6-month Progression-free Survival Rate Research Articles

Orelabrutinib, Rituximab, and High-Dose Methotrexate (HD-MTX) in Newly Diagnosed Primary Central Nervous System Lymphoma (PCNSL): A Retrospective Analysis on Efficacy, Safety, and Biomarker

Introduction: PCNSL is a rare malignant tumor arising in the brain, spinal cord, eyes, or leptomeninges. HD-MTX-based regimens remain the first option for newly diagnosed PCNSL because of high response rates as demonstrated by numerous studies (Qing et al. Cancer Manag Res 2021). Bruton's tyrosine kinase (BTK) is a crucial part of the B-cell receptor signaling pathway, and BTK inhibition has been proven effective in treating CLL and other B-cell lymphomas (Yoshitaka et al. Neuro-Oncology 2021). Orelabrutinib is a newly developed BTK inhibitor with high selectivity and a high concentration in the cerebrospinal fluid (Zhang et al, EHA 2022). Recent evidence has shown the efficacy and safety of orelabrutinib in PCNSL (Wu et al., Invest New Drugs 2022). Therefore, we conducted a retrospective study of clinical outcomes in newly diagnosed PCNSL patients (pts) treated with orelabrutinib combined with rituximab and HD-MTX (RMO) regimen in routine clinical care. Methods: This retrospective cohort included the pts (aged 18-80 years) with newly diagnosed PCNSL who received at least 2 cycles of RMO regimen (rituximab 375 mg/m2 iv day 1; MTX 3.5 g/m2 iv day1; orelabrutinib 150 mg qd po; 3 weeks per cycle) as the induction therapy in a real-world setting between May 2021 and June 2022. It was proposed to receive orelabrutinib monotherapy as maintenance after RMO therapy when deemed necessary. Efficacy was assessed by MRI/PET per the International PCNSL Collaborative Group (IPCG) criteria. The primary endpoint was overall response rate (ORR); secondary endpoints were CR rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty-Four pts with newly diagnosed PCNSL (20 male; 24 non-GCB subtypes) were included, with a median age of 58.5 years (range: 30-79). Four (11.8%) pts had an ECOG performance status of ≥3. All the pts (100%) achieved certain responses (Figure 1) with a complete response in 21 pts (61.8%). Eighteen (52.9%) pts completed 6 cycles of RMO as induction, with an ORR of 94.44% (17/18) and CR rate of 88.89% (16/18) at the 6th cycle assessment. As of the cut-off date (June 30, 2022), 8 pts received orelabrutinib maintenance therapy and had a CR status. Median PFS was not reached (95% CI, 7 months-not reached; Figure 2), with a 6-month PFS rate of 97.0% (95% CI, 91.3%-100.0%). Median OS was not reached either. In 22 pts who were available for gene alterations profiling, 18 pts (81.8%, 18/22) had an MYD88 mutation and achieved an ORR of 100% (CR, 55.6%). Four of these 18 pts were found to have a mutation in CD79B simultaneously. Plasma and CSF samples were collected from 5 patients at 2 hours after 15-day consecutive administration of orelabrutinib. The median CSF concentration of orelabrutinib was 21.6 ng/ml (range, 15.9-48.5), and the median CSF/plasma free ratio was 58.6% (range, 38.6%-82.5%). All these 5 pts achieved a response (3 CR; 2 PR). Six of 34 (17.65%) pts experienced adverse events (AEs). The most common AE was white blood cell count decreased (8.82%). Only 2 (5.88%) pts experienced 4 ≥grade 3 AEs, including white blood cell count decreased, anemia, platelet count decreased, and alanine aminotransferase increased. No treatment-related death occurred. Conclusion: This retrospective data suggested that orelabrutinib combined with RM had an encouraging anti-tumor activity in newly diagnosed PCNSL pts, with a toleratable safety profile. A prospective clinical trial is on the way to confirming this finding, and the results will be publicly disclosed after its completion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.

PSAT385 Single Center Experience with the Combination of Lenvatinib and Pembrolizumab for the Treatment of Anaplastic Thyroid Cancer

Abstract Introduction Anaplastic thyroid cancer (ATC) is rare with a poor prognosis. There are no approved treatments for non-BRAF-mutated ATCs, leading to an unmet need. Phase II studies of single-agent lenvatinib or immunotherapy showed minimal benefit (lenvatinib: overall response rate (ORR) 2.9%, progression free survival (PFS) 2.6 months, overall survival (OS) 3.2 months; spartalizumab: ORR 19%, PFS 1.7 months, OS 5.9 months). Synergism between lenvatinib and pembrolizumab (L/P) has been reported. We sought to assess the efficacy and safety of L/P in ATC. Methods Thisis a retrospective, single-center study of ATC patients treated with L/P, between 1/2015-10/2021. L/P had to be started before first restaging. Those with pembrolizumab added at the time of progression on lenvatinib alone were excluded. The endpoints were ORR and PFS (primary) and OS and safety (secondary). Response evaluation was assessed by a single radiologist using RECIST v1.1. Treatment start date was the date of either lenvatinib or pembrolizumab initiation. Results 18 patients were included: 61% men; median age 64; initial stage: IVA (17%), IVB (11%), IVC (72%); common distant metastases: lung (83%), mediastinum (39%), bone (22%). Previous therapies: surgery (78%), chemoradiation (39%), cytotoxic chemotherapy (11%), palliative neck radiation (17%), BRAF-targeted therapy (6%), and immunotherapy (6%). All patients had mutation testing, and the common included TP53 (67%), PTEN (50%), TERTp (39%), NF1 (28%), RAS (22%), PIK3CA (17%), BRAF-V600E (6%). 11/12 tested tumors had a PDL-1 score >1%. Lenvatinib was started at 14-24 mg daily. With respect to lenvatinib, pembrolizumab was started from -14 to +49 days (median +6 days) at a fixed dose of 200 mg every 3 weeks. ORR was evaluable in 12 patients (outside hospital restaging scans unavailable in 6 patients): 1/12 (8%) confirmed complete response, 7/12 (58%) partial response (3 confirmed), 2/12 (17%) stable disease, and 2/12 (17%) progressive disease. The median PFS was 4.1 months (95% CI, 2.2 to NA), with treatment durations ranging from 0.5-33.5 months. The median OS of the 18 patients was 6.2 months (95% CI, 4.6 to NA). Respective 12-month PFS and OS rates were 25% and 22%. Grade III/IV toxicities were fatigue (22%); anorexia, weakness, arthralgia, dry mouth, pneumonitis (6%, each). AEs leading to death were pulmonary hemorrhage (17%), gastrointestinal bleed, pulmonary embolism (6%, each). Lenvatinib dose reduction, interruption, and discontinuation rates were 28%, 6%, and 28%, respectively. Pembrolizumab dose interruption and discontinuation rates were 6% and 11%, respectively. Conclusions The combination L/P had an ORR of 66%. Although most responses were short-lived, a quarter of patients benefited for more than 1 year. The ORR, PFS, and OS were better than lenvatinib alone. The toxicity profile was as expected. Our results represent the largest single-institution experience thus far with L/P in ATC and warrant further investigation (NCT04171622). Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Safety and efficacy of daratumumab in Chinese patients with relapsed or refractory multiple myeloma: a phase 1, dose-escalation study (MMY1003)

Daratumumab monotherapy demonstrated favorable safety and efficacy in relapsed/refractory multiple myeloma (RRMM) patients in the global phase 1/2 GEN501 and phase 2 SIRIUS studies. MMY1003 evaluated daratumumab monotherapy specifically in Chinese patients with RRMM. This 3-part, open-label, phase 1, dose-escalation study included patients with ≥ 2 prior lines of therapy. Part 3 included patients who had received a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and experienced disease progression on their last regimen. Patients received intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 and 16 mg/kg in parts 2 + 3. Primary endpoints were dose-limiting toxicity (DLT; part 1), pharmacokinetics (parts 1 + 2), and adverse events (AEs). Fifty patients enrolled. The first 3 patients in part 1 received daratumumab 8 mg/kg; remaining patients in parts 1–3 received daratumumab 16 mg/kg. In the daratumumab 16 mg/kg group (n = 47), patients received a median of 4 prior lines of therapy; 32% were refractory to a PI and IMiD, and 79% were refractory to their last prior therapy. No DLTs occurred. Thirty-six (77%) patients reported grade 3/4 treatment-emergent AEs. Thirteen (28%) patients experienced infusion-related reactions. At an 18.5-month median follow-up, overall response rate was 43%. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and not reached, respectively; 12-month PFS and OS rates were 35% and 70%. Pharmacokinetic results (n = 22) were consistent with other studies. Safety, pharmacokinetics, and efficacy of daratumumab monotherapy were confirmed in Chinese patients with RRMM. This trial is registered on ClinicalTrials.gov (NCT02852837).

Phase II Study of Sintilimab Combined with Concurrent Chemoradiotherapy in Patients with Limited-Stage Small Cell Lung Cancer (SINCE-01 Trial)

<h3>Purpose/Objective(s)</h3> Sequent or concurrent chemoradiotherapy (CRT) is the standard of care for most patients with Limited-Stage Small Cell Lung Cancer (LS-SCLC). In the era of immunotherapy, we conducted this single-arm phase II study to test the hypothesis that CRT combined with PD-1 checkpoint inhibitor (Sintilimab) would improve the outcomes of patients with LS-SCLC. <h3>Materials/Methods</h3> Patients received sintilimab combined with concurrent CRT as follows: The chemotherapy regimen was etoposide (100 mg/m2 D1-3) and carboplatin (AUC=5 D1) once every 3 weeks for a total of 4 to 6 cycles. Sintilimab (200 mg once every 3weeks) was administered with chemotherapy. 1-2 cycles of induction chemotherapy combined with sintilimab before concurrent CRT were allowed. Residual-field irradiation (RFI) was adopted in the study: The gross tumor volume (GTV) defined as residual volumes of positive node and primary tumor of the post-chemotherapy. The clinical target volume (CTV) included GTV with a margin 0.5 cm. Planning target volume (PTV) involved CTV with a margin 0.5 cm. RFI consisted of 1.5 grays (Gy) twice daily in 30 fractions up to a total dose of 45 Gy or 2.0 Gy daily up to 60 Gy. Prophylactic cranial irradiation (PCI) was proposed ed to patients who attained a complete or partial response after CRT. The primary end points were progression-free survival (PFS) and objective response rate (ORR). Secondary outcomes were safety, tolerability and overall survival (OS). <h3>Results</h3> A total of 23 patients were screened, and 21 were enrolled. All patients completed concurrent CRT with sintilimab. Induction chemotherapy was given to 17 patients, and 16 received PCI, and the median cycles of sintilimab was 11 (range, 5-16). The median follow-up time was 10.3 months (range, 3.6-13.7months). And up till now, the median PFS has not yet been achieved. The 6-month and 1-year PFS rates were 84.2% and 78.9%, respectively. The 6-month and 1-year OS rates were 100% and 94.4%. Of the enrolled patients, 7 patients had a complete response, and 10 patients had partial responses, resulting in an ORR of 80.9%. A total of 4 patients had relapse, including 1 failure located in the supraclavicular regions, and 3 patients had metastasis (2 in the brain and 1 in the adrenal gland). No infield recurrence was noted. There were no grade 5 toxicities, but there were three grade 4 events (two neutropenia and one thrombocytopenia). And the median V20 Gy of double lungs in these patients was 13.0% (range, 7.0%-25.0%). Because RFI was adopted, the pneumonitis rate was as low as 14% (two grade 1 and two grade 2). All 6 radiation esophagitis events (28.6%) were grades 1 to 2. No unexpected toxicities were observed. <h3>Conclusion</h3> Preliminary study showed that sintilimab combined with concurrent CRT was well tolerated in the treatment of LS-SCLC. The initial results were very encouraging and the final outcomes are worth looking forward to. This provides a basis for the next phase III study of PD-1 checkpoint inhibitor combined with concurrent CRT in patients with LS-SCLC.

KRAS mutation predict response and outcome in advanced non-small cell lung carcinoma without driver alterations receiving PD-1 blockade immunotherapy combined with platinum-based chemotherapy: a retrospective cohort study from China.

The selection of patients for immunotherapy remains challenging given the lack of highly specific and highly sensitive biomarkers. Kirsten rat sarcoma (KRAS) mutation is the most frequent molecular alteration found in advanced non-small cell lung carcinoma (NSCLC). We explored whether KRAS mutation status predicted the effects of first-line immune checkpoint inhibitor (ICI) treatment and platinum-based chemotherapy in Chinese patients with advanced NSCLC. Clinical data were extracted from medical records of patients with advanced NSCLC at the First Affiliated Hospital of Guangzhou Medical University in China between January 2019 and March 2020. Overall survival (OS) and progression-free survival (PFS) rates were compared via log-rank tests, and independent prognostic factors were identified via Cox regression. Patients with advanced NSCLC without driver alterations who were treated with ICI and platinum-based chemotherapy (N=80) were identified, including 28.7% with KRAS mutations and 71.3% with non-KRAS mutations. Tumor programmed death-ligand 1 (PD-L1) expression was analyzed using a 1% cutoff, and 32.5% of patients were negative and 67.5% were positive. The median tumor mutational burden (TMB) was 7.29 mutations per megabase (muts/Mb) (range, 0.08-44.8 muts/Mb), with 32.5% of cases <5 muts/Mb and 67.5% ≥5 muts/Mb. The median PFS and OS for the entire cohort were 9.8 (95% CI: 9.1-10.5) and 17.6 (95% CI: 14.4-20.8) months, respectively. The 6-month PFS rate was 67.5% and the 1-year OS rate was 72.5%. Thirty-five patients survived until the last follow-up. TheOS and PFS of patients with KRAS mutations were significantly higher than those in the non-KRAS mutant group (P<0.05). The Cox multivariate analyses showed that brain metastasis [hazard ratio (HR) =0.232, 95% CI: 0.102-0.530; P=0.001], TMB (HR =5.675, 95% CI: 1.948-16.535; P=0.001), KRAS mutation (HR =2.552, 95% CI: 1.141-5.708; P=0.023) were independent predictors of OS in patients treated with ICIs and platinum-based chemotherapy. Liver metastasis (HR =0.344, 95% CI: 0.191-0.619; P<0.001) and KRAS/tumor protein p53 (TP53) co-mutation (HR =0.220, 95% CI: 0.067-0.725; P=0.013) were the prognostic factor for PFS of qualified patients. This work provides evidence that KRAS mutation in advanced NSCLC may be served as a potential predictive biomarker for immunotherapeutic efficacy.

Health-related quality of life (HRQoL) in patients (pts) with progressive, poorly differentiated, extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC) enrolled in NET-02: A phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy.

293 Background: NET-02 was a multi-centre, randomised (1:1), non-comparative phase II trial of nal-IRI/5-FU/folinic acid (ARM A) or docetaxel (ARM B) in pts with progressive PD-EP-NEC, aimed at selecting a treatment for evaluation in a phase III trial. Primary analysis (N = 58) showed ARM A, but not ARM B, achieved the target 6-month progression-free survival rate primary endpoint (McNamara et al. ASCO 2022). HRQoL was a secondary endpoint in NET-02. Methods: HRQoL was assessed using the EORTC QLQ-C30 and GINET21 (at baseline (BL), 6-weekly intervals and at disease progression). The mean change from BL was estimated for each scale by timepoint and treatment arm. Results are presented where there were ≥4 responses per time point. Scores were considered stable if they did not change by &gt; 10 points from BL. The mean BL C30 scores for all pts were compared to United Kingdom (UK) population normative C30 data using a 2-sample t-test. Results: Fifty-four of 58 pts (93%) completed a BL questionnaire; of these, 39 (72%) completed ≥1 post-BL questionnaire, with 21 (51%) completing questionnaires at progression. Global health status (GHS) and all functional scales in ARM A remained stable from BL to intervals pre-progression, with a sustained improvement in role functioning observed post-BL. In ARM B, GHS and all C30 functional scales decreased by &gt; 10 points between BL and week 18 (worsening of QoL). Both arms had a &gt; 10-point increase from BL in constipation and diarrhoea in ≥1 post-BL time point. In ARM A, pain, insomnia and financial problems decreased from BL. No C30 symptom scales in ARM B were consistently lower post-BL. Patterns of change in GINET21 mean score were similar in both arms: body image, disease-related worries, information/communication, sexual function and social function all had a &gt; 10-point reduction in score from BL (indicating improvement in symptoms/problems); endocrine and gastrointestinal symptoms remained stable; muscle/bone pain varied across time points, initially showing a reduction in pain followed by an increase, compared to BL. In comparison to the UK C30 norms (BL all pts), 11 of 15 C30 scales did not significantly differ (P &gt; 0.05). Mean scores for fatigue and appetite loss were significantly higher than UK C30 norms (worse symptoms in pts from NET-02) (P = 0.03, P = 0.0003 respectively). However, emotional functioning and GHS were significantly better in pts from NET-02 (P = 0.001, P = 0.03 respectively). Role and social functioning were lower in pts from NET-02 (both P = 0.06) (poorer level of functioning). Conclusions: HRQoL was maintained and potentially improved with nal-IRI/5-FU/folinic acid, but not docetaxel. Compared to the UK general population, BL QoL did not substantially differ in pts from NET-02. Clinical trial information: NCT03837977.

A single-arm feasibility phase II study of EMF (erlotinib + methotrexate + 5-fluorouracil) regimen in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).

Head and neck squamous cell carcinoma (HNSCC) is a huge burden in India with the majority of patients presenting in advanced unresectable stages. Innovative, low-cost but efficacious regimens that can be easily administered in the outpatient setting are the need of the hour. We envisaged assessing whether a readily available triplet therapy of erlotinib + methotrexate + 5-fluorouracil (EMF) is efficacious in terms of extending life and maintaining the quality of life in such patients. This was a single-arm, phase II, investigator-initiated interventional study. Thirty-five platinum-resistant/refractory patients of HNSCC were treated with a combination of erlotinib 150 mg, methotrexate 40 mg/m2 (d1, d8) and 5-fluorouracil 500 mg/m2 (d1, d8) every 28 days till progression or unacceptable toxicities. The primary endpoint was overall response rates (ORRs) at 3 months; additional endpoints were disease control rate (DCR) at 3 months, overall survival (OS) and progression-free survival (PFS), safety and patient-reported quality of life. The ORR and DCR at 3 months were 45.7% and 68.5%, respectively. The PFS was 5 months (95% confidence interval (95% CI): 3.9-6 months) and the OS was 9 months (95% CI: 7.4-10.5 months). The 3- and 6-month PFS rates were 86% ± 6% and 45% ± 9%, respectively, while the OS rates at 3 and 6 months were 91% ± 5% and 68% ± 8%, respectively. Rash, mucositis and fatigue were common adverse events occurring in 23 (65%), 14 (40%) and 9 (25.7%), respectively. The most common grade 3 events seen were rash in 5 (14.2%) and diarrhoea in 2 (5.7%). Clinically significant improvement from baseline was seen in many domains of Quality of Life Core Questionnaire and Quality of Life Head and Neck Module. The triplet regimen of EMF is a feasible and safe therapeutic option in patients with platinum-resistant/refractory HNSCC. It has demonstrated favourable response rates and improvement in quality of life; however, a randomised phase III study would add more robust value (NCT: CTRI/2020/02/023378).

Proxalutamide in patients with AR-positive metastatic breast cancer: Results from an open-label multicentre phase Ib study and biomarker analysis

AimProxalutamide is a novel second-generation non-steroidal androgen receptor (AR) antagonist. This study aimed to evaluate the preliminary efficacy and safety of proxalutamide in patients with AR-positive metastatic breast cancer (AR+ mBC). MethodsIn this open-label, dose-expansion, multicentre phase Ib trial, patients with AR+ mBC (immunohistochemistry [IHC] ≥1%) received proxalutamide orally once daily. Two proxalutamide dose cohorts (cohort A: 200 mg; cohort B: 300 mg) were sequentially investigated. Primary endpoints were disease control rate (DCR) at 8 and 16 weeks and recommended phase II dose (RP2D). ResultsForty-five patients with three median lines (range, 1–13) prior systemic therapy were enrolled (cohort A, n = 30; cohort B, n = 15). Among 39 evaluable patients, DCR at 8 and 16 weeks was 25.6% (95% confidence interval [CI], 11.9–39.4%), with 26.9% in cohort A and 23.1% in cohort B. No patient achieved partial response or complete response. Proxalutamide 200 mg/day was determined as RP2D. The 6-month progression-free survival (PFS) rate was 19.6% (95% CI, 10.2–37.5%). In the triple-negative subgroup, DCR at 8 weeks was 38.5%, with median PFS of 9.1 months (95% CI, 7.8–NA) in those who achieved response at 8 weeks (n = 5). Most common grade 3/4 adverse events were aspartate aminotransferase increase (8.9%) and γ-glutamyltransferase increase (8.9%). By biomarker analysis, patients with moderate AR expression of IHC (26%–75%), PIK3CA pathogenic mutations, or <60 ng/ml cell-free DNA yield showed longer PFS. ConclusionProxalutamide showed promising anti-tumour activity with good tolerability in patients with heavily pretreated AR+ mBC, supporting further investigation. Trial registrationThis clinical study was prospectively registered at chinadrugtrials.org.cn (Identifier: CTR20170757) and clinical trials.gov (Identifier: NCT04103853).

First-line treatment of camrelizumab combined with chemotherapy in advanced gastroenteropancreatic neuroendocrine carcinoma: Study protocol for a prospective, multicenter, phase II study.

BackgroundGastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a group of rare but highly aggressive malignancies. The standard chemotherapy regimens composed of etoposide and cisplatin/carboplatin (EP/EC) are of limited efficacy. This prospective, multicenter, phase II study is conducted to explore the effectiveness and safety of first-line anti-PD-1 antibody (camrelizumab) combined with chemotherapy in advanced GEP-NEC patients.MethodsPatients with unresectable or metastatic GEP-NEC will receive camrelizumab combined with standard first-line chemotherapy every 3 weeks (camrelizumab 200 mg, administered intravenously on day 1; etoposide 100 mg/m2, administered intravenously on days 1–3; cisplatin 75 mg/m2, administered intravenously on day 1 or carboplatin area under the curve 5 mg/ml per min, administered intravenously on day 1). All patients were naïve to systemic therapy in the advanced setting. The primary endpoint is a 6-month progression-free survival (PFS) rate. The secondary endpoints are objective response rate, PFS, overall survival and adverse reactions.DiscussionThis is the first study to investigate the therapeutic potential of camrelizumab plus chemotherapy for advanced GEP-NEC. It is expected that this trial will propose a new and effective treatment strategy for GEP-NEC in the first-line setting.Clinical Trial RegistrationThis trial is registered at the Chinese Clinical Trial Registry http://www.chictr.org.cn, identifier ChiCTR2100047314.Date of RegistrationJune 12, 2021.

Efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory soft tissue sarcoma: a multicenter, phase 2 trial.

BackgroundAnti-angiogenic agents have been reported to exert promising clinical activity for advanced soft tissue sarcoma (STS). Apatinib, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, is effective and safe for various solid tumors, but its role in STS remains unclear. The aim of this study was to explore the efficacy and safety of apatinib in patients with untreated or chemotherapy-refractory STS.MethodsIn this multicenter, single-arm, phase 2 trial, patients aged 18–70 years with untreated or chemotherapy-refractory STS were enrolled and received 500 mg apatinib per day. During treatment, patients were followed up with imaging every 8 weeks. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were objective response rate (ORR), overall survival (OS), and adverse events (AEs), which were graded following the National Cancer Institute common terminology criteria for AEs version 4.03.ResultsFrom June 2017 to October 2018, 53 patients were enrolled, 51 of whom received at least one dose of apatinib. Of the 53 patients, 41 (77.4%) had chemotherapy-refractory disease. The median follow-up was 13.3 months. The 6- and 12-month PFS rates were 46.8% and 25.2%, respectively, with a median PFS of 5.6 months [95% confidence interval (CI): 3.8–9.2 months]. The median PFS was 5.5 months for chemotherapy-refractory patients, 9.1 months for untreated patients, 13.9 months for patients with alveolar soft part sarcoma (ASPS), and 3.7 months for patients with clear cell sarcoma (CCS). The 12- and 24-month OS rates were 58.6% and 44.9%, respectively, with a median OS of 20.0 months (95% CI: 9.2–31.1 months). The median OS was 10.7 months for chemotherapy-refractory patients and not estimated for untreated, ASPS, nor CCS patients. In 50 evaluable patients, the ORR was 18.0% and the disease control rate was 86.0%. These results were similar to those of the per-protocol set. The most common grade 3 or 4 AEs included hypertension [30 (58.8%) of 51 patients], leukopenia [12 (23.5%)], proteinuria [8 (15.69%)], and hematuria [8 (15.69%)]. One patient died of unknown cause.ConclusionsThis study suggested that apatinib might be effective and tolerable in patients with untreated or chemotherapy-refractory STS (NCT03064243).

1255P da VINci: Safety and efficacy of the OTSGC-A24 vaccine and nivolumab in metastatic gastric cancer

Novel combination immune-oncology strategies aim to improve efficacy while maintaining low toxicity levels. In metastatic gastric cancer (GC), the efficacy of single agent immunotherapy in later lines of treatment is modest. OTSGC-A24 is a cocktail of peptide vaccines against GC specific antigens which induces cytotoxic T lymphocyte (CTL) activity and modulates the intra-tumoral immune contexture. We hypothesize that the combination of OTSGC-A24 and immunotherapy will improve response rates while maintaining low toxicities. da VINci is a phase Ib study combining OTSGC-A24 (SC 1mg Q2W) with nivolumab (IV 240mg Q2W) in HLA A*24:02 subtype patients with GC who progressed on ≥1 line of chemotherapy. Patients were immunotherapy naïve. The primary objective was to evaluate safety and dose limiting toxicities (DLT); secondary objectives included response rate (RECIST v1.1) and survival. Serial tumor biopsies were performed prior to treatment, after 4 weeks of the combination, and at progression. Sixty-eight patients were pre-screened from February 2019 to November 2021, 25 (36.8%) were eligible. Of these, 18 have commenced on treatment. No DLTs were observed. Most frequent all grade toxicities were injection site reactions (n=5 [27.8%], ≥G3=0), fatigue (n=5 27.8%], ≥G3=0), rash (n=5 [27.8%], ≥G3=1), transaminitis (n=3 [16.7%], ≥G3=0), fever (n=3 [16.7%], ≥G3=0). Three patients (16.7%) had partial response (PR), 6 patients (33.3%) had stable disease (SD) while 9 patients (50%) had progressive disease. The median progression-free survival (PFS) was 1.7 months (range 0.4 – 24.2) with a 6-month PFS rate of 27.8% (n=5). The median overall survival (OS) was 3.6 months (range 4.6 – 30.9). Of note, durable clinical benefits were observed in those with SD or PR where the median PFS was 13.1 months (range 2.5 – 24.2) and median OS was 18.6 months (range 2.5 – 30.9). OTSGC-A24 in combination with nivolumab was well tolerated without any unexpected safety signals. The combination showed promising anti-tumor activity with meaningful durable disease control in metastatic GC patients previously treated with chemotherapy. These results support further investigation in randomized studies. Translational studies are underway.

Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: The SAKK 19/18 phase II study

BackgroundPatients with advanced squamous-cell lung cancer (SQCLC) frequently (46%) exhibit tumor overexpression of fibroblast growth factor receptor (FGFR) messenger ribonucleic acid (mRNA). Rogaratinib is a novel oral pan-FGFR inhibitor with a good safety profile and anti-tumor activity in early clinical trials as a single agent in FGFR pathway-addicted tumors. SAKK 19/18 determined clinical activity of rogaratinib in patients with advanced SQCLC overexpressing FGFR1-3 mRNA. MethodsPatients with advanced SQCLC failing standard systemic treatment and with FGFR1-3 mRNA tumor overexpression as defined in the protocol received rogaratinib 600 mg BID until disease progression or intolerable toxicity. A 6-months progression-free survival rate (6mPFS) ≤15 % was considered uninteresting (H0), whereas a 6mPFS ≥38 % was considered promising (H1). According to a Simon 2-stage design, 2 out of 10 patients of the first stage were required to be progression-free at 6 months. Comprehensive Genomic Profiling was performedusing the Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific). ResultsBetween July 2019 and November 2020, 49 patients were screened and 20 were classified FGFR-positive. Among a total of 15 patients, 6mPFS was reached in 1 patient (6.7 %), resulting in trial closure for futility after the first stage. There were 7 (46.7 %) patients with stable disease and 5 (33.3 %) patients with progressive disease. Median PFS was 1.6 (95 % CI 0.9–3.5) months and median overall survival (OS) 3.5 (95 % CI 1.0–5.9) months. Most frequent treatment-related adverse events (TRAEs) included hyperphosphatemia in 8 (53 %), diarrhea in 5 (33 %), stomatitis in 3 (20 %) and nail changes in 3 (20 %) patients. Grade ≥3 TRAEs occurred in 6 (40 %) patients. No associations between mutational profile and treatment outcome were observed. ConclusionDespite preliminary signals of activity, rogaratinib failed to improve PFS in patients with advanced SQCLC overexpressing FGFR mRNA. FGFR inhibitors in SQCLC remain a challenging field, and more in-depth understanding of pathway crosstalks may lead to the development of drug combinations with FGFR inhibitors resulting in improved outcomes.

Apatinib for recurrent/progressive glioblastoma multiforme: A salvage option

Purpose: The recurrent/progressive glioblastoma multiforme (GBM) carries a dismal prognosis and the definitive treatment strategy has not yet been established. This study aimed to assess the efficacy and safety of apatinib in recurrent/progressive GBM patients. Materials and methods: The clinical data of 19 recurrent/progressive GBM patients who received apatinib treatment from November 2015 to December 2019 at Sun Yat-sen University Cancer Center were collected retrospectively in this study. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and assessed. Results: The overall ORR was 52.6%, and the DCR was 73.7%. Median PFS and OS were 5.1 and 10.4 months, respectively. The 6-month PFS and OS rates were 38.9% and 68.4%, respectively. The 12-month PFS and OS rates were 16.7% and 36.8%, respectively. The treatment-related toxicities were generally well-tolerated. The most common grade 3/4 AEs were hand-foot syndrome (36.8%) and hypertension (21.1%). Conclusion: Our study showed that apatinib therapy provided a better salvaging option for recurrent/progressive GBM patients and the toxicity was manageable.

Bevacizumab combined with re-irradiation in recurrent glioblastoma.

BackgroundGlioblastoma is characterized by rich vasculature and abnormal vascular structure and function. Currently, there is no standard treatment for recurrent glioblastoma (rGBM). Bevacizumab (BEV) has established role of inhibiting neovascularization, alleviating hypoxia in the tumor area and activating the immune microenvironment. BEV may exert synergistic effects with re-irradiation (re-RT) to improve the tumor microenvironment for rGBM.PurposeThe purpose of this study was to evaluate the safety, tolerability, and efficacy of a combination of BEV and re-RT for rGBM treatment.MethodsIn this retrospective study, a total of 26 rGBM patients with surgical pathologically confirmed glioblastoma and at least one event of recurrence were enrolled. All patients were treated with re-RT in combination with BEV. BEV was administered until progression or serious adverse events.ResultsMedian follow-up was 21.9 months for all patients, whereas median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.5–9.5 months). In addition, the 6-month and 1-year PFS rates were 65.4% and 28.2%, respectively. The median overall survival (OS), 6-month OS rate, and 1-year OS rate were 13.6 months (95% CI: 10.2–17.0 months), 92.3%, and 67.5%, respectively. The patient showed good tolerance during the treatment with no grade > 3 grade side event and radiation necrosis occurrence rate of 0%. Combined treatment of gross total resection (GTR) before re-RT and concurrent temozolomide during re-RT was an independent prognostic factor that affected both OS and PFS in the whole cohort (OS: 0.067, 95% CI: 0.009–0.521, p = 0.010; PFS: 0.238, 95% CI: 0.076–0.744, p = 0.038).ConclusionIn this study, re-RT combined with concurrent and maintenance BEV treatment was safe, tolerable, and effective in rGBM patients. Moreover, GTR before re-RT and selective concurrent temozolomide could further improve patient PFS and OS.

The Prognostic Value of Baseline Clinical and Radiologic Imaging Features in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab.

PurposeTo identify prognostic clinical and radiologic features in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab.Patients and MethodsClinical and imaging records of patients with unresectable HCC were retrospectively reviewed, and baseline features were recorded. Patients’ records and imaging studies were used to determine the patients’ overall survival (OS) and progression-free survival (PFS). Univariate and multivariate analyses were performed to determine prognostic features. Subanalyses of treatment-naïve patients (who never received local or systemic therapy) and previously treated patients were also performed.ResultsFifty-five patients were included in the final analysis, 23 (41.8%) of whom were treatment naïve. The median PFS and OS for the entire cohort were 3.0 months and 7.9 months. The 3-, 6- and 12-month OS rates were 85.5%, 79.8% and 45.7%, respectively. The 3-, 6- and 12-month PFS rates were 50.1%, 41.2% and 20.1%, respectively. On multivariate analysis, independent prognostic features for poor PFS of the entire cohort were pleural effusions (p = 0.047, HR: 6.3; CI: 1.03–38.90) and hepatic vein tumor thrombus (p = 0.005; HR: 23.37; CI: 2.63–207.67); independent prognostic features for poor OS were ascites (p = 0.008; HR: 37.37; CI: 2.53–467.64), pleural effusion (p = 0.003; HR: 110.17; CI: 5.00–2426.54), and low (<40HU) pre-contrast attenuation on CT images (p = 0.007; HR: 0.09; CI: 0.02–0.53). On subanalysis of treatment-naïve patients, the median OS and PFS were 7.4 months and 2.8 months, respectively. The 3-, 6- and 12-month PFS rates were 43.5%, 38.6% and 24.8%, respectively. Pleural effusion was the only independent poor prognostic feature (p = 0.036; HR: 206.34; CI: 1.41–30,167.58).ConclusionIndependent prognostic features for survival outcomes include the presence of ascites, pleural effusions, hepatic vein tumor thrombus, and HCC with low attenuation (<40 HU) on unenhanced CT images. Although several biochemical variables were significant on univariate analysis, none were independent predictors of OS or PFS.

Paclitaxel with or without pazopanib for ovarian cancer relapsing during bevacizumab maintenance therapy: The GINECO randomized phase II TAPAZ study

BackgroundAnti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab. MethodsIn the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/m2 plus pazopanib 600–800 mg daily or standard weekly paclitaxel 80 mg/m2. The primary endpoint was 4-month progression-free survival (PFS) rate. ResultsOverall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51–73%] with the combination versus 68% [95% CI, 54–85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1–6.1] versus 5.8 [95% CI, 4.8–7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone. ConclusionsIn rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery.ClinicalTrials.govregistration:NCT02383251.

Chemo-radiotherapy plus durvalumab for loco-regional relapse of resected NSCLC

Backgroundtumor recurrence after NSCLC surgical resection is the most common cause of treatment failure that sharply reduces the patient’s life expectancy. The optimal treatment strategy for loco-regional recurrences developing after surgical resection in patients with non–small-cell lung cancer (NSCLC) is not established yet.This report aims to describe the pattern of relapse, PFS, and OS in patients treated with radio-chemotherapy and durvalumab for loco-regional relapse after surgery.Methods We conducted a multicenter, retrospective study including subjects who underwent surgical resection for NSCLC and were treated with Pacific protocol after loco-regional relapse.ResultsTwenty-four patients met the inclusion criteria. At the time of diagnosis mean age was 65 years (range 47–78), the majority being male (58.3%). The 12-month progression-free survival rate was 68.7%, the 18-month progression-free survival rate was 45.8%, and the 24-month progression-free survival rate was 34.3%. There were three deaths: the 12-month survival rate was 91%, and the 18-month survival rate was 82.8%.ConclusionsIn this article, we propose a treatment strategy that might prolong post recurrence survival in patients with good performance status experiencing loco-regional relapse after surgery.

A Randomized Study on the Effect of Metformin Combined with Intensive-Exercise Diet Therapy on Glucose and Lipid Metabolism and Islet Function in Patients with Renal Cell Carcinoma and Diabetes.

Objective To evaluate the effect of metformin combined with intensive-exercise diet therapy on glucose and lipid metabolism and islet function in diabetes patients with localized renal cell carcinoma after laparoscopic resection. Methods A total of 120 renal cancer patients with diabetes mellitus treated in the oncology department of our hospital from January 2018 to December 2020 were recruited and assigned via random number table method at a ratio of 1 : 1 to receive either metformin (control group) or metformin plus intensive exercise diet therapy (study group) after laparoscopic nephrectomy. Outcome measures included glucose and lipid metabolism, pancreatic islet function, lifestyle, clinical efficacy, and adverse reactions. Results After the intervention, the fasting blood glucose (FBG), 2 h postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) of the two groups of patients decreased significantly, and the study group had significantly lower results. After treatment, the two groups had elevated levels of high-density lipoprotein cholesterol (HDL-C), fasting serum insulin (FINS), and homeostasis model assessment of β-cell function (HOMA-β), and higher results were obtained in the study group (P < 0.05). After the intervention, the study group showed higher results of health promoting lifestyle profile-II (HPLP-II) and a 12-month progression-free survival rate than the control group. There were no significant differences in the incidence of adverse reactions between the two groups. Conclusion Metformin combined with intensive-exercise diet therapy significantly improves the glucose and lipid metabolism and islet function of renal cancer patients with diabetes and effectively enhances the 12-month progression-free survival. Further trials are, however, required prior to clinical application.

Efficacy and safety of immune checkpoint inhibitors in post-TKI NSCLC patients harboring EGFR mutations.

Immune checkpoint inhibitors (ICIs) have been validated in epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC) patients. However, there exists no evidence regarding NSCLC patients harboring EGFR mutations, experiencing EGFR-TKI (tyrosine kinase inhibitor) treatment failure. We collected clinical information from real world and conducted a time series-based meta-analysis to determine the efficacy and safety of ICIs in patients harboring EGFR mutations and experienced EGFR-TKIs resistance. Twenty-two NSCLC patients with EGFR mutations after TKI resistance were included from two hospitals. PubMed, Embase and Cochrane Library were searched for relevant literature published until December 31, 2021. Endpoint outcomes included mortality and progression-free survival (PFS) at different times of follow-up. In total, 22 patients showed that the median PFS was 5.6months (range 2.0-9.0months). According to treatment strategies, the median PFS was 2.4months (range 2.0-5.3months) in the ICI monotherapy group and 5.9months (range 2.8-9.0months) in the ICI combined Chemotherapy group. Additionally, sixteen studies, including 5 trials, 10 controlled cohorts and 1 real-world study, were assessed, involving a total of ICI-treated NSCLC patients with EGFR mutation after TKI failure. The 6-month survival and PFS rate were 0.82 (95% CI 0.36-0.97) and 0.55 (95% CI 0.34-0.74), respectively. ICI combined chemotherapy showed the best survival outcome among these groups, as demonstrated by the 12-month survival rate and PFS. No new safety signals were identified with the combination therapy. The frequency of treatment-related adverse events was similar to that in previously reported studies of chemotherapy combined with checkpoint inhibitors. The addition of ICIs plus chemotherapy may significantly improve progression-free survival among patients with locally advanced or metastatic non-squamous NSCLC who EGFR-TKIs resistance.