Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Background: Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3 + 3 escalating dose design, receiving oral pyrotinib (240 mg, 320 mg, or 400 mg daily), intravenous camrelizumab (200 mg), and CapeOX (oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717. Findings: Among 41 patients, 10 were in phase 1a (3 at 240 mg, 3 at 400 mg, and 4 at 320 mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320 mg daily due to dose-limiting toxicities (diarrhea [n = 3] and vomiting [n = 1]) observed at 400 mg. Based on all available data, the RP2D of pyrotinib was set at 320 mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Interpretation: Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. Funding: This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).

Efficacy and safety of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of esophageal squamous cell cancer: A prospective, open label, randomized phase II study.

BACKGROUND: Esophageal squamous cell cancer (ESCC) accounts for approximately 90% of esophageal cancer cases in China. There are no standard regimens for second or third-line chemotherapy of metastatic squamous esophageal cancer. The objective of this study was to investigate the security and effectiveness of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of ESCC. METHODS: One hundred and twenty-eight patients with metastatic ESCC confirmed by histopathology were enrolled into this study. These patients had failure of the first-line chemotherapy combination of fluorouracil or platinum or paclitaxel and had not undergone chemotherapy with irinotecan or raltitrexed previously. Patients were randomly divided into irinotecan combined with raltitrexed group (experiment group) and irinotecan monotherapy group (control group). Overall survival (OS) and progression-free survival (PFS) were the primary endpoint. RESULTS: In the control group, the median PFS (mPFS) and median OS (mOS) of patients were 3.37 and 5.3 months. In the experiment group, mPFS and mOS were 3.91 and 7.0 months. There was statistical significance of PFS and OS between two groups (PFS P = 0.002, OS P = 0.01). In subgroup analysis, in the second-line treatment, the mPFS of control and experiment group, was 3.90 and 4.60 months, mOS was 6.95 and 8.5 months, which was statistically significant differences between the two groups. (PFS P = 0.001, OS P = 0.005), In the third-line and beyond treatment, mPFS of control and experiment group was 2.80 and 3.19 months, mOS were 4.5 and 4.8 months. But there was no significant difference of PFS or OS between the two groups (PFS P = 0.19, OS P = 0.31). There was no statistical significance of toxicity side effects between two groups. CONCLUSIONS: The PFS and OS of irinotecan plus raltitrexed may be better than that of irinotecan monotherapy, especially in second line treatment, which should be confirmed with a phase III study including much more patients.

Exploration of the underlying biological differences and targets in ovarian cancer patients with diverse immunotherapy response.

Background: Preclinical trials of immunotherapy in ovarian cancer (OC) have shown promising results. This makes it meaningful to prospectively examine the biological mechanisms explaining the differences in response performances to immunotherapy among OC patients. Methods: Open-accessed data was obtained from the Cancer Genome Atlas and Gene Expression Omnibus database. All the analysis was conducted using the R software. Results: We firstly performed the TIDE analysis to evaluate the immunotherapy response rate of OC patients. The machine learning algorithm LASSO logistic regression and SVM-RFE were used to identify the characteristic genes. The genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were selected for molecular typing. Our result showed that the patients in Cluster1 might have a better prognosis and might be more sensitive to immunotherapy, including PD-1 and CTLA4 therapy options. Pathway enrichment analysis showed that in Cluster2, the pathway of EMT, TNFα/NF-kB signaling, IL2/STAT5 signaling, inflammatory response, KRAS signaling, apical junction, complement, interferon-gamma response and allograft rejection were significantly activated. Also, genomic instability analysis was performed to identify the underlying genomic difference between the different Cluster patients. Single-cell analysis showed that the DPT, COL6A6, LSAMP and RUNX1T1 were mainly expressed in the fibroblasts. We then quantified the CAFs infiltration in the OC samples. The result showed that patients with low CAFs infiltration might have a lower TIDE score and a higher proportion of immunotherapy responders. Also, we found all the characteristic genes DPT, RUNX1T1, PTPRN, LSAMP, FDCSP and COL6A6 were upregulated in the patients with high CAFs infiltration. Immune infiltration analysis showed that the patients in Cluster2 might have a higher infiltration of naive B cells, activated NK cells and resting Dendritic cells. Conclusions: In summary, our study provides new insights into ovarian cancer immunotherapy. Meanwhile, specific targets DPT, RUNX1T1, PTPRN, LSAMP, FDCSP, COL6A6 and CAFs were identified for OC immunotherapy.

Fabrication of Resveratrol-Loaded Scaffolds and Their Application for Delaying Cell Senescence In Vitro.

In this research, resveratrol (RSV)-loaded scaffolds have been prepared to control the release of resveratrol and used to delay hepatic stellate cell (HSC) senescence in vitro. The functional carboxyl group-COOH is first introduced to the surface of poly(ε-caprolactone/d,l-lactide) (P(CL-DLLA)) under the coadministration of ultra-violet (UV) treatment and photo initiator and then resveratrol are conjugated onto the surface of the modified scaffolds through esterification. The characterization of the structure of RSV-AA-P(CL-DLLA) shows that resveratrol has been successfully conjugated onto the modified surface. Cell growth exhibits a higher level of cell viability and much more obvious agglomeration on the surface of the synthetic RSV-AA-P(CL-DLLA). Meanwhile the activity of senescence-associated ß-galactosidase (SA-ß-gal) and reactive oxygen species (ROS) is downgulated for cells on RSV-AA-P(CL-DLLA), which suggests that cell senescence is delayed on RSV-AA-P(CL-DLLA). And then it is attested that cells have a lower level of p53 but SIRT1 expression is upregulated on RSV-AA-P(CL-DLLA), which might be related to resveratrol release from RSV-AA-P(CL-DLLA). It also suggested cell senescence on RSV-AA-P(CL-DLLA) has been regulated by p53 and the SIRT1 signaling pathway. In all, the present study shows that RSV-AA-P(CL-DLLA) can be successfully prepared to promote cell growth and delay cell senescence and could be used for cell-based therapy in tissue engineering.

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells.

The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.