medical Products Administration as the treatment for small cell lung cancer (SCLC) patients, who had progressed/relapsed on or after at least two regimens of chemotherapy. Here we report the results of one cohort which received penpulimab plus anlotinib in a Phase II study. Methods: In Cohort 4 of an open-label, multi-center, multi-cohort Phase II study evaluating the efficacy and safety of penpulimab plus anlotinib in pts with advanced head, neck or chest tumors(NCT04203719), the SCLC patients, who failed to platinum-based systemic chemotherapy treatment, received penpulimab (200 mg IV Q3W) and anlotinib (12/10 mg PO 2 weeks on/1 week off). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival. Results: 20 patients (median age was 61 [range:37–75] years old, Eastern Cooperative Oncology Group performance status 0/1 [5%/95%], male/female [65%/35%]) were enrolled and received combination therapy (17 received 12 mg anlotinib, 3 received 10 mg anlotinib; and all received 200 mg penpulimab). At data cut-off (Jan 25, 2021), the confirmed ORR was 50.0% (10/20, 1 complete response and 9 partial response) and DCR was 75.0% (15/20). 9 PFS events (45%) had occurred, and the median PFS was 4.7 months (95% CI: 3.6-not reached). Grade 3 treatment-related adverse events (TRAEs) occurred in 30% (6/20, 2 hypertension, 1 hypertriglyceridaemia, 1 gamma-glutamyltransferase increased, 1 palmar-plantar erythrodysaesthesia syndrome and 1 hyponatraemia) of patients, No Grade 4 or 5 TRAEs had occurred. Conclusions: Penpulimab plus anlotinib showed favorable antitumor activity and an acceptable safety profile in SCLC patients who failed to platinum-based systemic chemotherapy. This new combination therapy warrants further evaluation for the treatment of SCLC. Clinical trial information: NCT04203719.

Comprehensive analysis of somatic reversion mutations in homologous recombination repair genes in a large cohort of Chinese pan-cancer patients.

e15093 Background: Mutations leading to homologous recombination deficiency increases the sensitivity towards platinum-based chemotherapy, as well as the PARP inhibitor. The acquired resistance caused by reversion mutations diminishes the prolonged benefit from the treatment. Herein, we aimed to investigate the prevalence and characteristics of reversion mutations in Chinese population. Methods: The next-generation sequencing data from 23,712 pan-cancer patients (including over 17 cancer types) were retrospectively analyzed for pathogenic/likely pathogenic (P/LP) germline mutations in homologous recombination repair (HRR) genes and possible somatic reversion mutations emerged later. Somatic mutations predicted to restore the open reading frame were identified and further classified into definitive or putative reversion mutations depending on whether the somatic mutation could be confirmed to occur on the same allele as the germline mutation by sequencing reads. Results: From the 23,712 patients, 685 (2.9%) were identified with P/LP germline HRR gene mutations, among which we identified 11 cases with 21 definitive and 4 putative somatic reversion mutations upon treatment, including 8 cases of breast cancer, 3 cases of ovarian cancer, 1 case of pancreatic cancers, and another case of lung cancer. The reversion mutations occurred in 3 genes: BRCA1 (7 cases), BRCA2 (5 cases) and PALB2 (1 case), but not in any other HRR genes in our cohort. Therefore, the incidence of reversion mutations in HRR genes was 1.6% (11/685), with the highest incidence observed in BRCA1 (5.26%) followed by BRCA2 (2.7%) and PALB2 (1.96%). Interestingly, multiple somatic reversion mutations could be observed in 3 patients, indicating heterogeneity in the resistance mechanisms. Among 6 patients with detailed treatment history available, 5 of them had reversion mutations detected after systemic platinum-based chemotherapy and/or PARP inhibitor treatment. The other patient of metastatic breast cancer had 6 prior lines of treatment including 2 cycles of thoracic perfusion of endostatin and lobaplatin before BRCA2 reversion mutation was detected. This patient subsequently received olaparib monotherapy with a progression free survival of only 2 months. Conclusions: This retrospective study demonstrated that the reversion mutations were observed in three HRR-associated genes ( BRCA1, BRCA2 and PALB2) with four cancer types (breast cancer, ovarian cancer, lung cancer and pancreatic cancer) from this Chinese patient cohort. The reversion mutations frequently occurred after resistance to platinum-based chemotherapy and/or PARP inhibitor, and may predict poor outcome from ensuing PARP inhibition therapy. Therefore, monitoring HRR mutation status along the course of the disease could be beneficial especially to informing resistance mechanism and guiding subsequent therapies.

Treatment patterns and outcomes among patients with microsatellite stable (MSS) advanced endometrial cancer in the United States: Endometrial Cancer Health Outcomes (ECHO) retrospective chart review Study.

5581 Background: Traditional platinum-based systemic chemotherapy continue to be the SOC for aEC in the first line. Phase 2 clinical trials of chemotherapy (GOG 129 series) and some targeted therapies (229 series) for second line advanced endometrial cancer (aEC) have proved disappointing. Recently the treatment landscape for aEC patients has significantly changed with newer targeted therapies focusing on the microsatellite instability (MSI) status of endometrial tumors. The objective of the ECHO study was to describe real-world treatment patterns and outcomes in non-MSI-high or DNA mismatch repair proficient (pMMR) aEC patients in clinical practice in the United States (US) prior to 2019. Methods: The ECHO study is a multicenter, retrospective chart review study in women diagnosed with aEC in the US. Data were obtained from medical records of adult women (≥18 years) diagnosed with advanced or inoperable aEC (stages III or IV) with known MSI status, who had received at least one prior systemic therapy and progressed between July 1, 2016 – June 30, 2019. De-identified patient data extracted by treating oncologists included patient demographics, clinical and treatment characteristics, and clinical outcomes. Kaplan-Meier analyses were performed to estimate real-world progression-free survival (rwPFS) and overall survival (OS). Results: A total of 124 non-MSI-high or pMMR aEC patients who had progression following first line therapy were included in this interim analysis. Average age was 63 years, 62.9% White/Caucasian, 16.9% Hispanic/Latino, and 86% had ECOG ≤1. Metastases were observed in 70% of patients at diagnosis, with the most common metastatic sites being lung (47.6%), liver (32.3%), and distant lymph nodes (29%). As 2nd line therapy, 69% of patients received mono or combination chemotherapy (primarily with doxorubicin), 13% hormonal therapy, and 18% targeted therapy ± chemotherapy. Median duration of 2nd line therapy was 4 months. The majority (86.3%) discontinued 2nd line therapy, with disease progression the most common reason (66.4%). A quarter (26.6%) of patients initiated an additional line of therapy. Median rwPFS from initiation of 2nd line therapy was 5 months (95% confidence interval [CI]: 4-9). Median OS from initiation of 2nd line therapy was 12 months (95%CI: 9-18). Estimated OS rates from initiation of 2nd line therapy at 6, 12, and 24 months were 66%, 47%, and 30%, respectively. Conclusions: In this retrospective, chart review study, patients with non-MSI-high/pMMR aEC in the US who failed at least one systemic therapy had poor prognosis on subsequent therapies. There continues to be a significant unmet need in this group of women. Novel therapies are needed that delay progression and/or improve overall survival and further research is indicated to explore this.

A phase II study of PRV111 nanoengineered cisplatin patch as a neoadjuvant therapy for early-stage oral squamous cell carcinoma (OSCC).

6056 Background: OSCC is a devastating disease causing substantial morbidity and mortality. Despite advancements in the conventional therapeutic approaches, surgical resection often leads to permanent disfigurement, while radiotherapies and systemic platinum-based chemotherapy result in significant toxicities, affecting patient wellbeing and quality of life. Thus, development of novel therapeutic approaches is paramount to improve health outcomes and survival of patients with OSCC. Systemic toxicity is often dose limiting, but could be tentatively reduced by locoregional administration. We have developed PRV111, a nanotechnology based patch for local and regional delivery of highly concentrated potent cisplatin, designed to penetrate tumor tissue, reach and enter regional lymph nodes and avoid systemic circulation. Here we present the results of phase 1/2 CLN-001 trial, designed to improve efficacy and reduce toxicity by neoadjuvant treatment with PRV111. Methods: A phase 1/2, single arm, open-label CLN-001 (NCT03502148) study has enrolled 12 patients with confirmed OSCC; unknown nodal involvement, no distant metastasis, and tumor size ≤ 4.0 cm. Three weeks prior to surgery, patients were administered 1 cycle of standalone neoadjuvant PRV111, consisting of up to 4 treatment visits (each visit dose: ≤12mg of cisplatin, each patch loading dose: 2mg of cisplatin). The primary endpoints were safety, efficacy and tumor reduction in ̃ 7 days by greater than 30%. Secondary endpoints included nanoengineered patch consistent and complete adhesion to mucosal surfaces and uniform drug release. Exploratory endpoints included immunogenesis/immunomodulation. Results: PRV111 successfully met all clinical primary endpoints, as well as safety and efficacy objectives. It caused over 70% tumor reduction in ̃7 days with over 87% response rate across 10 subjects. No dose-limiting toxicities, serious adverse event, or systemic toxicities were reported and no locoregional recurrences were evident in 6 months. PRV111 induced ̃15 times increase in tumor infiltrating lymphocytes compared with the initial biopsy. Concentrations of cisplatin found in the tumor and regional lymph nodes were over 300 and 100 times higher respectively as compared with IV cisplatin, with only negligible amount of cisplatin found in the blood. Grade 1 or 2 oral and tongue pain induced by the treatment were the most common adverse events. Furthermore, 97.5% successful patch performance was achieved across 182 patches used in the study. Conclusions: Adding neoadjuvent PRV111 to the care for patients with OSCC may improve the surgical outcome and increase event free survival. Given these encouraging results, future studies are needed to establish the application of this non-invasive platform in head and neck SCC and other epithelial cancers, including anal, colorectal, genitourinary, nasal, and skin. Clinical trial information: NCT03502148.