Later-line Treatment Research Articles

Vascular endothelial growth factor receptor (VEGFR) -tyrosine kinase inhibitors combined with programmed death receptor-1 (PD-1) inhibitors as third- or later-line treatment in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): A retrospective study.

68 Background: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to programmed death receptor-1 (PD-1) inhibitors. Recent studies suggest that combining vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) with PD-1 inhibitors may enhance the anti-cancer activity for mCRC patients. Multiple antiangiogenic drugs have been approved by the FDA and NMPA for the treatment of later-line mCRC. Nevertheless, the effects of various anti-angiogenic drugs when used in combination with immunotherapy for mCRC treatment is not yet fully established. Methods: We conducted a non-interventional, retrospective study. Data were compiled from patients with mCRC at Shandong Cancer Hospital. Eligible patients must have received a combination of anti-angiogenic drugs and PD-1 inhibitors following at least two lines of standard treatment. The treatment period spanned from August 2019 to April 2024. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Results: At the cut-off date (April 29th, 2024), 79 eligible patients were available for analysis. Of these, 49 patients received fruquintinib in combination with PD-1 inhibitors (F group), 30 patients received investigator-selected other anti-angiogenic agents in combination with PD-1 inhibitors (NF group). The baseline characteristics of the two groups were well balanced. The median overall survival (OS) was significantly longer in the F group compared to the NF group (hazard ratio [HR]: 0.36, 95% CI 0.14-0.96, P=0.042). The median OS was not reached (95% CI 21.1-NA) in the F group, whereas it was 19.1 months (95% CI 12.6-NA) in the NF group. Subgroup analyses of OS were generally consistent with benefit in the whole population across nearly all subgroups. In contrast to NF group, individuals in F group demonstrated a significant enhancement in overall survival (OS) when patients had received prior bevacizumab (HR: 0.26, 95% CI 0.07-0.75, P=0.015), had no prior treatment with cetuximab (HR: 0.23, 95% CI 0.26-0.97, P=0.045), or had experienced surgical resection at baseline (HR: 0.34, 95% CI 0.12-0.95, P=0.041). The median PFS between two groups showed no statistically significant difference (HR: 0.65, 95% CI 0.38-1.13, P=0.127), F group 6.1 months (95% CI 4.6-10.3) versus NF group 4.4 months (95% CI, 3.0-7.5). Conclusions: Fruquintinib demonstrated improved OS over other anti-angiogenic agents when combined with immunotherapy for third or later-line MSS mCRC treatment.

The efficacy of anti-EGFR therapy across different lines of treatment in RAS wild-type left-sided metastatic colorectal cancer.

86 Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs) are recommended as a first-line treatment in RAS wild-type (RASwt ) left-sided metastatic colorectal cancer (mCRC). However, the efficacy of these therapies across different treatment lines remains unclear. This study aims to evaluate the efficacy of anti-EGFR mAb across first, second, third, and later-line treatments. Methods: We conducted a retrospective analysis of patients diagnosed with RASwt mCRC who received anti-EGFR mAb in all treatment lines at Siriraj Hospital between 2008 and 2023. The impact of anti-EGFR mAb treatment line on progression-free survival (PFS) and overall survival (OS) was determined using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 350 patients with RASwt mCRC receiving anti-EGFR mAb, 33% (115 of 350) were treated in the first-line, while 16%, 45% and 6% were treated in the second-, third- and later-line settings, respectively. Eighty-six percent of patients had left-sided tumors, and anti-vascular growth factors were used in 34% of patients. The median follow-up time was 30.4 months (mo). Among patients with left-sided tumors, those receiving first-line anti-EGFR mAb treatment exhibited a significantly longer mPFS (11.9 mo, 95% CI 7.4-16.3, p<0.001). The mPFS in the second-, third- and later-line settings were 6.1 mo (95% CI 4.6-7.5), 4.9 mo (95% CI 3.8-6.0), and 5.1 mo (95% CI 2.3-7.9), respectively. There were no significant differences in terms of OS across treatment lines (p=0.27). Conclusions: Although first-line treatment with anti-EGFR mAb had the longest mPFS in left-sided mCRC, OS did not significantly differ among treatment lines. Therefore, anti-EGFR mAb can be incorporated as a part of therapy at any line of treatment.

A retrospective observational study to evaluate the efficacy of trifluridine/tipiracil ± bevacizumab in metastatic colorectal cancer with MSI-high/deficient MMR.

152 Background: MSI-high (MSI-H)/deficient MMR (dMMR) metastatic colorectal cancer (mCRC) have reported to be resistant to various cytotoxic agents including fluorouracil. On the other hand, preclinical study showed that trifluridine was effective to fluorouracil-refractory dMMR CRC cell lines. Previous studies on trifluridine/tipiracil (FTD/TPI) ± bevacizumab (BEV) for mCRC as later line treatment showed an objective response rate (ORR) of 1.1-5.6% and disease control rate (DCR) of 44-76.6%. However, there are no reports on the efficacy of FTD/TPI± bevacizumab in MSI-H/dMMR mCRC patients. Methods: We retrospectively evaluated the efficacy and safety of FTD/TPI ± BEV as second- or later-line treatment which patients with MSI-H/dMMR mCRC received between June 2012 and January 2023 at the 10 institutions. The primary endpoint was investigator-assessed objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse event rates. We also compared the FTD/TPI + BEV (FTB group) with FTD/TPI (FT group). Results: A total of 18 patients (FTB/FT, 9/9) were included. Patient characteristics were as follows (FTB/FT): median age, 70 (70/70) years; ECOG PS of 0/1, 7 (5/2)/11(4/7); primary tumor location of right side/left side, 12(6/6)/6(3/3); BRAF V600E mutant/wild-type, 6(3/3)/11(6/5); number of previous treatment lines of 1/≥2, 2(1/1)/16(8/8); number of metastatic sites of 1-2/≥3, 8(4/4)/10(5/5); prior use of anti-PD-1 therapy, 10(3/7). Efficacies in the whole population were as follows: ORR, 16.7% (95%CI, 3.6-41.4); DCR, 72.2%; median (m) PFS, 5.5 months; mOS, 11.8 months. Efficacies in each group (FTB vs. FT) were as follows: ORR (22.2% vs. 11.1%) and DCR (88.9% vs. 55.6%) were favored in FTB group than in FT group, while the median PFS were similar between two groups (5.6 months vs. 5.2 months). OS in FTB group was longer than in FT group (median, 18.9 months vs. 7.1 months; hazard ratio, 0.22; p value=0.03). Of 11 (FTB/FT, 7/4) patients who received subsequent treatment, 6 in FTB group and 1 in FT group received anti-PD-1 therapy. The most common grade 3 or more adverse events in each group (FTB vs. FT) were neutropenia (77.8% vs.77.8%), anemia (22.2% vs. 33.3%) and febrile neutropenia (0% vs. 22.2%). Conclusions: FTD/TPI ± BEV showed a promising efficacy and favorable safety. Although this was retrospective study with a small sample size, FTD/TPI ± BEV therapy may have better efficacies for MSI-H/dMMR mCRC than those for MSS/proficient MMR mCRC in previous prospective studies. Next generation sequencing as biomarker analysis using pretreated tissue samples is ongoing.

Treatment sequences in patients with metastatic colorectal cancer in Japan: Real-world evidence of 1 st - to 5 th -line treatments.

76 Background: The development of later-line drugs for metastatic colorectal cancer (mCRC) has expanded treatment options for systemic chemotherapy in patients with mCRC. However, few studies have investigated patients who received later-line treatment in a real-world setting, and available information on treatment sequences and transition rates from early- to later-line treatments is limited. Methods: This was a retrospective study using hospital administrative data collected by MDV (Medical Data Vision, Tokyo, Japan) from April 2008 through February 2023 in Japan. Treatment regimens were derived from standard treatments recommended in the Japanese guidelines. The study population was determined using an algorithm from a similar study previously conducted in Japan. Our analysis focused on patients who started CRC surgery or 1 st -line treatment after January 2017 to reflect recent late-line real-world practice. Transition rates from 1 st - to 5 th -line treatment were calculated, and treatment sequences were summarized using a Sankey diagram. Logistic regression was performed to identify the factors associated with the transition from 2 nd - to 3 rd -line treatment. Results: A total of 722,005 patients with a CRC diagnosis record were identified in the MDV database. Of these, 26,456 patients were included in the study population. The median age was 69 years and 61.4% of patients were male. The rates of transition to subsequent lines from 1 st to 5 th line ranged from 65.7% to 70.4% (1 st to 2 nd 68.3%; 2 nd to 3 rd 70.4%; 3 rd to 4 th 69.9%; 4 th to 5 th 65.7%). Among 8528 patients who received 2 nd -line treatment, ~70% of patients (6006) continued 3 rd -line treatment, and 30% of patients (2522) received best supportive care. Comparing these 2 patient groups, younger age (<65 years, OR: 1.50, 95%CI: 1.35-1.67; p<0.001) and longer treatment durations of 1 st (≥180 days, OR: 1.26, 95%CI: 1.14-1.39; p<0.001) and 2 nd (≥120 days, OR: 1.67, 95%CI: 1.52-1.84; p<0.001) lines were significant factors for 3 rd -line treatment continuation. Prior therapy with oxaliplatin or irinotecan plus molecular targeted drugs was also associated with a higher likelihood of proceeding to 3 rd -line treatment (OR: 1.42, 95%CI: 1.28-1.58; p<0.001). Conclusions: In this study, ~70% of patients were able to transition to subsequent lines at the time of each line transition. However, 30% of patients were unable to continue treatment in real-world practice. To increase treatment continuation rates and maintain patient quality of life, new treatment options and further research are necessary to meet patients’ treatment needs, especially in the later-line treatment setting where unfavorable effects from previous treatments are accumulated.

Surufatinib combined with TAS-102 as a late-line therapy in patients with metastatic pancreatic cancer (mPDAC): Updated results of a single-arm, phase II trial.

739 Background: Patients (pts) with mPDAC recurrent after FOLFIRINOX and AG chemotherapies have few treatment options. Previous reports of NCT05481463 showed promising clinical benefits of surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus TAS-102 (combination of trifluridine and tipiracil hydrochloride) in recurrent mPDAC pts. Here, we report the updated results. Methods: This is a single-arm, phase II trial (NCT05481463). Eligible pts with histologically confirmed mPDAC, who had progressed after ≥ 2 lines of previous therapies were treated with surufatinib (250mg, qd, po, q4w) and TAS-102 (35 mg/m 2 , bid, po, days 1–5 and 8–12, q4w). The primary endpoint was progression-free survival (PFS). Key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Up to Sep 18, 2024, 20 pts were enrolled (median age 58 years, male 70.0%, TNM stage IV 100.0%, ECOG PS 1 100.0%, liver metastasis 50.0%, peritoneum metastasis 50.0%). Median baseline CA19-9 level of the 20 pts was 996.7u/ml, with a range from 2u/ml to 16612u/ml. 40.0% of pts had received 3L prior therapies before enrollment and 70.0% with primary site on pancreatic body and tail. All pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 15.0% (3 PRs), DCR was 30.0% (3 PRs, 3SDs). 35.0% pts had stable or shrinking tumors. Median PFS was 2.35m (95% CI 1.91-3.94). Median OS was 6.44m (95% CI 3.81-NR). In subgroup analysis, significantly longer PFS&OS were observed in pts without liver metastasis (mPFS: 3.42m vs 2.01m, p=0.049; mOS: 9.92m vs 3.70m, p=0.026), or with ≤ 2 metastatic organs (mPFS: 3.94m vs 1.91m, p=0.005; mOS: 10.09m vs 3.81m, p=0.003). Additionally, OS was significantly prolonged in pts with baseline CA19-9 level ≤ 996.7u/ml, in contrast with those with baseline CA19-9 level more than 996.7u/ml (9.92m vs 3.70m, p=0.008). All pts experienced treatment emergent adverse events (TEAEs). Most common (≥ 10%) TEAEs (any grade) were anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%). Grade ≥ 3 TEAEs included neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%). Conclusions: Surufatinib plus TAS-102 showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory mPDAC, especially in patients without liver metastasis, with ≤ 2 metastatic organs, or with baseline CA19-9 level ≤ 996.7u/ml. The results warrant further investigations in a large cohort. Clinical trial information: NCT05481463 .

MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with KRAS G12R alteration.

725 Background: Pancreatic ductal adenocarcinoma (PDAC) is largely driven by oncogenic alterations in the KRAS , TP53 , CDKN2A/B , and SMAD4 genes. KRAS G12R accounts for nearly 20% of KRAS alterations in PDAC, is biologically unique, and offers the potential for improved response to MEK inhibitor (MEK-inh)-based therapy. As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the efficacy of MEK-inh-based therapy matched to the unique molecular alterations in the tumor of each patient as recommended by the molecular tumor board. Methods: From March 2022 to December 2023, 8 patients with metastatic PDAC were treated with MEK-inh-based therapy. Molecular profiling was performed by Tempus (648 genes) in 7 patients, and FoundationOne (324 genes) in 1 patient. Description of molecular alterations, matched therapies, and efficacy of treatment are provided. Results: The median age of patients starting MEK inhibitor-based therapy was 69 years, with 62% of them being female. The molecular characteristics and matched therapies are summarized (Table). MEK-inh-based therapy was administered to 3 (37.5%) patients as a first or second-line treatment, and to 5 (62.5%) patients as a third to fifth-line treatment for metastatic PDAC. The overall survival and progression free survival (PFS) on MEK-inh-based therapy was 8.4 and 4.9 months, respectively. Four patients had PFS beyond 4 months (4.9, 5.5, 5.6 and 6.9 months). Conclusions: Individualized MEK-inh-based therapy demonstrated efficacy in late-line treatment of metastatic PDAC with KRAS G12R alterations. Using this approach earlier in the treatment course and in combination with RAS inhibitors or cytotoxic systemic therapies may further enhance outcomes. Tumor alterations and matched therapies. Gene altered Number of patients (%) Number of patients matched (%) Drug family matched KRAS G12R 8 (100) 8/8 (100) MEK inhibitor TP53 7 (87.5) 4/7 (57) VEGF/VEGR inhibitor* CDKN2A 4 (50) 4/4 (100) CDK4/6 inhibitor** SMAD4 2 (25) 2/2 (100) MEK inhibitor + (EGFR or Pan-HER inhibitor)*** *PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091.

MEK inhibitor-based therapy in metastatic pancreatic adenocarcinoma with KRAS G12D or KRAS G12V alteration.

726 Background: Up to 95% of pancreatic ductal adenocarcinomas (PDAC) are driven by oncogenic alterations in the KRAS gene, with KRAS G12D (40%) and KRAS G12V (30%) mutations being the most common. However, in most cases, KRAS alterations are accompanied by alterations in other tumor suppressors such as TP53 , CDKN2A/B , and SMAD4 . Therefore, targeting KRAS alone may not be sufficient for effective treatment of PDAC . As part of the MCW-Master-PREDICT (NCT05802069) observational study, we evaluated the effectiveness of MEK inhibitor (MEK-inh)-based therapy, tailored to the unique molecular alterations of each patient’s tumor, in treating metastatic PDAC (mPDAC) with KRAS G12D or KRAS G12V alterations. Methods: From April 2022 to December 2023, 19 patients ( KRAS G12D=10 (53%), KRAS G12V=9 (47%)) were treated with MEK-inh-based therapy. Comprehensive genomic profiling was performed using Tempus xT (648 genes) in 15 patients (79%), FoundationOne (324 genes) in 4 patients (21%), and STRATA (429 genes) in 1 patient. The genomic characteristics, matched therapies, and treatment outcomes are provided (Table). Results: Of the 19 patients, 11 (58%) were female. The median age at the initiation of MEK-inh-based therapy was 67 years. Six (32%) patients received MEK-inh-based therapy as first or second-line treatment, while 13 (68%) patients were treated in the third to fifth-line. Among the 19 patients, the median overall survival (mOS) and median progression-free survival (mPFS) from the initiation of MEK-inh-based therapy were 5 and 2 months, respectively. The mOS from the time of MEK-inh-based therapy was 5.1 months for KRAS G12D, and 4.7 months for KRAS G12V (P=0.87). The mPFS from the time of MEK-inh-based therapy was 2.3 months for KRAS G12D and 1.4 months for KRAS G12V (P=0.12). Among all 19 patients, 4 (21%) patients had mPFS above 4 months ( KRAS G12V=1, KRAS G12D=3; 4.1, 4.3, 4.7, 9.9 months). Conclusions: The efficacy of MEK-inh-based therapy was limited in the late-line treatment of mPDAC for patients with KRAS G12D and KRAS G12V mutations. The potential role of MEK inhibitors in earlier lines of therapy, and their combination with KRAS inhibitors, requires further prospective evaluation. Tumor alterations and matched therapies. Altered gene KRAS G12V(N=9) KRAS G12D(N=10) Patients matched(N=19) Type of matched therapy KRAS G12D/V 9 (100%) 10 (100%) 19 (100%) MEK inhibitor TP53 7 (78%) 8 (80%) 8 (42%) VEGF/VEGR inhibitor* CDKN2A/B 8 (89%) 5 (50%) 9 (47%) CDK4/6 inhibitor** SMAD4 3 (33%) 4 (40%) 4 (21%) MEK inhibitor + (EGFR or pan-HER inhibitor) *** *PMID: 27466356; **PMID: 33472910; ***PMID: 36127339, PMID: 24625091. N= number of patients.

Association of early tumor shrinkage with survival in patients with HER2-positive advanced gastric cancer treated with trastuzumab deruxtecan.

360 Background: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody and a cytotoxic topoisomerase I inhibitor, has been approved as third or later-line treatment for unresectable HER2-positive advanced gastric cancer (AGC) based on the results of phase II DESTINY-Gastric 01 trial. However, there are few studies on real-world clinical outcomes and clinicopathological factors associated with efficacy of T-DXd in patients with HER2-positive AGC. Methods: This single-center retrospective study enrolled patients with AGC treated with T-DXd as third- or later-line chemotherapy between March 2018 and December 2023. Early tumor shrinkage (ETS) was defined as the relative change in the sum of longest diameters of RECIST target lesions at 8 ± 2 weeks compared with baseline. Prognostic outcomes were assessed using the log-rank test and Cox proportional hazards regression model. Results: A total of 57 patients were enrolled. The median age was 66 years (range, 31–82); 68% were male; 79% had HER2 3+; 23% had pulmonary metastasis; 67% were treated with T-DXd in the third-line setting. At a median follow-up of 27.6 months, the median progression-free survival (PFS) was 4.5 months (95% confidence interval [CI], 3.8–5.5), and the median overall survival (OS) was 7.3 months (95% CI, 4.9–9.4). Among 40 patients with target lesions, the overall response rate was 35.0% and the disease control rate was 90.0%. Patients with ETS had notably longer PFS (median PFS (months) 8.6 vs 4.1, P < 0.01) and OS (median OS (months) 9.1 vs 6.1, P < 0.01) than those without ETS. In multivariate analysis, ETS was associated with significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.08–0.63; P = 0.004) and OS (HR, 0.27; 95% CI, 0.12–0.65; P = 0.004), whereas pulmonary metastasis was associated with significantly shorter OS (HR 2.46, 95% CI, 1.07–5.65; P = 0.03). Conclusions: This study showed that achieving an ETS was significantly associated with a favorable prognosis in patients with HER2-positive AGC treated with T-DXd.

Efficacy and safety of anlotinib as a later-line treatment for advanced colorectal cancer.

194 Background: Colorectal cancer (CRC) is increasingly prevalent in China, with rising incidence and mortality rates. Often, early-stage CRC presents with no symptoms, leading to most patients being diagnosed at an advanced stage, where prognosis is poor. First- and second-line treatments for advanced CRC typically include chemotherapy combined with cetuximab or bevacizumab. However, third-line therapies such as regorafenib, furosemide, and TAS102 have shown limited efficacy. Anlotinib, a multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated improved progression-free survival (PFS) in refractory metastatic CRC (mCRC) in a phase III trial (NCT02332499), showing both efficacy and manageable toxicity. This report provides updated results from extended follow-up. Methods: This study enrolled 73 patients with advanced colorectal cancer who had undergone at least two prior standard treatments and were treated with oral anlotinib hydrochloride (8-12 mg daily, days 1-14 of a 21-day cycle) between November 2021 and March 2024 at Tangdu Hospital. Patients were treated until disease progression or intolerable adverse events. Efficacy was assessed using RECIST version 1.1, and adverse reactions were evaluated using CTCAE version 5.0. The primary endpoints were PFS, disease control rate (DCR), and adverse events (AEs), while secondary endpoints included overall survival (OS). Results: Of the 73 patients included, 38 had an ECOG performance status (PS) of 0-1, and 35 had a PS of 2. Clinical staging identified 18 patients with stage IIIB/IIIC and 55 with stage IV disease. Patients received anlotinib doses of 8 mg (n=11), 10 mg (n=44), or 12 mg (n=18), with 48 patients also receiving chemotherapy and 25 receiving anlotinib alone. The median PFS was 4.0 months (95% CI: 3.4-4.6), and the median OS was 7.0 months (95% CI: 5.7-8.3). Subgroup analysis indicated that patients under 60 years of age, those without liver metastases, and those with ECOG PS 0-1 derived greater benefit from anlotinib. The most common treatment-related adverse event was hypertension (19.2%). Other notable adverse events included elevated AST (11.0%), proteinuria (6.8%), and jaundice (6.8%). Most adverse reactions were grade 1-2, although 1 patient experienced grade ≥3 gastrointestinal bleeding. Conclusions: Anlotinib showed promising efficacy and a favorable safety profile as a later-line treatment for advanced colorectal cancer. These findings suggest that anlotinib may be a viable clinical option for advanced CRC, though larger-scale clinical trials are necessary to confirm these results and further define its role in treatment.

Beamion BCGC-1: A phase Ib/II trial of the HER2-selective tyrosine kinase inhibitor (TKI) zongertinib (BI 1810631) + trastuzumab deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1) for patients with metastatic breast cancer (mBC) and metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC).

TPS509 Background: Approximately 15% of mGEAC tumors overexpress HER2. Currently, the HER2-targeted antibody-drug conjugate (ADC), T-DXd, is approved in mGEAC as a second-line or later-line treatment option following the failure of prior trastuzumab-containing therapy. Zongertinib (BI 1810631) is a novel, orally administered HER2-selective TKI that spares EGFR. In a Phase I trial (NCT04886804), zongertinib showed encouraging tolerability and efficacy in patients with HER2 aberration-positive advanced solid tumors, including mGEAC. Beamion BCGC-1 (NCT06324357) is a Phase Ib/II dose escalation/optimization trial investigating zongertinib plus T-DXd or T-DM1 in patients with HER2+ mGEAC or mBC. Here we focus on the mGEAC cohorts, in which patients will receive zongertinib in combination with T-DXd. Methods: Across the whole trial, approximately 240 patients will be enrolled from approximately 48 sites in 6 countries. In the mGEAC cohorts, approximately 80 patients with histologically/cytologically confirmed locally advanced/metastatic, unresectable, HER2-positive, pre-treated mGEAC will be enrolled. All patients must have investigator-assessed progression and documented HER2-positive disease (overexpressed and/or amplified; confirmed by immunohistochemistry and in situ hybridization). In Phase Ib, approximately 20 patients will receive escalating doses of zongertinib plus a fixed approved dose of T-DXd (6.4 mg/kg, once every 21 days). Dose escalation will be guided by a Bayesian Logistic Regression Model, with overdose control. In Phase Ib, the primary endpoint is the occurrence of dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (first 21-day cycle); secondary endpoints include objective response (RECIST v1.1), DLTs during the on-treatment period and pharmacokinetics. In Phase II, up to 60 patients with mGEAC will be randomized 1:1 to receive one of two zongertinib dose levels (dose levels informed by Phase Ib), plus a fixed approved dose of T-DXd. In Phase II, the primary endpoint is objective response; secondary endpoints include progression-free survival, disease control, treatment-emergent adverse events leading to dose reduction, pharmacokinetics and patient-reported outcomes. Patients will remain on treatment until disease progression, undue toxicity or any other protocol-defined stopping criterion. Enrollment is ongoing. Clinical trial information: NCT06324357 .

Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage.

Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC. This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR). As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%. The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.

Intraperitoneal chemotherapy is now back for ovarian cancer.

The Intraperitoneal Carboplatin for Ovarian Cancer (iPocc) trial demonstrated that intraperitoneal (IP) administration of carboplatin is more effective than intravenous (IV) administration for advanced ovarian cancer, especially in cases with large residual tumors, challenging previous assumptions that IP chemotherapy is only beneficial for small residual tumors. Additionally, the iPocc trial showed that IP chemotherapy has a comparable safety profile to IV chemotherapy, with the exception of port-related toxicities. This review summarizes the principles, development, and significance of IP chemotherapy and discusses its future potential in light of recent studies. Notably, the iPocc trial, conducted under Japan's new clinical trial regulations, achieving regulatory approval based on investigator-initiated results. The iPocc regimen offers a viable treatment option for patients with advanced ovarian cancer (stages II-IV). However, bevacizumab is recommended for later-line treatments rather than combining it with IP chemotherapy until further trials support such combinations. Future studies are needed to identify biomarkers that predict response to the iPocc regimen. The trial's success underscores the dedication of patients and families who contributed to this groundbreaking research.

Circulating tumor DNA (ctDNA) trajectories predict survival in trifluridine/tipiracil-treated metastatic colorectal cancer patients.

Late-line treatment in metastatic colorectal cancer (mCRC) can improve prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. We investigated the prognostic role of circulating tumor DNA (ctDNA) in mCRC patients before and during treatment with trifluridine/tipiracil (FTD/TPI). This noninterventional translational biomarker phase II study enrolled 30 mCRC patients (60% male, 40% female). Using a 77-gene panel, ctDNA was detectable in 90% of patients. Tumor levels were assessed based on aneuploidy (ichorCNA) as well as the highest variant allele frequency, and correlated with overall survival (OS). Uni- and multivariate survival analyses were performed with clinical variables. Longitudinal changes in tumor levels over time were analyzed with linear mixed and joint models. The median OS was 8.1 months, with a recorded disease control rate of 30%. High ctDNA levels (≥ 5%) were associated with inferior survival after undergoing FTD/TPI therapy. Elevated tumor level trajectories over time were associated with higher risks of death. Therefore, ctDNA can help identify patients who are unlikely to benefit significantly from this treatment in late-stage disease, thus preventing unnecessary treatments and their associated side effects, ultimately enhancing quality of life.

Prognostic value of liver metastasis in patients with esophageal squamous cell carcinoma treated with nivolumab.

Nivolumab has been approved for unresectable recurrent advanced esophageal cancer. The present study aimed to provide real-world data on diverse patient profiles, including the elderly and those with poor performance status, while exploring therapeutic efficacy biomarkers. This retrospective study included 42 patients with esophageal cancer who received nivolumab after second- or later-line treatment at Kyoto Prefectural University of Medicine (Kyoto, Japan) from February 2020 to December 2021. The study evaluated real-world patient data for the outcomes, safety and clinical characteristics impacting efficacy. The median patient age was 70 years (range, 52-80), and 36 patients (85%) were male. A total of 22 patients (52%) were ≥70 years of age, and three (7%) had an Eastern Clinical Oncology Group Performance Status of 2, which was not included in the clinical trial. The response and disease control rates were 26 and 78%, respectively. With a median follow-up period of 7.9 months, the median progression-free survival and overall survival were 3.5 (95% CI, 2.0-6.0) and 19 (95% CI, 6.4-not reached) months, respectively. Patients with liver metastases had significantly worse progression-free survival and overall survival, while lung and lymph node metastases did not clearly impact nivolumab efficacy. Multivariate analysis revealed that liver metastases may predict both worse progression-free survival [hazard ratio (HR) 2.37; 95% CI, 1.07-5.24; P=0.03) and overall survival (HR, 2.75; 95% CI, 1.00-7.53; P=0.04). This study provided real-world evidence of nivolumab's favorable efficacy across diverse profiles, including the elderly and those with impaired performance status. No serious immune-related adverse events occurred and liver metastasis emerged as a predictive biomarker for nivolumab efficacy in esophageal squamous cell cancer.

Treatment of metastatic urothelial carcinoma in the United Kingdom, France, Germany, Italy, and Spain.

The treatment landscape of metastatic urothelial carcinoma (mUC) has evolved with the emergence of programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitors. This study assessed mUC treatment patterns in Europe. Data were derived from the Adelphi mUC Disease Specific Programme™ (November 2020 to April 2021), a large, cross-sectional, patient record-based survey of physicians in France, Germany, Italy, Spain, and the United Kingdom. Patient characteristics, treatment patterns across lines of therapy, and treatment durations were assessed. Physicians (N = 232) provided data for 1922 patients with mUC. Mean (SD) patient age at the time of data collection was 69.1 (7.9) years, and 81% presented with bladder tumors. Most patients received platinum-based chemotherapy in first-line (cisplatin plus gemcitabine, 43%; carboplatin plus gemcitabine, 28%), followed by PD-1/L1 inhibitors in second-line (pembrolizumab, 35%; atezolizumab, 19%). In third-line, 41% received best supportive care and 36% received single-agent chemotherapies. Mean treatment duration was longer in second-line than first-line (6.1 vs 4.8 months). Most patients received platinum-based chemotherapy in first-line, followed by a PD-1/L1 inhibitor. A substantial proportion received best supportive care after second-line. Findings indicate unmet need for the later-line treatment of mUC and provide important context for the emergence of novel therapies.

Efficacy of pembrolizumab in microsatellite-stable, tumor mutational burden-high metastatic colorectal cancer: genomic signatures and clinical outcomes.

Pembrolizumab, an immune checkpoint inhibitor (ICI), shows significant survival benefits in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but its efficacy in microsatellite-stable (MSS) mCRC is limited. Although ICIs are effective in tumor mutational burden-high (TMB-H) solid tumors, the impact on MSS-TMB-H mCRC, a rare subset within MSS mCRC, remains unclear. We conducted a retrospective analysis using clinical and genomic data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository in Japan. Patients with MSS-TMB-H mCRC who underwent tissue-based comprehensive genomic profiling and were treated with pembrolizumab or other later-line therapies were included. Pembrolizumab's efficacy was compared with that of trifluridine/tipiracil (FTD/TPI) and regorafenib. Genomic profiles of MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-low (TMB-L) CRCs were analyzed across 71 cancer-related genes. Among 127 TMB-H mCRC cases treated with pembrolizumab in the C-CAT repository, 77 were MSS and 50 were MSI-H. Pembrolizumab showed significantly shorter time to treatment failure (TTF) and overall survival (OS) in patients with MSS-TMB-H mCRC compared with those with MSI-H-TMB-H mCRC [median TTF 2.0 versus 10.6 months; hazard ratio (HR) 4.79, 95% confidence interval (CI) 2.65-8.64, median OS 4.5 versus 33.6 months; HR 9.86, 95% CI 3.93-24.77, both P < 0.0001]. Among MSS-TMB-H mCRC patients, 19 received pembrolizumab, 73 received FTD/TPI (±bevacizumab), and 18 received regorafenib as their first later-line therapy. Pembrolizumab showed significantly shorter TTF and OS compared with FTD/TPI (median TTF 1.6 versus 4.1 months; HR 2.66, 95% CI 1.41-5.02, P= 0.0017, median OS 5.4 versus 13.8 months; HR 2.42, 95% CI, 1.09-5.38, P= 0.025). Genomic analysis of 6737 CRCs revealed that MSS-TMB-H CRCs harbored fewer pathogenic alterations than MSI-H-TMB-H CRCs but had a profile similar to MSS-TMB-L CRCs. Pembrolizumab may be less effective than FTD/TPI in later-line treatment of MSS-TMB-H mCRC, potentially due to genomic similarities between MSS-TMB-H and MSS-TMB-L CRC, suggesting the need for alternative therapeutic strategies in this subgroup.

Real-World and Clinical Trial Validation of a Deep Learning Radiomic Biomarker for PD-(L)1 Immune Checkpoint Inhibitor Response in Advanced Non-Small Cell Lung Cancer.

This study developed and validated a novel deep learning radiomic biomarker to estimate response to immune checkpoint inhibitor (ICI) therapy in advanced non-small cell lung cancer (NSCLC) using real-world data (RWD) and clinical trial data. Retrospective RWD of 1,829 patients with advanced NSCLC treated with PD-(L)1 ICIs were collected from 10 academic and community institutions in the United States and Europe. The RWD included data sets for discovery (Data Set A-Discovery, n = 1,173) and independent test (Data Set B, n = 458). A radiomic pipeline, containing a deep learning feature extractor and a survival model, generated the computed tomography (CT) response score (CTRS) applied to the pretreatment routine CT/positron emission tomography (PET)-CT scan. An enhanced CTRS (eCTRS) also incorporated age, sex, treatment line, and lesion annotations. Performance was evaluated against progression-free survival (PFS) and overall survival (OS). Biomarker generalizability was further evaluated using a secondary analysis of a prospective clinical trial (ClinicalTrials.gov identifier: NCT02573259) evaluating the PD-1 inhibitor sasanlimab in second or later line of treatment (Data Set C, n = 54). In RWD Test Data Set B, the CTRS identified patients with a high probability of response to ICI with a PFS hazard ratio (HR) of 0.46 (95% CI, 0.26 to 0.82) and an OS HR of 0.50 (95% CI, 0.28 to 0.92) in the first-line ICI monotherapy cohort, after adjustment for baseline covariates including the PD-L1 tumor proportion score. In Clinical Trial Data Set C, the CTRS demonstrated an adjusted PFS HR of 1.03 (95% CI, 0.43 to 2.47) and an OS HR of 0.33 (95% CI, 0.14 to 0.91). The CTRS and eCTRS outperformed traditional imaging biomarkers of lesion size in PFS and OS for RWD Test Data Set B and in OS for the Clinical Trial Data Set. The study developed and validated a deep learning radiomic biomarker using pretreatment routine CT/PET-CT scans to identify ICI benefit in advanced NSCLC.

Prognostic and predictive factors in patients with metastatic gastric cancer treated with immune checkpoint inhibitors

Introduction. Microsatellite instability, PD-L1 CPS expression, high tumor mutational burden (TMB), and the presence of Epstein-Barr virus are the main tumor predictors of the response to immunotherapy in patients with metastatic gastric cancer (mGC). However, selecting patients for immunotherapy in mGC seems challenging due the lack of an optimal cut-off for PD-L1 CPS expression in microsatellite-stable gastric adenocarcinomas, significant benefit from anti-PD-L1 inhibitors in late-line treatment, and inaccessibility of Epstein-Barr virus and TMB determination in real clinical practice.Aim. The aim of our study is to determine prognostic and predictive biomarkers of patients, who received ICIs for mGC.Materials and methods. Our study included patients with mGC treated with anti-PD1 antibodies between 2018 and 2023 in five oncology centers in Moscow. Variables with p &lt;0.05 obtained from a univariate analysis, were selected to perform multivariate analysis. According to the number of prognostic factors, patients were stratified into two groups with favorable and unfavorable prognosis. The optimal cut-off of the neutrophil-lymphocyte ratio (NLR) to predict of the efficacy of immunotherapy was determined using ROC analysis. The Kaplan–Meier method was performed to analyze survival curves of patients according to prognostic groups and NLR levels and the log-rank-test was used to compare the differences. Statistics was performed using the IBM SPSS v. 22 and PRISM 10.Results. Between January 1, 2018 and February 28, 2023, 122 patients with mGC who received ICIs were included. NLR was analyzed in 71 (58 %) patients out of 122. The median NLR was 2.36 (0.41–10.00). The cut-off of NLR for predicting mortality was 1.8 (AUC 0.81, p &lt;0.001). The median of PFS and OS in patients with high NLR (NLR ≥1.8) were 2 and 4 months, respectively; mOS and mPFS in the low NLR group were not achieved (p &lt;0.001). Eight factors were statistically significant in univariate analysis of patients with MSS: ECOG status (0–1 and 2–3), signet-ring cell histology, primary tumor, the number of organs with metastases (1–2 and 3 or more), ascites, pain, the line of immunotherapy (I–II and III–IV) and N LR level. Multivariate analyses revealed the presence of ascites (p = 0.001), immunotherapy administration in III– IV lines (p = 0.02), and NLR≥1.8 (p = 0.004) were independent prognostic factors for OS. Each factor was assigned with a score from 1 to 2, depending on its significance: presence of ascites – 2 points, high NLR – 2 points, III–IV line of immunotherapy – 1 point. Patients were stratified into two prognostic groups according to the number of prognostic factors – the group with favorable prognosis (0–2 points, n = 20) and unfavorable prognosis (3–5 points, n = 22). The mOS of patients with favorable and unfavorable prognosis was 6 months and 3 months, respectively (p = 0.048).Conclusion. Ascites, NLR level of ≥1.8 and administration of ICIs in late setting are associated with low efficacy of immunotherapy in patients with MSS mGC. Further research should be planned including more patients and those who did not receive ICIs to determine the prognostic significance of our model.

Immunotherapy Following Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients with Anaplastic Lymphoma Kinase‑Positive Non‑small Cell Lung Cancer in Japan.

Although anaplastic lymphoma kinase inhibitors (ALKis) are the effective initial treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), most patients experience resistance to ALKis, leading to the need for alternative therapies. Immune checkpoint inhibitors (ICIs) are a standard NSCLC treatment. On the other hand, their efficacy remains unclear for ALK-positive NSCLC. We aim to describe the treatment patterns and treatment outcomes for patients with ALK-positive NSCLC receiving later-line ICI treatment. This retrospective cohort study used claims data from Japanese acute care hospitals and included patients with lung cancer (International Classification of Diseases, 10th version (ICD-10), code: C34) diagnosed between 1 December 2015 and 31 January 2023. We extracted patients who received ALKis as first-line therapy and subsequent lines of treatment. Patient characteristics and treatment patterns and durations were descriptively summarized. Time to treatment discontinuation (TTD) for ICIs was examined using Kaplan-Meier estimates. Of 478 patients who received ALKi as first-line treatment, 30 received ICIs, 249 ALKis, and 154 non-ICI/ALKi therapy as second-line treatment. Most patient characteristics showed no differences among the groups. ICIs were more likely to be administered to patients who underwent shorter durations of ALKi treatment. The median TTD for ICIs was 66 days, with a 1 year TTD rate of 13%. Given the rarity of ALK-positive NSCLC, this study contributes to add evidence through an expanded database and increased sample size, supporting previous suggestions that ICIs have limited effectiveness in patients positive for ALK.

Third- or Further-Line Treatment in Patients with MSS Type Metastatic Colorectal Cancer

BackgroundThe survival benefit from later-line treatment for patients with metastatic colorectal cancer (mCRC) remains disappointing. Here, in a real-world study, we were aimed to evaluate which choice will affect the survival of mCRC patients after standard treatment in Chinese patients.MethodsA total of 129 patients with refractory mCRC were involved in the study. They received targeted monotherapy or combined with chemo-agents or PD-1 inhibitor before death. Overall survival (OS) and progression-free survival (PFS) were reviewed and evaluated from clinical features and treatment options.ResultsAmong the 129 patients, the median age was 56 years (25–81). The mOS from third-line was 12.5 months. OS of patients who treated with chemo plus targeted therapy group in third-line was shown to be superior to pd-1 inhibitor in combination with antiangiogenic agents or antiangiogenic monotherapy group (15.6 m vs. 10.5 m vs. 8.4 m, p < 0.05). Patients had received triplet-drugs (bevacizumab plus low-dose irinotecan and oxaliplatin) and had prolonged survival compared to those had not (21.3 m vs 10.3 m, p = 0.004). OS between patients who had immunotherapy history or not was not significantly different (p > 0.05). The mPFS was 3.5 months in patients who had administered with antiangiogenic targeted agents plus anti-pd-1 and 4.7 months in chemo plus targeted therapy group and 2.2 months in the other group. In the triplet drugs group, preliminary results showed that ORR was 13.3% and DCR was 80%. The median PFS was 5.1 m, and the median OS was 10.6 m.ConclusionsTriplet drugs resulted in significantly longer overall survival, and immunotherapy may have limited benefit in MSS type CRC patients.