Disease Control Rate Research Articles

A single-arm, exploratory study of disitamab vedotin (DV) combined with camrelizumab and platinum-based chemotherapy as first-line treatment in patients with HER2 expressing locally advanced or metastatic esophageal squamous cell carcinoma (ESCC).

TPS217 Background: Esophageal cancer (EC) is one of the most common cancers worldwide with esophageal squamous cell carcinoma (ESCC) being the predominant histological subtype. PD-1 blockades combined with chemotherapy are now standard-of-care in first-line setting for patients with ESCC. HER2 expression, prevalent in an estimated 7.6% to 28.5% of ESCC cases, correlates with diminished overall survival, suggesting HER2-targeted therapy as a potential novel approach. To our knowledge, there is currently no clinical trial regarding anti-HER2 therapy in ESCC. Clinical evidence has suggested the potential synergistic anti-tumor effect of Disitamab Vedotin (DV) with PD-1 inhibitors in HER2-expressing gastric or gastroesophageal junction (G/GEJ) cancers. This single-arm, exploratory study aimed to evaluate the safety and preliminary anti-tumor activity of DV combined with camrelizumab and platinum-based chemotherapy in ESCC. Methods: This is a single-arm, exploratory study (NCT06055153). Approximately 20 patients will be enrolled in this study, phase 1 will initiate with a 3+3 dose-escalation scheme (2.5mg/kg to 2.0mg/kg) to identify dose-limiting toxicities (DLTs) and establish a safe dosage of DV. The expansion cohort will subsequently evaluate this dose for both efficacy and safety. The study population will included both male and female patients over the age of 18 with histologically confirmed ESCC, and locally advanced unresectable, recurrent unresectable or metastatic EC verified by imaging examination. This group also includes those patients who have experienced relapse or progression more than six months post the conclusion of last therapeutic regimen. Required HER2 expression levels in tumor specimens range from IHC 1+ to 3+. According to RECIST v1.1, participants must have at least one measurable lesion, an ECOG performance status of 0 or 1, and a minimum expected survival of 12 weeks with suitable organ function. Treatment protocol includes intravenous administration of DV (either 2.5 mg/kg or 2.0 mg/kg on day 1), Camrelizumab (200 mg on day 1), and Cisplatin (75mg/m2) or Nedaplatin (75mg/m2) on a 21-day cycle, continued until disease progression or the advent of unacceptable toxicity. The primary outcomes for evaluation are DLT for safety and the objective response rate (ORR) for efficacy. Adverse events will be monitored in accordance with the CTCAE 5.0 criteria. Secondary endpoints encompass progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and time to response (TTR). Clinical trial information: NCT06055153 .

Enfortumab vedotin and pembrolizumab as first-line treatment in recurrent or metastatic head and neck squamous cell carcinoma: A cohort of the EV-202 trial.

TPS148 Background: Novel treatment strategies are needed to treat recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) given the poor durability of response and prognosis with standard therapy. In KEYNOTE-048, among patients with R/M HNSCC and PD-L1 combined positive score (CPS) ≥1, first-line (1L) treatment with pembrolizumab demonstrated a median overall survival (OS) of 12.3 months. Nectin-4 is widely expressed in a variety of solid tumors, including bladder cancers and HNSCC. Enfortumab vedotin (EV) is a Nectin-4–directed antibody–drug conjugate approved for use in previously treated (EV monotherapy) or 1L (EV + pembrolizumab) locally advanced or metastatic urothelial carcinoma (la/mUC). EV + pembrolizumab showed superior OS and progression-free survival (PFS) vs chemotherapy in 1L la/mUC. EV-202 is a multicenter, open-label, phase 2 study (NCT04225117) evaluating the efficacy and safety of EV in multiple tumor-specific cohorts. In the previously treated R/M head and neck cancer cohort, 11 of 46 patients (23.9%) had a confirmed objective response with EV monotherapy; median PFS was 3.9 months (Swiecicki P, et al. ASCO 2023. Poster #6017). We hypothesize that EV + pembrolizumab may demonstrate benefit as a 1L therapy in patients with R/M HNSCC and CPS ≥1. Methods: Patients in the R/M HNSCC cohort of EV-202 have histologically or cytologically confirmed HNSCC, an ECOG performance status 0 or 1, no prior systemic therapy administered in the R/M setting (with the exception of systemic therapy completed >6 months prior if given as part of treatment for locally advanced disease), and CPS ≥1. A total of 40 patients are expected to be enrolled. An interim analysis will be conducted when 20 patients are evaluable for tumor response; 5 responders will be needed to proceed. Of 40 total patients, 14 must demonstrate response to claim promising antitumor activity. Patients will receive EV 1.25 mg/kg intravenously on days 1 and 8 and 200 mg of pembrolizumab intravenously on day 1 of each 21-day cycle until discontinuation, for reasons including disease progression or toxicity. Disease assessments will be performed 9 weeks from the first dose and every 6 weeks thereafter until disease progression, start of subsequent anticancer therapy, death, consent withdrawal, loss to follow-up, or study end, whichever occurs first. The primary endpoint is investigator-assessed, confirmed ORR per RECIST v1.1. Secondary endpoints include investigator-assessed duration of response, disease control rate, PFS, OS, and safety/tolerability. Analyses will also be evaluated per iRECIST. Exploratory analyses will include pharmacokinetics, immunogenicity, quality of life, and assessment of biomarkers that may correlate with treatment outcome, including Nectin-4 expression. Recruitment for this cohort began in November 2023 and is ongoing. Clinical trial information: NCT04225117 .

Pretreatment CT-based machine learning radiomics model to predict response in unresectable hepatocellular carcinoma treated with lenvatinib plus PD-1 inhibitors and interventional therapy.

94 Background: Lenvatinib plus PD-1 inhibitors and interventional (LPI) therapy has demonstrated promising treatment effects in unresectable hepatocellular carcinoma (uHCC). However, biomarkers for predicting the response to LPI therapy remained to be further explored. The current study aimed to develop a radiomics model to noninvasively predict the efficacy of LPI therapy for uHCC. Methods: Clinical data of patients who were diagnosed with uHCC and accepted LPI therapy were collected in our institution. The clinical model was built by clinicopathological information. Nine machine learning classifiers were tested and the multilayer perceptron classifier with optimal performance was utilized as the radiomics model. The clinical-radiomics model was constructed by integrating clinical and radiomics scores. Results: 151 patients were enrolled in this study (2:1 randomization, 101 and 50 in the training and validation cohorts), of which three patients achieved complete response, 69 showed partial response, 46 showed stable disease and 33 showed progressive disease (evaluated by mRECIST criteria). The objective response rate (ORR), disease control rate (DCR), and conversion resection rate were 47.7, 78.1 and 23.2%, respectively. 14 features were selected from the initially extracted 1223 for radiomics model construction. The area under the curves of the radiomics model (0.900 for training and 0.893 for validation) were comparable to that of the clinical-radiomics model (0.912 for training and 0.892 for validation), and both were superior to the clinical model (0.669 for training and 0.585 for validation). Meanwhile, the radiomics model could categorize participants into high- and low-risk groups for progression-free survival and overall survival in the training and validation sets. Conclusions: The current study developed a novel and promising machine learning radiomics model, which could efficiently predict the efficacy of LPI therapy for uHCC, with comparable performance to clinical-radiomics model.

An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.

23 Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×107 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for > 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .

Exploratory phase I study of HF1K16 for the treatment of patients with refractory/recurrent advanced glioma.

TPS32 Background: Glioblastoma (GBM) is the most common primary and aggressive malignant brain tumor in adults. Almost all patients with glioblastoma eventually have disease relapse and the median overall survival (OS) remains at only 30 weeks for those recurrent GBM patients. However, very few therapies had been approved over the past two decades, emphasizing the need for novel treatments. It is now wildly acknowledged that the immune microenvironment in brain offers adequate opportunities to implement immunotherapy for the treatment. Since most recurrent tumors had previously been exposed to the genotoxic stress of irradiation and/or chemotherapy, it is predicted to resulted in a higher mutational load and more immunogenic. However, The limited success of T cell immunomodulatory approach for advanced glioma has prompted a deeper understanding of the brain tumor and the immune microenvironment. GBM tumors are well-appreciated to be a immunosuppressive and a hallmark of GBM immunosuppression is the appearance of circulating myeloid-derived suppressor cells (MDSCs) at higher levels. Our preliminary data suggests that HF1K16, a liposome ATRA (all trans retinoic acid) suspension, is capable of relieving immune suppression induced by MDSCs. Further, we recently completed a phase I dose escalation study which showed that HF1K16 is safe, well-tolerated with preliminary efficacy in brain tumor. Thus, we hypothesized that HF1K16 may reverse GBM-associated immune suppression and leading to an increase in TILs and improved survival. Methods: This is an advanced glioma-specific expansion arm for adult patients with prior confirmed brain tumor and failed standard treatment. We plan to enroll 20~30 evaluable patients. Key eligibility criteria include candidates age ≥ 18 years, Karnofsky performance status ≥ 60 with and at least one measurable lesion. The primary endpoint is determination of overall response rate (ORR), duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) according to RANO criteria. Secondary endpoints include longitudinal assessment of the peripheral immune response by changes in MDSC and T cell subsets and numbers. HF1K16 infusions were administered in 21-day cycles (q.o.d days 1-14). Prior to and during treatment, peripheral blood mononuclear cells were collected and analyzed with flow cytometry to monitor the changes in myeloid cell phenotype and T cell composition. The recruitment of patients is anticipated completed in 2024. Clinical trial information: NCT05388487 .

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.

TPS219 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773 .

CHAPTER-GIST-101: A phase I study of pimitespib combined with imatinib in patients with imatinib-refractory gastrointestinal stromal tumor.

TPS97 Background: Gastrointestinal stromal tumor (GIST) is soft-tissue sarcoma of the gastrointestinal tract. Most GISTs harbor mutations in KIT or PDGFRA, recognized as key drivers of GIST development and progression. Imatinib (IM), which inhibits KIT/PDGFRA tyrosine kinase, exerts significant clinical activity in GIST, but most GISTs develop resistance to IM, mainly due to secondary kinase-domain mutations in KIT. Therefore, standard therapies for patients (pts) with IM-refractory GIST have room for improvement. Heat shock protein 90 (HSP90) is one of the molecular chaperones. Many of HSP90's client proteins, such as KIT, PDGFRA, and BRAF, have been identified as cancer-related proteins required for tumor development, and their activation, especially in mutant forms, is dependent on HSP90.Therefore, HSP90 inhibitors have a potential to overcome IM-resistance. Pimitespib (PIMI) is a novel HSP90 inhibitor, approved in Japan for pts with fourth line GIST based on the results of the phase 3 study (CHAPTER-GIST-301). We reported at ESMO 2023 (1917MO) that PIMI effectively inhibited tumor growth in an IM-resistant xenograft model, and further enhanced the anti-tumor activity when given with IM, and that PIMI + IM was well tolerated with no dose-limiting toxicity and suggested preliminary efficacy in pts resistant to IM in a dose-escalation part (DEP) of CHAPTER-GIST-101 study. Methods: The CHAPTER-GIST-101 study (NCT05245968) is a global phase 1 study in pts with IM-refractory advanced GIST in the second-line setting, consisting of three parts: the DEP, its expansion part (ExP), and another DEP for Chinese pts. The DEP used a 3+3 design to determine the maximum tolerated dose of PIMI (120 mg/day or 160 mg/day, orally, on 5 days on/2 days off) in combination with IM (400 mg/day once daily) and the ExP is for the efficacy and safety with determined dose of 120 mg/day PIMI + IM. The ExP is a global, open-label, randomized, part evaluating the efficacy and safety of PIMI in combination with IM, PIMI monotherapy, and standard therapy sunitinib (SU) in each arm of 20 pts. Pts are randomized 1:1:1 to receive either PIMI 120 mg on 5 days on/2 days off with IM 400 mg once daily, PIMI 160 mg on 5 days on/2 days off followed by IM 400 mg once daily after discontinuation of PIMI, or SU 50 mg on 4 weeks on/2 weeks off. The primary endpoint is progression-free survival (PFS) by the independent radiological review. The secondary endpoints include investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, PK and safety. Exploratory pharmacogenomics analysis is also planned. After the DLT evaluation for the DEP, enrollment for the ExP began in March 2023 in Japan, Singapore, Taiwan and Australia, and for the DEP for Chinese pts is also ongoing in China to evaluate tolerability and efficacy of this combination. Clinical trial information: NCT05245968 .

Preliminary analysis of PD-1 inhibitors combined with chemotherapy as neoadjuvant therapy for local advanced non-small cell lung cancer (NSCLC).

200 Background: The benefits of neoadjuvant immunotherapy and chemotherapy for resectable NSCLC suggest that this combined treatment may provide more surgical opportunities and survival benefits for potentially resectable locally advanced NSCLC. Methods: We retrospectively collected data from 28 patients with stage III EGFR/ALK/ROS wild-type NSCLC. Eligible patients received 2-8 cycles of neoadjuvant chemoimmunotherapy (squamous carcinoma: PD-1 inhibitor combined with albumin-bound paclitaxel and cisplatin/carboplatin; adenocarcinoma: PD-1 inhibitor combined with pemetrexed and carboplatin), followed by re-evaluation for surgery. Afterwards, patients underwent surgery after downstaging, with some receiving adjuvant immunotherapy maintenance for one year. Primary endpoints included major pathological response (MPR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: All 28 patients were male, with 7 (25%) in stage IIIA, 10 (35.7%) in IIIB, 4 (14.3%) in IIIC, 2 (7.14%) in IVA, and 2 (7.14%) in IVB. There were 22 cases of squamous cell carcinoma, 4 of adenocarcinoma, 1 of large cell lung cancer, and 1 of lymphoepithelioma-like carcinoma. 23 patients (82.1%) completed neoadjuvant treatment and underwent resection, achieving 100% R0 resection rate (23/23); 5 patients did not undergo surgery, 3 of whom received combined radiochemotherapy due to disease progression, 1 delayed surgery due to immunotherapy associated myocardial damage, and 1 died from massive hemoptysis and hemorrhagic shock. The objective response rate (ORR) was 60.7%, 95%CI [40.6-78.5%] and the disease control rate (DCR) was 85.7%, 95%CI [67.3-96.0%]. Among the 23 patients who underwent surgery, the pCR was 60.9%, 95%CI [38.5-80.3%], MPR was 4.3%, 95%CI [0.1-21.9%], clinical downstaging rate was 50%, 95%CI [30.6-69.4%] and pathological downstaging rate was 86.9%, 95%CI [66.4-97.2%]. 17 patients (77.3%) underwent lobectomy, and 5 (22.7%) underwent bilobectomy with a median blood loss of 100 ml, IQR [55.0-100]. There were no surgery-related deaths. Postoperatively, one patient developed chylothorax, one had a lung infection, and the two improved after conservative treatment. 11 patients (47.8%) received post-surgery immunotherapy maintenance, and 2 of them (8.7%) developed immune-related pneumonia. As of April 7, 2024, the median follow-up time was 21.5 months (95%CI: 17-34 Mo), At 12 months。 PFS rate was 82.1% (95%CI: 69.1-97.6%); OS rate was 96.3% (95%CI: 89.4-100%). Conclusions: Neoadjuvant immunotherapy combined with surgery for unresectable locally advanced NSCLC may benefit patients and significantly extend survival.

Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.

2 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7th, 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]

An open-label single-center investigator-initiated exploratory clinical study in patients with refractory or recurrent solid tumors using SBRT as “in situ vaccination”: R-ISV-FOLactis trial.

44 Background: The immunotherapy of sarcomas remains a challenge. As a breakthrough tool for cancer immunotherapy, the therapeutic cancer vaccine is in rapid development. In situ vaccination can be realized by intratumoral immune injection and radiotherapy. We have developed a bifunctional engineered Lactococcus lactis (FOLactis) expressing an encoded fusion protein of fms-like tyrosine kinase 3 ligand (Flt3L) and OX40 ligand (OX40L). We hypothesized that intratumoral injection of "FOLactis" combined with SBRT will realize tumor control and the synergetic application of PD-1 mAb systematically will further improve the effect of immunotherapy. Methods: This exploratory clinical study is designed as an open-label trial aimed at treating patients with advanced solid tumors who are unresponsive or intolerable to standard treatment. Patients will be treated with SBRT, intratumoral injection of "FOLactis", and PD-1 blockade. The primary endpoint was the objective response rate (ORR) of target lesions after 3 months and 6 months. The secondary endpoint included the disease control rate (DCR) of target lesions, progression-free survival (PFS), overall survival (OS), etc. Results: From July 2022 to December 2023, 30 patients were eligible for this trial (63% were sarcomas). 53.3% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb before respectively. The ORR and DCR of target lesions after 3 months were 27.6% and 93.1%, while these of systemic efficacy were 17.2% and 55.2%, respectively. In sarcomas, the ORR, DCR of target lesions were 11.1% and 88.9%, while these of systemic efficacy were 5.5% and 50%, respectively. Considering the deferred response in sarcomas, we also calculated the ORR after 6 months as the primary endpoint. The ORR, DCR of target lesions after 6 months were 56.3% and 100%, while these in sarcomas were 41.7% and 100%, respectively. Systemic median PFS were 2.87 months. Median PFS of target lesions and mOS has not reached. Among the evaluable target lesions, 6-month EFS was 50% in sarcomas (6/12) and 50% in all patients (8/16). Expression of CD4+, CD8+ T cells and dendritic cells was significantly increased between pre-treatment and post-treatment peripheral blood in responders. The most common treatment-related adverse events (TRAEs) were fever (83.3%), lymphocytopenia (53.3%), hypocalcemia (30%), neutrophilia (26.7%) and nausea (26.7%). Grade≥3 TRAE occurred in 11 patients, including lymphocytopenia (30%), fever (6.7%), leukopenia (3.3%), anemia (3.3%) and cardiac insufficiency (3.3%). Conclusions: In situ vaccination with“FOLactis", along with SBRT was tolerable and induced anti-tumor immunity, which would also augment systemic response when synergized with PD-1 mAb. This in situ vaccination is probably a promising option for advanced solid tumors. Clinical trial information: ChiCTR2200060660 .

Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study

IntroductionKRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. MethodsEligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. ResultsAs of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7–58.6), and the disease control rate was 90.5% (95% CI: 83.7–95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6–11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). ConclusionsIBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer After Trastuzumab Failure (PROVE): A Prospective Phase 2 Study.

Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Efficacy of everolimus plus hormonal treatment after cyclin-dependent kinase inhibitor; real-life experience, A TOG study.

In advanced breast cancer, endocrine therapy is preferred in the absence of visceral crisis. Cyclin-dependent kinase inhibitors (CDKi) are the gold standards. The selection of subsequent treatments after CDKi treatment is still controversial, and the efficacy of everolimus (EVE) combinations is unknown. In this study, we aimed to investigate the efficacy of EVE after CDKi administration in real-life experiences. The study received data from 208 patients from 26 cancer centers. Demographic and histologic features, diagnosis, progression, last visit dates, and toxicities were recorded. This study was a retrospective case series. One hundred and seven patients received palbociclib, while 101 patients received ribociclib as a CDKi. The overall response and disease control rates of EVE combinations were 60% and 88%, respectively. In univariate analysis, the absence of liver metastasis, age > 40years, better type of response, and immediate treatment after CDKi were related to increased progression-free survival. Liver metastasis and response type were significantly associated with overall survival. In the multivariate analysis, response remained significant in terms of progression-free survival, while response type, liver metastatic disease, and hematologic toxicity were prognostic in terms of overall survival. This study provides evidence of the benefits of EVE combinations after CDKi treatment. EVE combinations may be more appropriate for patients with non-liver metastasis, and the first treatment response shows the benefit of treatment. In addition, immediate treatment after CDKi treatment is more beneficial than later lines of treatment.

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including &lt;i&gt;HER2&lt;/i&gt;, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (&lt;i&gt;n&lt;/i&gt; = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (&lt;i&gt;n&lt;/i&gt; = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

Combination Therapy Consisting of Transarterial Chemoembolization, Lenvatinib, and Programmed Cell Death Protein 1 Blockade for Hepatocellular Carcinoma with Inferior Vena Cava Tumor Thrombus: A Case Series Study and Literature Review

Introduction: Patients with hepatocellular carcinoma (HCC) and inferior vena cava tumor thrombus (IVCTT) have poor prognosis. Combination therapy involving the blockade of programmed cell death protein 1 (PD-1) and tyrosine kinase inhibitors is an efficient treatment strategy for advanced HCC. However, surgical treatment after a combination of systemic therapy and transarterial chemoembolization (TACE) for HCC with IVCTT has not been widely reported, and the efficacy and safety of this treatment have not been studied. Methods: In the 21 cases reported herein, the patients were treated with TACE, lenvatinib, and PD-1 blockade. The treatment responses, progression-free survival (PFS), overall survival (OS), disease control rate, and toxicities were evaluated, and the related literature was reviewed. Results: The overall response and disease control rates were 66.7% and 85.7%, respectively. The median PFS time was 16.0 months, with a 1-year PFS rate of 55.60%. The median OS was not reached, with a 1-year OS rate of 66.70%. Four patients underwent hepatectomy without serious complications and survived for 29.1, 24.7, 14.2, and 13.8 months. Three patients survived tumor-free, and 1 patient experienced intrahepatic recurrence. Pathological complete response and major pathological responses were observed in 1 and 3 patients, respectively. Treatment-related adverse events of any grade occurred in 8/9 patients (88.9%), and grade 3 treatment-related adverse events occurred in 1 patient. Conclusion: The combination of TACE, lenvatinib, and PD-1 is effective for HCC with IVCTT and has acceptable adverse effects.

Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer

BackgroundThis study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting.MethodsThis was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.ResultsA total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients.ConclusionsRh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6–66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3–4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

Hypofractionated radiotherapy plus PD-1 antibody and SOX chemotherapy as second-line therapy in metastatic pancreatic cancer: a single-arm, phase II clinical trial

PurposeTo assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.MethodsPatients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients’ clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.ResultsBetween February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.ConclusionsClinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=130211, identifier: ChiCTR2100049799, date of registration: 2021–08-09.

Analysis of the efficacy and safety of dual immunotherapy in patients with driver gene and programmed death ligand-1 double negative advanced non-small cell lung cancer

Objective: To discuss the efficacy and safety of the dual immunotherapy of nivolumab plus ipilimumab in patients with advanced non-small cell lung cancer (NSCLC) who are double negative for driver gene and programmed death-ligand 1 (PD-L1) expression. Methods: We conducted a retrospective collection of clinical data for 61 patients with advanced NSCLC who were negative for both driver genes and PD-L1 and received dual immunotherapy with nivolumab plus ipilimumab at the First Affiliated Hospital of Guangzhou Medical University from January 2019 to June 2023. Based on treatment conditions, patients were divided into first-line and non-first-line dual immunotherapy groups. Patients were followed up monthly, with the follow-up period ending on October 1, 2023. The efficacy was evaluated using Solid Tumor Response Evaluation Criteria, and adverse reactions were assessed according to the Common Terminology Criteria for Adverse Events developed by the National Cancer Institute in the United States. Survival curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare the differences in progression-free survival (PFS) and overall survival (OS) between first-line and non-first-line dual immunotherapy patients. The influence factors of PFS were analyzed using a multivariate Cox proportional hazards regression model. Results: Among the 61 NSCLC patients, 49 were male (80.3%), with an age range of 23-88 years [(65.3±7.4) years]. There were 14 cases (23.0%) classified as stage ⅢC and 47 cases (77.0%) classified as stage Ⅳ according to TNM staging. Forty cases (65.6%) received non-first-line treatment. The objective response rate (ORR) was 24.6% (15/61), and the disease control rate (DCR) was 52.5% (32/61). All 61 patients were followed up, with a median follow-up time of 17.8 months. The median PFS was 6.0 months (95%CI: 5.5-6.4 months), and the median OS was 17.0 months (95%CI: 14.8-19.2 months). For patients receiving first-line dual immunotherapy, the median PFS was longer than for those receiving non-first-line dual immunotherapy [7.0 months (95%CI: 6.0-7.9 months) vs 4.0 months (95%CI: 3.3-4.6 months), P<0.001]; similarly, the median OS for patients receiving first-line dual immunotherapy was longer than for those receiving non-first-line dual immunotherapy [19.0 months (95%CI: 18.1-19.9 months) vs 13.0 months (95%CI: 10.8-15.1 months), P<0.001]. Multivariate Cox risk regression model analysis showed that distant tumor metastasis (HR=1.414, 95%CI: 1.253-1.725), non-first-line dual immunotherapy (HR=1.412, 95%CI: 1.184-1.652), and tumor mutation burden<10 mut/Mb (HR=1.328, 95%CI: 1.151-1.546) were risk factors for PFS, while non-squamous carcinoma (HR=0.917, 95%CI: 0.823-0.984) was a protective factor for PFS. Immune-related adverse reactions occurred in 41 cases (67.2%), including 21 cases (32.8%) of grade 3-4 adverse reactions. Eight cases (13.1%) discontinued treatment, and there were no deaths. Conclusions: Dual immunotherapy with nivolumab plus ipilimumab can be a treatment option for driver gene and PD-L1 double-negative advanced NSCLC. Distant tumor metastasis, non-first-line dual immunotherapy, and tumor mutation burden<10 mut/Mb are risk factors affecting patients' PFS, while non-squamous cell carcinoma is a protective factor affecting patients' PFS.