Platinum-based Combination Chemotherapy Research Articles

Prognostic Potential of Metabolic Activity on 18 F-FDG Accumulation in Advanced NSCLC Receiving Combining Chemotherapy Plus PD-1 Blockade.

Combined chemotherapy plus programmed death-1 (PD-1) blockade is an established treatment against patients with advanced non-small cell lung cancer (NSCLC). However, a promising predictor besides programmed death ligand-1 expression remains uncertain. We examined the prognostic significance of baseline 18 F-FDG-positron emission tomography for predicting first-line combined chemotherapy plus PD-1 blockade in NSCLC patients. Forty-five patients with advanced NSCLC who received 18 F-FDG-positron emission tomography immediately before combined platinum-based chemotherapy with PD-1 blockade as first-line setting were eligible for this study, and assessment of maximum of standard uptake value (SUV max ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18 F-FDG uptake was performed. The objective response rate, median progression-free survival, and overall survival were 51.2%, 206 days, and 681 days, respectively. High SUV max , TLG, and MTV significantly correlated with age and performance status (PS), C-reactive protein (CRP), and PS, CRP, albumin, and baseline tumor size, respectively. Univariate analysis identified albumin, TLG and MTV as significant predictors of progression-free survival, and CRP, albumin, TLG and MTV as significant factors for predicting overall survival. High TLG was confirmed as an independent factor associated with poor prognosis in multivariate analysis. In particular, TLG is identified as the most powerful predictor in patients with good PS, adenocarcinoma, programmed death ligand-1≥1%, and low baseline tumor size. The tumor metabolic volume by MTV and TLG at pretreatment was clarified as a significant predictor for combined chemotherapy with PD-1 blockade, but not maximal glycolytic level by SUV max .

KMT2C mutation in a Chinese man with primary multidrug-resistant metastatic adenocarcinoma of rete testis: a case report

BackgroundAdenocarcinoma of the rete testis (AORT) is an extremely rare malignant tumor with poor prognosis and limited responsiveness to traditional chemotherapy. Few previous studies have focused on the molecular mechanisms underlying therapy resistance in AORT and further scrutiny is required to enable searches for targeted drugs to guide treatment selection.Case presentationThe current case concerns a 55-year-old man with AORT who presented with isolated bone metastasis at initial diagnosis and experienced rapid disease progression after multi-line platinum-based combination chemotherapy. Next-generation sequencing revealed a novel somatic lysine methyltransferase 2C (KMT2C) c.5605 T > C mutation in exon 36 with an abundance of 49.27%. The patient received antiangiogenic drug treatment for 2 months but this was discontinued due to unacceptable anorexia and nausea. He survived for 12 months after diagnosis.ConclusionA potential correlation between AORT primary multi-drug resistance and KMT2C mutations is implied. Further studies are needed to determine the efficacy of PARP1/2 inhibitors for tumors with KMT2C mutations.

Opportunities and challenges of immune checkpoint inhibitors for extensive-stage small-cell lung cancer.

Small-cell lung cancer (SCLC) accounts for 15%-20% of primary lung cancers, and it is characterized by low differentiation, rapid proliferation, and early metastasis. At least two-thirds of SCLC patients present with the extensive stage (ES) at the time of initial clinical diagnosis. Over the last 2 decades, platinum-based combination chemotherapy has remained the standard first-line treatment for SCLC. With the introduction of the immunotherapy era, immunotherapy plus chemotherapy has replaced conventional chemotherapy as the first-line treatment option for ES-SCLC and is recommended by National Comprehensive Cancer Network clinical guidelines. Therefore, in this review, we present the latest research advances in SCLC treatment, predictive biomarkers, and other topics of high interest to provide options for patients with SCLC.

Long-term survival of early stage I epithelial ovarian cancer: A multicenter retrospective observational study (321)

<b>Objectives:</b> Therapy for early-stage epithelial ovarian cancer (EOC) involves complete surgical staging with or without adjuvant chemotherapy. The current international multi-center study aimed to investigate the long-term survival of different histological subtypes for stage I EOC. <b>Methods:</b> A multi-center cohort study was performed among all patients with FIGO stage I (IA-IC3) EOC treated at four European referral centers between 1985 and 2021. Overall survival (OS) and progression-free (PFS) survival were compared between the different stage I groups using Kaplan-Meier survival curves. <b>Results:</b> A total of 1115 patients met the inclusion criteria. Of them, 48.4% (<i>n</i>=540) were in stage IA, 6.6% (<i>n</i>=73) stage IB, and 45% (<i>n</i>=502) stage IC: stage IC1 54% (<i>n</i>=271), stage IC2 31.5% (<i>n</i>=158), and stage IC3 14.5% (<i>n</i>=73). The predominant histologic subtypes included highgrade serous (25.4%), low-grade endometrioid (24.8%), and clear cell (19%). Complete surgical staging, including lymphadenectomy, was performed in 62.1%, and 60% received adjuvant platinum-based chemotherapy. The median follow-up was 48 months. The median five-year (5y) OS and PFS rates were 94% and 86%, respectively, with no difference between stage IA and IB. However, a significantly better OS and PFS were observed for stage IA as compared to stage IC (p=0.007 and p<0.001, respectively). Considering histologic subtypes, a significant better PFS was documented for low-grade mucinous and low-grade endometrioid subgroup (HR: 0.22; 95% CI: 0.09-0.45, p=0.001; HR: 0.49; 95% CI: 0.29-0.83, p=0.007, respectively), as well a better OS for the latter (HR: 0.43; 95% CI: 0.22-0.86, p=0.017). In stage IA-B, the different histology subtypes showed a comparable prognosis (5y: OS: 96% and PFS: 92%), with the exception of a worsened OS for high-grade mucinous cases (HR: 5.90; 95% CI: 1.55-22.4, p=0.009). Among stage IC, the histologic subgroups showed comparable OS (5y 92%), but significantly better PFS for low-grade mucinous and low-grade endometrioid subtypes (HR: 0.21; 95% CI: 0.05-0.86, p=0.031; HR: 0.44; 95% CI: 0.23-0.84, p=0.013, respectively). In the subgroup of high-grade serous ovarian cancer patients in stage IC disease, the chemotherapy with carboplatin/paclitaxel seems to be superior compared to single-agent platinum (5y OS: 100% vs 83%; p=0.009). In multivariate analysis, partial staging procedure (compared to complete) was found as risk factor for worsen PFS (HR: 1.73; 95% CI: 1.13-2.66, p=0.012), while low-grade endometrioid histology (compared to high-grade serous) showed better outcome regarding OS (HR: 0.46; 95% CI: 0.22-0.95, p=0.036) and PFS (HR: 0.42; 95% CI: 0.25-0.73, p=0.002). <b>Conclusions:</b> Overall, stage I ovarian cancer patients treated in referral centers exhibited an excellent prognosis regardless of the histologic type. Histologic subtype and quality of surgical treatment affect the prognosis. Our data suggest platinum-based combination chemotherapy for the subgroup of FIGO stage IC high-grade serous ovarian cancer.

Donor-Derived Ovarian Cancer in a Male Recipient After Kidney Transplant: A Case Report

Patients who receive kidney transplants and experience long-term immunosuppressive therapy are tied to higher risk of developing cancers. Reports concerning about donor-associated cancers are rarely reported, especially for male ovarian cancer. Here we report a case of donor-derived ovarian malignancy of a man after 3 years of renal transplantation. This case complied with the Helsinki Congress and the Istanbul Declaration. The donor is the recipient's mother who developed ovarian malignancy 6 months after the transplantation surgery and died 1.5 years later after diagnosis due to tumor progression. The patient devolved into abnormal renal function 3 years after the transplantation. The transplanted kidney lost its function and was subsequently surgically removed. The ovary cancer was confirmed as high-grade serous ovarian cancer by pathology and had potentially metastasized to donor kidney. Then the male patient received regular maintenance and dialysis. Four years after transplantation, he gradually developed the symptoms of coughing and sputum and computed tomography examination revealed a lung space-occupying lesion that was confirmed to be a metastatic tumor with the same pathology as before. Platinum-based combination chemotherapy can effectively control the condition; by the last follow-up evaluation, the progression-free survival of the patient was 23.5 months, and the overall survival was 36 months. This case demonstrates that donor-derived ovarian tumor can be transferred into the recipient via the transplanted kidney even in the male recipient. This observation provides clinicians with effective treatment options for this rare type of patient population.

Abstract CT212: A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations

Abstract Background: HER2 mutations are present in 2-4% of NSCLC tumors; of these ~50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, EGFR-targeted agents that inhibit mutant HER2 are associated with off-target wild type-related toxicities. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combinations regimens, and the risk of ILD with ADCs. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). Methods: It is planned that ~96 pts from 3 sites in the US, Netherlands, and Japan will be recruited. In Phase Ia, consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID (~36 pts); QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg [~30 pts]). BI 1810631 dose escalation will continue (guided by Bayesian Logistic Regression Model) until MTD and/or RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. In Phase Ib an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Overall pt inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ (defined as overexpression, gene amplification, non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1) advanced, unresectable and/or metastatic solid tumors refractory/not suitable for standard therapy; exhausted treatment options; measurable or evaluable lesions (according to RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on the number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, PFS, disease control, and duration of disease control (Phase Ib). The trial is actively recruiting; 5 pts have been enrolled to date and 2 dose levels have been completed. Citation Format: John Heymach, Frans Opdam, Minal Barve, Neil Gibson, Behbood Sadrolhefazi, Josep Serra, Noboru Yamamoto. A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations [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 CT212.

A randomized phase II trial of mirvetuximab soravtansine (IMGN853), in folate receptor alpha (FRα)-high recurrent ovarian cancer eligible for platinum-based chemotherapy.

TPS5618 Background: Despite radical primary surgery and carboplatin/paclitaxel-based chemotherapy in combination with anti-angiogenic bevacizumab and/or PARP inhibitors (PARPi), most patients (pts) with advanced ovarian cancer (OC) will relapse. Following the implementation of these targeted therapies to first-line treatment, repeated use of bevacizumab and/or PARPi is often not approved nor has conclusively been proven efficacious for all pts with recurrent OC. New combination partners for platinum-based chemotherapy remain important to improve outcome. The antibody-drug conjugate Mirvetuximab soravtansine (MIRV) is comprised of a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. Results from the phase III trial FORWARD I revealed in an exploratory analysis that pts with high FRα expression following PS2+ Scoring (cut off: ≥75% of tumor cells with FRα membrane staining and ≥ 2+ intensity) had significant progression-free survival (PFS) improvements with a hazard ratio of 0.55 compared to mono-chemotherapy (median PFS 5.6 vs 3.2 months, P=0.015) and high activity was most recently confirmed in the SORAYA trial with an overall response rate (ORR) of 32.4%. Preliminary data for the combination of MIRV with carboplatin exist from the Phase 1b FORWARD II trial, which resulted in an ORR of 71%, observed in 17 pts with a median PFS of 15 months, and an ORR of 80% in the FRα medium/high (&gt;50% PS2+) subset of 10 pts. MIRV is well-tolerated with a manageable safety profile. Methods: Eligible pts for this multicenter, randomized, two-arm, open-label, comparative phase II trial must have recurrent, FRα high epithelial cancer of the ovary, fallopian tube or peritoneum and have measurable disease. Pts are eligible for platinum-based chemotherapy with a platinum-free interval of more than 3 months and had at least one prior chemotherapy, but are not candidates to receive bevacizumab for the current relapse. Pts can be included irrespective of wildtype BRCA1/2 mutation status, pts with a deleterious mutation are required to have received prior PARPi therapy. Following pre-screening for high FRα expression in FFPE tumor tissue according to PS2+ scoring, 136 pts are randomized (1:1) to: a) Control arm: Platinum-based combination chemotherapy (for 6 cycles) followed by PARPi if indicated or standard of care or b) Experimental arm: Carboplatin + MIRV 6 mg/kg adjusted ideal body weight (AIBW) IV d1 (6 cycles q21d) followed by MIRV monotherapy 6 mg/kg AIBW IV q21d until disease progression. The primary endpoint of PFS will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, ORR, and quality of life. Enrollment started in September 2021. Clinical trial information: NCT04274426.

A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced/metastatic solid tumors with HER2 aberrations.

TPS9143 Background: HER2 mutations are present in 2–4% of NSCLC tumors; of these ̃50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. Historically, ex20ins mutations have responded poorly to TKIs. Moreover, TKIs that inhibit both mutant EGFR and HER2 are typically limited by toxicities associated with inhibition of wild-type EGFR. Despite the promise of trastuzumab deruxtecan and other agents in this setting, the development of orally available selective TKIs is important given the heterogeneity of HER2 aberrations, potential for combination regimens, and the risk of ILD with ADCs. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type and mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This Phase Ia/Ib, open-label, non-randomized study aims to determine the safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). Methods: ̃96 pts from 5–7 sites in the US, Netherlands, Japan, and China will be recruited. Phase Ia: consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID (̃36 pts); QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg [̃30 pts]). BI 1810631 dose escalation will continue until MTD/RP2D for each schedule is determined, as well as a preferred Phase Ib schedule. Phase Ib: an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Overall pt inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ (defined as overexpression, gene amplification, non-synonymous somatic mutation, or gene rearrangement involving HER2 or NRG1) advanced/unresectable/metastatic solid tumor refractory/not suitable for standard therapy; exhausted treatment options; measurable/evaluable lesions (per RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, disease control, duration of disease control, and PFS (Phase Ib). The trial is actively recruiting with 6 pts enrolled to date. More patients may be recruited depending on whether 2 dose levels have been completed and the MTD/RP2D determined. Clinical trial information: NCT04886804.

Randomized Trial of Cytoreductive Surgery for Relapsed Ovarian Cancer

(Abstracted from N Engl J Med 2021;385:2123–2131) Standard of care treatment for advanced ovarian cancer involves primary macroscopic resection of all tumor followed by platinum-based combination chemotherapy with or without additional systemic therapy including bevacizumab or a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor. The Descriptive Evaluation of Preoperative Selection Criteria for Operability in Recurrent Ovarian Cancer (DESKTOP) series aims to assess the role of surgery in management of recurrent ovarian cancer.

79TiP A phase I, open-label, dose escalation, confirmation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations

HER2 mutations are present in 2–4% of NSCLC tumors; of these ∼50% are exon 20 insertion (ex20ins) mutations. There is an unmet need for effective targeted therapy against HER2 mutations in solid tumors, particularly in NSCLC. BI 1810631 is a HER2 selective TKI that covalently binds to both wild-type/mutated HER2 receptors, including ex20ins, whilst sparing EGFR signaling; preclinical data suggest good tolerability and efficacy. This phase Ia/Ib, open-label, non-randomized study aims to determine safety, MTD, PK, pharmacodynamics, and preliminary efficacy of BI 1810631 in pts with HER2+ solid tumors (NCT04886804). ∼96 pts from 3 sites in the US, Netherlands, and Japan will be recruited. Phase Ia: consecutive cohorts of pts will receive BI 1810631 QD or BID at escalating doses. Starting dose level: 15 mg BID; QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee (expected starting dose: 60 mg). BI 1810631 dose escalation will continue until MTD and/or RP2D is determined, as well as preferred phase Ib schedule. Phase Ib: an initial 30 pts with HER2 ex20ins mutation-positive, pre-treated NSCLC will be enrolled, with possible inclusion of additional cohorts in the future. Inclusion criteria (Phase Ia): ≥18 years of age; histologically/cytologically confirmed HER2+ advanced, unresectable and/or metastatic solid tumors refractory/not suitable for standard therapy; exhausted treatment options; measurable or evaluable lesions (according to RECIST v1.1); ECOG PS ≤1. Phase Ib criteria: HER2 ex20ins mutation-positive NSCLC; received ≥1 line of platinum-based combination chemotherapy in the advanced/metastatic setting. Primary endpoints: MTD based on the number of DLTs/number of pts with DLTs (Phase Ia); objective response (Phase Ib). Secondary endpoints: number of pts with DLTs throughout entire treatment period and PK parameters (Phase Ia/Ib); duration of response, PFS, disease control, and duration of disease control (Phase Ib). The trial is actively recruiting; 5 pts have been enrolled to date and 2 dose levels have been completed. NCT04886804. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Rick Burgon, of Ashfield MedComms, an Ashfield Health Company, during the development of this abstract. Boehringer Ingelheim.

Effect of kangai injection combined with platinum-based chemotherapy on the immune function of patients with advanced non-small-cell lung cancer: A meta-analysis

BackgroundKangai injection (KAI) is a well-known Chinese patent medicine applied for several different types of cancers in the clinic as an auxiliary therapeutic approach, which is refined from three herbal extracts (Astragalus, Ginseng and Matrine). PurposeTo systematically evaluate the effect of combination treatment of platinum-based chemotherapy and KAI on patients with advanced non-small-cell lung cancer (NSCLC). Study designA meta-analysis of randomized clinical trials. Materials and methodsThe randomized controlled trials (RCTs) about stage Ⅲ-Ⅳ NSCLC using KAI combined platinum-based chemotherapy were electronically retrieved from eight electronic databases up to July 2021. We applied RevMan 5.4, Stata 16.0, TSA 0.9.5.10 Beta and GRADE Pro-GDT to evaluate the quality of the included RCTs and perform the meta-analysis. Results19 RCTs were included, consisting a total sample size of 1,389 cases. Meta-analysis revealed that compared with chemotherapy alone, KAI combined with platinum-based chemotherapy was associated with significantly higher objective response rate (ORR) [RR = 1.36, 95%CI (1.21,1.54), p< 0.00001], higher disease control rate (DCR) [RR = 1.15, 95%CI (1.09,1.21), p< 0.00001], greater Karnofsky performance status (KPS) [RR = 1.75, 95%CI (1.41,2.18), p< 0.00001], lower white blood cell toxicity [RR = 0.67, 95%CI (0.55,0.82), p = 0.0001], lower platelet toxicity [RR = 0.60, 95%CI (0.47,0.75), P < 0.0001], and lower incidence of vomiting [RR = 0.66, 95%CI (0.57,0.76), p< 0.00001]. In terms of the immune function, KAI united with chemotherapy significantly raised the ratio of CD3+ cells [MD = 10.65, 95%CI (8.21,13.09), p< 0.00001], CD4+ cells [MD = 7.67, 95%CI (6.31,9.03), p< 0.00001], NK cells [MD = 4.97, 95%CI (3.03,6.92), p< 0.00001], and CD4+/ CD8+ [MD = 0.32, 95%CI (0.19,0.45), p< 0.00001], and decreased the percentage of CD8+ cells [MD = -5.56, 95%CI (-7.51,-3.61), p< 0.00001]. ConclusionsThis meta-analysis identified that the combination treatment of KAI and platinum-based chemotherapy was more beneficial to patients with advanced NSCLC when compared to chemotherapy alone, which could significantly improve the clinical efficacy, enhance the immune function, and reduce chemotherapy toxicity. Our study provides a theoretical basis and treatment guidance for patients with NSCLC.

The Role of Surgery in High-Grade Neuroendocrine Cancer: Indications for Clinical Practice.

Pulmonary neuroendocrine tumors (pNET) represent a particular type of malignant lung cancers and can be divided into well-differentiated low-grade NET and poorly-differentiated high-grade NET. Typical and atypical carcinoids belong to the first group while large cell neuroendocrine carcinomas (LCNEC) and small-cell lung cancers (SCLC) belong to the second one. The aim of this mini-review is to focus on the role of surgical therapy for high grade neuroendocrine tumors. SCLC has the worst prognosis among all lung cancer neoplasms: in fact, the two-year survival rate is about 5% and median survival usually ranges between 15 and 20 months. The surgical treatment of SCLC has thus infrequently been judged as a valuable aspect of the therapeutic approach, the gold standard treatment being a combination of platinum-based chemotherapy and radiotherapy. As LCNEC are rare, there is a lack of extensive literature and randomized clinical trials, therefore the curative approach is still controversial. Current treatment guidelines suggest treating LCNEC by surgical resection in non-metastatic stages and recommend adjuvant chemotherapy according to SCLC protocol. Upfront surgery is suggested in early stages (from I to IIB), a multimodality approach is recommended in locally advanced stages (III) while surgery is not recommended in stage IV LCNEC. The rate of surgical resection is quite low, particularly for SCLC, ranging from 1 to 6% in limited diseases; lobectomy with radical lymphadenectomy is considered the gold standard surgical procedure in the case of limited disease SCLC and resectable LCNEC; pneumonectomy, although reported as an effective tool, should be avoided in the light of local and distant recurrence rates.

A prospective clinical trial of camrelizumab in combination with chemoradiotherapy in patients with metastatic esophageal squamous cell carcinoma.

326 Background: Patients with metastatic esophageal squamous cell carcinoma (mESCC) have dismal prognosis, immune checkpoint inhibitors (ICIs) have been reported to offer objective response rate (ORR) of approximately 30% with a median progression-free survival (PFS) of 3.6 months for mESCC. Emerging evidence suggests that radiation might be a potent immunomodulator in multiple malignancies. In this trial, we aimed to assess the efficacy and safety of the combination of camrelizumab with radiotherapy and chemotherapy in mESCC. Methods: Patients with ECOG performance status of 0-1 and normal renal, liver and bone marrow function who initially diagnosed with mESCC or progressed after prior systemic treatments were received camrelizumab 200 mg of 21-day cycles plus radiotherapy (30-50Gy/10-25f) and platinum-based combination chemotherapy. The primary endpoint was disease control rate (DCR); secondary endpoints were PFS, overall survival (OS), objective response rate (ORR) and safety. Chinese Clinical Trial Registry identifier: ChiCTR2000040533. Results: From September 2018 to March 2021, 34 patients (85.3% men; median age, 60 years; 85.3% ECOG PS=1; 61.8% ≥2 organ metastases) were recruited. At a median follow-up of 14.3 months, the DCR was 70.6% (24 of 34; 95%CI, 52.3 to 84.3); ORR was 38.2% (13 of 34; 95%CI, 22.7 to 56.4); 44.1% had decrease in measurable disease; ≥6 months clinical benefit rate (CBR) was 41.2% (14 of 34; 95%CI, 25.1 to 59.2). Median PFS and OS of 9.5 months (95% CI, 7.1 to NR) and 19.5 months (95% CI, 13.9 to NR), respectively. Of the 34 patients, 32 (94.1%) had treatment-related adverse events (TRAEs) of any grade and 13 (38.3%) had grade 3-4 TRAEs that including reactive cutaneous capillary endothelial proliferation (17.6%), myelotoxicity (23.5%) and interstitial pneumonia (2.9%). No treatment-related death occurred. To the cut-off date of observation, 15 (44.1%) patients died and 12 (35.3%) are still receiving the treatment without events. Conclusions: The combination of camrelizumab with radiotherapy and chemotherapy has notable efficacy compared with historical controls in mESCC with manageable safety. This combination therapy strategy should be validated in a larger trial in the future. Variable N=34 Clinical trial information: ChiCTR2000040533. [Table: see text]

Current Advances in Immune Checkpoint Inhibition and Clinical Genomics in Upper Tract Urothelial Carcinoma: State of the Art.

Upper tract urothelial carcinoma (UTUC) is a rare and challenging-to-treat malignancy. In most patients it is a sporadic tumor entity, less commonly it falls on the spectrum of Lynch syndrome, an autosomal dominant familial tumor syndrome. Localized UTUC with high-risk features as well as the metastatic disease scenario might require systemic therapy. Platinum-based combination chemotherapy is currently the recommended management option. However, the introduction of immune checkpoint inhibitors into the therapeutic armamentarium has led to a paradigm shift in treatment standards. Immunotherapy has been shown to be safe and effective in treating at least metastatic UTUC, although UTUC-specific high-level evidence is still lacking. Recent technological advances and noteworthy research efforts have greatly improved the general understanding of the biological landscape of UTUC. According to the main findings, UTUC represent a particular subtype of urothelial carcinoma frequently associated with activated FGFR3 signaling, a luminal–papillary phenotype and a T-cell-depleted microenvironment. This improved knowledge promises precision oncology approaches that match treatment decision strategies and genomic profile to ultimately result in better clinical outcomes. The aim of this review was to summarize the main currently available evidence on immune checkpoint inhibition and clinical genomics in UTUC.

Pretreatment Fibrinogen-Albumin Ratio (FAR) Associated with Treatment Response and Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Anti-PD-1 Therapy Plus Platinum-Based Combination Chemotherapy.

PurposePD-1 inhibitors have been routinely used to treat advanced non-small cell lung cancer (NSCLC) and have significantly improved clinical outcomes. In this study, we aimed to explore the influence of pretreatment fibrinogen-albumin ratio (FAR) on treatment response and survival in advanced NSCLC patients treated with first-line anti-PD-1 therapy plus platinum-based combination chemotherapy.Patients and MethodsA total of 91 patients with advanced NSCLC were included in the study. All patients received at least two cycles of systemic first-line anti-PD-1 therapy plus platinum-based combination chemotherapy. Receiver operating characteristics analysis was performed to determine the optimal cutoff values of FAR. Univariate and multivariate analyses were used to identify independent prognostic factors, and the Kaplan–Meier method was used to estimate survival curves.ResultsMultivariate logistic regression analysis showed that N stage (N2-3) and high FAR (≥0.175, optimal cutoff value) were independent predictors for objective response rate (P = 0.0002, P = 0.0005, respectively). Multivariate Cox regression analysis of progression-free survival and overall survival showed that high FAR (≥0.145) was independent prognostic factors (P = 0.0061, P = 0.0024, respectively). Progression-free survival and overall survival were significantly shorter in the high FAR (≥0.145) group than those in the low FAR (<0.145) group (P = 0.0024, P = 0.0024, respectively).ConclusionPretreatment FAR was an independent predictor for treatment response and independent prognostic factors in advanced NSCLC patients treated with first-line anti-PD-1 therapy plus platinum-based combination chemotherapy.

Computed Tomography Image under Artificial Intelligence Algorithm to Evaluate the Nursing and Treatment Effect of Pemetrexed Combined Platinum-Based Chemotherapy on Elderly Lung Cancer.

This study was to evaluate the clinical efficacy of pemetrexed combined with platinum-based chemotherapy in the treatment of elderly lung cancer using electronic computed tomography (CT) images based on artificial intelligence algorithms. In this study, 80 elderly patients with lung cancer treated were selected and randomly divided into two groups: patients treated with pemetrexed combined with cisplatin were included in the pemetrexed group and patients treated with docetaxel combined with cisplatin were included in the docetaxel group, with 40 cases in each group. The DenseNet network was compared with the Let Net-5 and ResNet model and applied to the CT images of 80 elderly patients with lung cancer. The diagnosis accuracy of the DenseNet network (97.4%) was higher than that of the Let Net-5 network (80.1%) and ResNet model (95.5%). Carcinoembryonic antigen (CEA), cytokeratin fragment antigen 21–1 (CYFRA 21–1), and squamous cell-associated antigen (SCC) after chemotherapy in the pemetrexed group and docetaxel group were all lower than those before chemotherapy, showing statistically obvious differences (P < 0.05). The satisfaction degree of nursing care in the pemetrexed group (92.67%) was significantly higher than that in the docetaxel group (85.62%), and the difference was statistically significant (P < 0.05). Adverse reactions such as fatigue, diarrhea, and neutrophils in the pemetrexed group were lower than those in the docetaxel group, and the difference was statistically great (P < 0.05). The DenseNet convolutional neural network has high diagnostic accuracy; methotrexate combined with platinum chemotherapy can improve the chemotherapy effect in elderly patients with lung cancer, with low degree of adverse reactions and good overall tolerance, which can be used as the first-line treatment for elderly patients with lung cancer.

Real-world outcomes in patients with advanced endometrial cancer: A retrospective cohort study of US electronic health records

ObjectivesTo characterize clinical outcomes of women with advanced/recurrent endometrial cancer (AEC) in routine practice using electronic health records from a real-world database. MethodsAdult women diagnosed with AEC (stage III/IV, or early stage with locoregional/distant recurrence) between January 1, 2013 and September 30, 2020, inclusive, were eligible provided they received platinum-based chemotherapy at any time following diagnosis and had ≥2 clinical visits. Follow-up was from initiation of systemic treatment after advanced diagnosis (index) until March 30, 2021, last available follow-up, or death, whichever occurred first. Outcomes, by histological subtype, included Kaplan–Meier estimates of overall survival (OS) and time to first subsequent therapy or death (TFST). ResultsOf the 2202 women with AEC, most were treated in a community setting (82.7%) and presented with stage III/IV disease at initial diagnosis (74.0%). The proportion with endometrioid carcinoma, uterine serous carcinoma (USC), and other AEC subtypes was 59.8%, 25.0%, and 15.2%, respectively. The most common first systemic treatment following advanced/recurrent diagnosis was platinum-based combination chemotherapy (82.0%). Median OS (95% CI) from initiation of first systemic treatment was shorter with USC (31.3 [27.7–34.3] months) and other AECs (29.4 [21.4–43.9] months) versus endometrioid carcinoma (70.8 [60.5–83.2] months). Similar results were observed for TFST. Black/African American women had worse OS and TFST than white women. ConclusionsWomen with AEC had poor survival outcomes, demonstrating the requirement for more effective therapies. To our knowledge, this is the most comprehensive evaluation of contemporary treatment of AEC delivered in a community setting to date.

Abstract P05-01: A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors

Abstract Background KRAS p.G12C is an oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Sotorasib, a specific, irreversible KRASG12C inhibitor, was recently approved by the FDA for treatment of adults with KRAS p.G12C-mutated locally advanced or metastatic NSCLC who received at least one prior systemic therapy. Sotorasib combined with trametinib, a selective allosteric MEK1/MEK2 inhibitor, displayed synergist antitumor activity in tumor xenografts. Here we report the first safety and interim efficacy of sotorasib in combination with trametinib in advanced KRAS p.G12C-mutated solid tumors in this phase 1b CodeBreaK101 master study. Methods In this dose exploration/expansion study, patients (pts) with KRAS p.G12C-mutated solid tumors were treated with 960 mg QD sotorasib and trametinib (1 or 2 mg QD). For NSCLC, prior anti-PD1/PD-L1 and/or platinum-based combination chemotherapy and targeted therapy (if applicable) was required. For CRC, at least 1 prior systemic regimen including fluoropyrimidine, oxaliplatin, and irinotecan-based regimens was required. 1° endpoint was safety/tolerability. 2° endpoint was efficacy. Results Based on a July 12, 2021 snapshot, 41 pts (22 male, median age: 60.0 y [34-84]) were enrolled and treated with combination of sotorasib and trametinib (18 pts NSCLC, 18 pts CRC, 5 pts other). Thirty-three pts (80.5%) received ≥2 prior lines of therapy (range, 0–8); 11 pts (26.8%) received prior KRASG12C inhibitor. Median treatment duration of the sotorasib and trametinib combination was 84.0 days (Q1, 42.0; Q3, 140.0). No new or unexpected toxicities were identified. The most common treatment-related adverse events (TRAEs) included diarrhea (43.9% pts), rash (34.1% pts), nausea (29.3% pts), and vomiting (22.0% pts), predominantly ≤grade 2. Ten pts (24.4%) discontinued sotorasib and/or trametinib due to a TRAE (2 pts-diarrhea). One dose-limiting toxicity (grade 3 maculo-papular rash, trametinib-related) was observed out of 33 pts treated with 2 mg trametinib/960 mg sotorasib QD. For the 1 mg trametinib/960 mg sotorasib QD CRC exploration cohort (N=3); 1 confirmed partial response (PR) and 1 stable disease (SD) were reported in pts with prior KRASG12C inhibitor; 1 SD was reported in a KRASG12C inhibitor-naïve pt. For the 2 mg trametinib/960 mg sotorasib QD CRC cohort (N=15), all 4 pts with prior KRASG12C inhibitor had SD; for naïve pts, 1-confirmed PR, 7-SD, and 3-progressive disease (PD) were reported. In NSCLC pts (N=18) treated with 2 mg trametinib/960 mg sotorasib QD, of pts with prior KRASG12C inhibitor, 2-SD and 1-PD were reported; of naïve pts, 3-confirmed PR, 10-SD, 1-PD, and 1-not evaluable were reported. Conclusions Combination of sotorasib and trametinib is safe and tolerable. The maximum tolerated dose tested was 2 mg trametinib/960 mg sotorasib QD. Antitumor activity was observed including responses in pts with prior KRASG12C inhibitor. Triplet combination therapy of sotorasib with trametinib and panitumumab currently are under investigation in solid tumors. Citation Format: Suresh Ramalingam, Marwan Fakih, John Strickler, Ramaswamy Govindan, Bob T. Li, Sarah Goldberg, David Gandara, Timothy Burns, Minal Barve, Catherine Shu, Richard Frank, Davendra Sohal, Pegah Jafarinasabian, Tian Dai, Omar Mather, David Hong. A phase 1b study evaluating the safety and efficacy of sotorasib, a KRASG12C inhibitor, in combination with trametinib, a MEK inhibitor, in KRAS p.G12C-Mutated Solid Tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P05-01.

Clinical Outcomes of Three or More Courses of First-line Chemotherapy for Metastatic Urothelial Carcinoma.

The current standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma (UC) is platinum-based combination chemotherapy. Recently, immune checkpoint inhibitors have been reported to be effective for UC. Knowing whether immunotherapy or chemotherapy is suitable as first-line treatment is beneficial for patients. A retrospective study was conducted on the clinical outcomes of Japanese patients who received three or more courses of first-line chemotherapy for metastatic UC to assess the outcome of conventional treatments in real clinical situation. Patients who received first-line chemotherapy between August 2009 and December 2019 were included. Progression-free survival (PFS) and overall survival (OS) were assessed. The median PFS and OS were 7.1 and 27.1 months, respectively, for patients with no disease progression at the end of three courses. Of 28 patients, 25 (89.3%) received second-line drug therapy and 10 (35.7%) received focal therapy for disease control. Patients with focal therapy had significantly longer OS than those without focal therapy (p=0.019, log-rank test). OS of metastatic UC at our Institution is relatively long, suggesting that aggressive second-line drug therapy and focal therapy may have contributed to such result.

15 First-line platinum-based chemotherapy combined with PD-1/PD-L1 inhibitors (ICI) prevents hyperprogression in non-small cell lung cancer (NSCLC) patients by reducing circulating immature neutrophils

BackgroundHyperprogression (HPD) has been described in ≃14–26% of NSCLC patients upon single-agent ICI1 and has not been reported upon ICI and platinum-based chemotherapy (PCT) combinations. Both high circulating neutrophils2 and senescent T-cells3 correlated with HPD, however the exact neutrophils-T-cells interplay and the role of specific neutrophils subsets in driving HPD is unknown.MethodsNSCLC patients treated with 1st line ICI as single-agent or in combination with PCT were assessed for HPD and circulating neutrophils’ phenotype. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI – TGR before ICI) &gt;50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. T-cells were isolated from healthy donors and cocultured with patients‘ LDNs to characterize the neutrophils-T-cells interplay. LDNs subtypes were isolated from patients and treated in-vitro with cisplatin to assess cell death.Results46 NSCLC patients were treated with single-agent ICI and 17 with PCT+ICI (table 1). In the ICI single-agent cohort, PD and HPD occurred in 21 (41%) and 4 (9%) patients. Before ICI start, HPD patients had significantly higher median% of circulating immature CD10- LDNs neutrophils [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD patients (figure 1). In the ICI-PCT cohort no HPD was reported. 5 patients had baseline CD10- LDNs ≥ 43.5% (median% of CD10- LDNs in HPD patients upon single-agent ICI), 2 of them had stable disease and 3 PD upon ICI-PCT. In these 5 patients, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD patients upon single-agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03] (figure 2). After 7 days of coculture with T-cells, immature CD10- LDNs significantly reduced T-cells survival and promoted a T-cell senescent phenotype (CD28 loss, CD57 gain) impairing T-cells proliferation and increasing IFN-gamma production (figure 3). Cisplatin treatment significantly increased necrotic cell death among CD10- LDNs compared to CD10+ LDNs (figure 4).Abstract 15 Table 1Patients characteristics in the single-agent ICI and PCT+ICI cohortsAbstract 15 Figure 1Patterns of response, progression and hyperprogression to single-agent ICI and correlation with mature (CD10+) or immature (CD10-) LDNs’ subtypesAbstract 15 Figure 2Neutrophils dynamic variation upon treatment (5 patients with high baseline CD10- LDNs and PD/SD to chemo-ICI vs 4 patients with HPD upon single-agent ICI)Abstract 15 Figure 3Mature (CD10+) and immature (CD10-) LDNs in coculture with T-cells from an healthy donor differently influence CD8 and CD4 T-cells survival, proliferation, IFN-gamma production and expression of a senescent (CD28- CD57+) phenotype.Abstract 15 Figure 4Cisplatin in-vitro treatment at different concentration (1 uM and 5 uM) increases necrotic (7AAD expression) cell death preferentially of immature (CD10-) rather than mature (CD10+) LDNsConclusionsHigher baseline immature CD10- LDNs impair T-cell survival and promote T-cell senescence being a circulating biomarker of HPD upon single-agent ICI. The addition of PCT prevents HPD by inducing immature neutrophils cell death.ReferencesFerrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with pd-1/pd-l1 inhibitors or with single-agent chemotherapy. JAMA Oncol 2018;4:1543–52. https://doi.org/10.1001/jamaoncol.2018.3676Kim Y, Kim CH, Lee HY, Lee S-H, Kim HS, Lee S, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019;14:1608–18. https://doi.org/10.1016/j.jtho.2019.05.033Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, et al. Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res 2020. https://doi.org/10.1158/1078-0432.CCR-20-1420.Ethics ApprovalPatients blood was obtained after signature of informed consent and within an observational prospective study (INT 22_15) approved by local Institutional Ethical Committee.