Growth Factor Receptor Monoclonal Antibody Research Articles

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

[Chinese expert consensus on maintenance treatment with anti-EGFR monoclonal antibody for RAS wild-type metastatic colorectal cancer (2024 edition)].

For patients with metastatic colorectal cancer (mCRC) who achieve disease control during first-line standard therapy, post-induction strategies should emphasize on quality of life improvement while maintaining disease control. Chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody is the standard first-line treatment for RAS wild-type mCRC patients. After anti-EGFR-based first-line induction therapy achieves at least stable disease, anti-EGFR-based maintenance treatment could maintain disease control while keeping a good safety profile. Based on research evidence and clinical practice, the Chinese expert consensus on anti-EGFR-based maintenance strategy for RAS wild-type mCRC aims to futher clarify the treatment timing, regimen options, adverse reaction management and follow-up strategy, providing standardized guidance to maximize the clinical benefit in RAS wild-type mCRC.

A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .

Real-world evidence of FOLFIRI combined with anti-angiogenesis inhibitors or anti-EGFR antibodies for patients with early recurrence colorectal cancer after adjuvant FOLFOX/CAPOX therapy in Japan: A retrospective observational study using administrative database.

110 Background: Oxaliplatin-containing regimens (FOLFOX or CAPOX) are the most common adjuvant treatments after curative resection of colorectal cancer (CRC). However, real-world evidence (RWE) of treatment sequence/outcomes for patients with early recurrence CRC after receiving adjuvant chemotherapy are limited. Methods: This retrospective cohort study was based on an administrative database in Japan. The primary objective was to describe the treatment sequence for patients with early recurrence CRC and treated by combination of FOLFIRI and anti-angiogenesis inhibitors (AAIs) or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) after adjuvant FOLFOX or CAPOX therapy. The study included patients with CRC who underwent surgical resection, started adjuvant chemotherapy ≤3 months (mo) after the first surgery, had early recurrence of CRC (defined as initiation of FOLFIRI + AAIs/anti-EGFR mAbs second line [2L] regimen) within 1 year after adjuvant chemotherapy ended. Patient characteristics at baseline of 2L (60 days prior to 2L initiation) and treatment sequence were summarized descriptively; time to discontinuation (TTD) for adjuvant and 2L therapy were analyzed using Kaplan-Meier method. Cox proportional hazard model was used to identify risk factors associated with TTD of 2L regimen. Results: The cohort included 832 patients: median (range) age was 67 (24-86) years, 56.4% males, 65.5% with left-sided CRC. Most patients received CAPOX (71.3%) as adjuvant therapy. Median (95% CI) duration of adjuvant therapy was 5.4 mo (5.3-5.5). As 2L therapy, 72.5% and 27.5% of patients received FOLFIRI + AAIs (AAIs group) and FOLFIRI + anti-EGFR mAbs (anti-EGFR group), respectively. Median TTD (95% CI) of the AAIs and anti-EGFR groups in 2L were 6.2 mo (5.8-6.9) and 6.1 mo (5.2-7.4), respectively. Among patients with recurrence within 6 mo (72.6%), the median TTD (95% CI) for AAIs and anti-EGFR groups were 6.1 mo (5.5- 6.5) and 5.8 mo (5.1-7.8), respectively. Among patients with recurrence during 6 to 12 mo (27.4%), the median TTD (95% CI) of AAIs and anti-EGFR groups were 8.1 mo (6.1-9.2) and 6.2 mo (4.6-8.0), respectively. Age ≥70 years was negatively associated with TTD of 2L, HR = 1.19 (95% CI: 1.02-1.39); p=0.03. Conclusions: This is the first RWE based on administrative data on treatment sequence/ outcomes for patients with early recurrence CRC treated by FOLFIRI + AAIs/anti-EGFR mAbs after adjuvant FOLFOX/CAPOX therapy in Japan. The treatment outcomes for patients with early recurrence CRC were similar to previous clinical trials in 2L advanced CRC. The results suggested that these two 2L regimens had similar TTD; however, the timing of relapse may influence the efficacy of AAIs and anti-EGFR mAbs.

Impact of early tumor shrinkage and depth of response in patients with BRAF V600E-mutant metastatic colorectal cancer.

142 Background: Early tumor shrinkage (ETS) and the depth of response (DpR) are early on-treatment surrogate markers for survival in patients with metastatic colorectal cancer (mCRC) receiving anti-epidermal growth factor receptor (EGFR) monoclonal antibody. However, the utility of ETS and DpR for BRAF V600E mutant (MT) mCRC which has a poor prognosis remains unclear. The aim of this study is to evaluate the association between ETS and DpR and clinical outcomes in BRAF V600E MT mCRC. Methods: mCRC patients who were diagnosed BRAF V600E MT and treated with 1st line chemotherapy from June 2011 to March 2023 at single cancer institute were enrolled. We analyzed the association between ETS and DpR and clinical outcome in patients who had at least one target lesion. Subgroup analysis of clinical factors related to progression free survival (PFS) and overall survival (OS) was performed using multivariate analysis. ETS was defined as the relative change in the sum of the longest diameters of RECIST target lesions at first follow-up CT scan compared to baseline and DpR was defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline. Results: In total, 54 patients of BRAF V600E MT mCRC had at least one target lesion. In total of StageI-IV CRC patients, the incidence of BRAF V600E MT was 6.3% (233/3705). Patients with ETS ≥ 20% and DpR ≥ 25% (median value) were 24 (44.4%) and 27 (50%) respectively. PFS was 7.5 months (95% confidence interval (CI), 5.0-9.9) and OS was 17.1 months (95% CI, 11.7-20.2). Patients with ETS ≥ 20% had longer PFS and tended to have longer OS than those with non-ETS, with a median PFS of 9.8 months vs. 4.8 months (P Log-rank = 0.048, hazard ratio (HR), 0.55; 95% CI, 0.30-1.00), and a median OS of 22.6 months vs. 11.6 months (P Log-rank = 0.18, HR, 0.67; 95% CI, 0.37-1.21). Patients with DpR ≥ 25% had also longer PFS and OS than those with non-DpR, with a median PFS of 11.0 vs. 4.3 months (P Log-rank < 0.01, HR, 0.36; 95% CI, 0.20-0.66) and a median OS of 22.6 vs. 10.1 months (P Log-rank = 0.047, HR, 0.55; 95% CI, 0.31-1.00). Median time to DpR was 3.05 months. In multivariate analysis, DpR was significantly associated with both longer PFS (HR: 0.27, 95% CI: 0.14–0.55, P < 0.01) and OS (HR: 0.52, 95% CI: 0.29–0.96, P = 0.04). Conclusions: ETS and DpR may be early surrogate markers for clinical outcome in BRAF V600E MT mCRC who were treated with 1st line chemotherapy.

Efficacy, safety and genomic analysis of SCT200, an anti-EGFR monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type metastatic colorectal cancer: a phase Ⅱ study

Limited therapeutic options are available for metastatic colorectal cancer (mCRC) patients after failure of first- and second-line therapies, representing an unmet medical need for novel therapies. This is an open-label, single arm, multicenter, phase Ⅱ study aiming to perform the efficacy, safety and genomic analysis of SCT200, a noval fully humanized IgG1 anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in patients with fluorouracil, irinotecan and oxaliplatin refractory RAS and BRAF wild-type mCRC. SCT200 (6mg/kg) was given weekly for the first six weeks, followed by a higher dose of 8mg/kg every two weeks until disease progression or unacceptable toxicity. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) and secondary endpoints included ORR in patients with left-sided tumor, disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. From February 12, 2018 to December 1, 2019, a total of 110 patients aged between 26 and 77 years (median: 55; interquartile range [IQR]: 47-63) with fluorouracil, oxaliplatin, and irinotecan refractory RAS and BRAF wild-type mCRC were enrolled from 22 hospitals in China. As the data cut-off date on May 15, 2020, the IRC-assessed ORR and DCR was 31% (34/110, 95% confidence interval [CI] 22-40%) and 75% (82/110, 95% CI 65-82%), respectively. Thirty one percent (34/110) patients achieved confirmed partial response (PR). The median PFS and median OS were 5.1 months (95% CI 3.4-5.2) and 16.2 months (95% CI 11.1-not available [NA]), respectively. The most common≥grade 3 treatment-related adverse events (TRAEs) were hypomagnesemia (17%, 19/110) and acneiform dermatitis (11%, 12/110). No deaths occurred. Genomic analysis suggested positive association between MYC amplification and patients' response (P=0.0058). RAS/RAF mutation and MET amplification were the most frequently detected resistance mechanisms. Patients with high circulating tumor DNA (ctDNA) at baseline or without ctDNA clearance at the 7th week after the first dose of SCT200 administration before receiving SCT200 had worse PFS and OS. SCT200 exhibited promising clinical efficacy and manageable safety profiles in RAS and BRAF wild-type mCRC patients progressed on fluorouracil, irinotecan and oxaliplatin treatment. The baseline ctDNA and ctDNA clearance status at the 7th week after the first dose of SCT200 administration before receiving SCT200 could be a potential prognostic biomarker for RAS and BRAF wild-type mCRC patients with SCT200 therapy. This study was sponsored by Sinocelltech Ltd., Beijing, China and partly supported by the National Science and Technology Major Project for Key New Drug Development (2019ZX09732001-006, 2017ZX09304015).

Potential Efficacy of Shiunko for Anti-Epidermal Growth Factor Receptor (EGFR) Monoclonal Antibody-Induced Skin Fissure: A Single Institutional Case Series.

Anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) is the key drug for RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). However, anti-EGFR mAb-induced skin fissures often affect a patient's quality of life. Shiunko, a traditional Japanese topical herbal medicine, is used for burns and dermatitis and may potentially have wound-healing effects. Herein, we report cases of patients with mCRC who were treated with Shiunko for anti-EGFR mAb-induced skin fissure. We retrospectively reviewed consecutive patients with mCRC who received an anti-EGFR mAb-containing regimen and were treated with Shiunko twice a day for skin fissures at the National Cancer Center Hospital East between March 2022 and December 2022. Skin fissures were assessed at baseline and at every visit until 28 days after Shiunko initiation according to CTCAE v5.0. Among the 11 patients, 5 patients were female; the median age was 61 (range, 43-79) years. The median treatment duration with anti-EGFR mAb before Shiunko initiation was 13.1 (range, 6-52) weeks. Skin moisturizer and topical steroids were applied for skin fissures in 11 and 5 patients, respectively. All patients had grade 2 skin fissures at baseline of Shiunko initiation. Two weeks after Shiunko initiation, complete recovery was noted in 4 patients and improvement to grade 1 was noted in 6 patients. There were no Shiunko-related adverse events. Ten patients continued anti-EGFR mAb treatment until disease progression, while 1 patient discontinued anti-EGFR mAb treatment due to severe eruptions. Shiunko could be a treatment option for anti-EGFR mAb-induced skin fissure. Further studies are warranted to investigate the efficacy and safety of Shiunko for anti-EGFR mAb-induced skin fissure.

Effect of ramucirumab plus paclitaxel in advanced gastric cancer according to the status of programmed cell death-ligand 1 (PD-L1) expression.

Ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibody (mAb), inhibits angiogenesis and reduces tumor activity. Programmed cell death-ligand 1 (PD-L1) might act upon VEGFR2 to induce cancer cell angiogenesis and metastasis. Herein, we investigated the efficacy of combining ramucirumab and paclitaxel according to the status of PD-L1 expression in patients with advanced gastric cancer (AGC). This analysis included AGC patients who received ramucirumab plus paclitaxel as 2nd line therapy between December 1, 2018, and February 28, 2022, at Samsung Medical Center. All patient data analyses included an evaluation of PD-L1 expression using the combined positive score (CPS). We analyzed the efficacy and the survival of patients according to their PD-L1 expression. We included 117 patients in this analysis, and 80 patients (68.4%) had a PD-L1 CPS of one or more, 37 (31.6%) had five or more, and 19 (16.2%) had ten or more scores. Progression-free survival (PFS) and overall survival (OS) did not differ significantly between patients with a PD-L1 CPS of less than one and one or more {PD-L1 <1% vs. PD-L1 ≥1%; PFS: median 3.6 months [95% confidence interval (CI): 2.4-4.8 months] vs. median 4.1 months (95% CI: 3.5-4.7 months), P=0.93; PD-L1 <1% vs. PD-L1 ≥1%; OS: median 7.0 months (95% CI: 5.4-8.6 months) vs. median 8.1 months (95% CI: 6.4-9.8 months), P=0.32}. PFS and OS did not differ significantly between patients with a PD-L1 CPS of less than 5 and 5 or more [PD-L1 <5% vs. PD-L1 ≥5%; PFS: 3.9 months (95% CI: 3.3-4.5 months) vs. 4.4 months (95% CI: 3.0-5.8 months), P=0.57; OS: 7.4 months (95% CI: 6.5-8.3 months) vs. 10.0 months (95% CI: 1.1-18.9 months), P=0.07]. Interestingly, with a PD-L1 CPS cutoff of 10, PFS and OS did differ significantly [PD-L1 <10% vs. PD-L1 ≥10%; PFS: 3.8 months (95% CI: 3.3-4.3 months) vs. 5.7 months (95% CI: 4.1-7.3 months), P=0.05; OS: 7.2 months (95% CI: 6.5-7.9 months) vs. 18.9 months (95% CI: 6.5-31.3 months), P=0.04]. No biomarkers have been established to predict survival times after ramucirumab plus paclitaxel treatment. This analysis suggests that a PD-L1 CPS cutoff of 10 might be novel a biomarker to predict the survival of AGC patients treated with ramucirumab and paclitaxel.

Prolonging the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®): An orthogonal assessment of physicochemical, biological and microbiological properties of original opened glass vials and diluted saline preparations

The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type metastatic colorectal cancers. However, stability data of these mAbs are generally missing or incomplete. Here, we report for the first time an orthogonal analysis of the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®), either undiluted vial leftovers or saline dilutions in polyolefin/polyamide infusion bags. All samples were stored at 2–8 °C protected from light, according to their summary of product characteristics (SmPCs). Alternatively, opened vials and preparations were maintained at 25 °C for 15 h, and then stored again at 2–8 °C protected from light to mimic a temporary interruption of the cold chain. Vial leftovers proved stable up to 180 days when stored according to their SmPCs, while compounded preparations in infusion bags maintained their physiochemical, biological and microbiological stability up to 30 days. Additionally, no changes were detected up to 30 days for the same samples undergoing a thermal excursion. Our results provide additional rationale to the SmPCs, crucial especially in the case of reassignment and pre-preparation of bags. This information will allow hospitals to achieve significant cost savings, and better organization of the entire therapeutic process.

Monoclonal antibody cetuximab impairs matrix metalloproteinases 2 and 9, epithelial-mesenchymal transition and cell migration in feline oral squamous cell carcinoma in vitro.

Feline oral squamous cell carcinoma (FOSCC) is characterised by invasive and metastatic behaviour and is poorly responsive to current treatments, hence the need for new therapeutic strategies. FOSCC shares molecular targets with human head and neck squamous cell carcinoma (HNSCC), among these the epidermal growth factor receptor. Cetuximab is an anti-epidermal growth factor receptor monoclonal antibody employed in the therapy of HNSCC and, interestingly, previous work in vitro suggested that it displays cytostatic and cytotoxic properties also against FOSCC. With the present study, we aimed at further investigating the effects of cetuximab on invasion and metastasis pathways proven to be relevant in human patients. To this purpose, FOSCC cell lines SCCF1, SCCF2 and SCCF3 were treated with cetuximab for 48/72 h and subjected to Western blot for matrix metalloproteinases-2/9 (MMP-2/9) and epithelial-mesenchymal transition markers vimentin, E-, P- and N-cadherin. Treatment with cetuximab resulted in downregulation of MMP-2/-9 in all of the three cell lines in a dose-dependent manner. Moreover, cetuximab downregulated vimentin and P-cadherin in SCCF1, upregulated E-cadherin whilst downregulating P-/N-cadherins in SCCF2, and impaired P-/N-cadherins in SCCF3. An in vitro scratch test also demonstrated that cetuximab delayed cell migration in SCCF3. These data suggest that cetuximab mitigates invasion and metastasis processes by impairing MMPs and epithelial-mesenchymal transition pathways in FOSCC, indicating that this monoclonal antibody may help to counteract malignant progression and improve the management of locally invasive disease.

Prognostic and predictive biomarkers for anti-EGFR monoclonal antibody therapy in RAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis

BackgroundRAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.MethodsWe performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.ResultsThirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47–5.73) and 2.69 (1.82–3.98)] and OS [HRs = 2.66 (1.95–3.65) and 2.45 (1.55–3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.ConclusionsIn RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.

Protocol for the EACH trial: a multicentre phase II study evaluating the safety and antitumour activity of the combination of avelumab, an anti-PD-L1 agent, and cetuximab, as any line treatment for patients with recurrent/metastatic head and neck squamous cell cancer (HNSCC) in the UK

IntroductionHead and neck cancer is the eighth most common cancer in the UK. Current standard of care treatment for patients with recurrent/metastatic squamous cell head and neck carcinoma (HNSCC) is...

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with chemoradiotherapy for induction chemotherapy resistant locally advanced nasopharyngeal carcinoma: A prospective phase II study

ObjectivesTo investigate the efficacy and safety of nimotuzumab (NTZ) combined with concurrent chemo-radiotherapy (CCRT) in induction chemotherapy (IC) resistant locally advanced nasopharyngeal carcinoma (LANPC). Materials and methodsA single-arm, open-label phase II clinical trial was conducted (NCT04508816). Eligible patients were 18–70 years old, pathologically confirmed NPC at stage III-IVA, stable disease or progressive disease after IC by imaging evaluation, and ECOG performance status with 0–1. All patients received intensity-modulated radiotherapy (IMRT) concurrent with chemotherapy and NTZ (200 mg/w). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. ResultsFrom May 2015 to July 2020, 56 NPC patients were enrolled. With the median follow-up of 34 months (range from 8 to 77 months), the 3-year and 5-year PFS and OS rates were 79.3 % and 72.1 %, 94.0 % and 87.2 %, respectively. ORR of the nasopharynx and cervical lymph nodes involvement were 98.2 % and 98.1 % three months after IMRT. Univariate analysis revealed that pretreatment PET/CT was the factor that influenced PFS (P = 0.038). Patients treated with ≥6 weeks of NTZ showed improved 3‐year PFS rate (83.0% vs. 73.9 %, P > 0.05) and 5-year PFS rate (83.0% vs. 61.6 %, P>0.05) compared with <6 weeks NTZ. The acute toxicities were mainly grade 1/2 hematologic. Severe toxicities were uncommon. The major grade 3/4 AE was neutropenia (26.8 %). ConclusionsThe results demonstrated that NTZ combined with CCRT in IC resistant LANPC was effective with mild toxicity.

Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer.

The ephrin type-A 2 receptor tyrosine kinase (EPHA2) is involved in the development and progression of various cancer types, including colorectal cancer (CRC). There is also evidence that EPHA2 plays a key role in the development of resistance to the endothelial growth factor receptor (EGFR) monoclonal antibody Cetuximab used clinically in CRC. Despite the promising pharmacological potential of EPHA2, only a handful of specific inhibitors are currently available. In this concept paper, general strategies for EPHA2 inhibition with molecules of low molecular weight (small molecules) are described. Furthermore, available examples of inhibiting EPHA2 in CRC using small molecules are summarized, highlighting the potential of this approach.

Risk factor analysis for anti-epidermal growth factor receptor monoclonal antibody-induced skin toxicities in real-world metastatic colorectal cancer treatment.

Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are effective in treating RAS wild-type metastatic colorectal cancer (mCRC). However, their administration induces skin toxicity, markedly reducing patients' quality of life. This study is aimed at identifying the risk factors associated with anti-EGFR monoclonal antibody-induced skin toxicities. Patients with mCRC (n = 116) who received anti-EGFR monoclonal antibody treatment were retrospectively evaluated. Primary endpoint was evaluation of the risk factors for grade ≥ 2 overall skin toxicities during all the treatment periods. Furthermore, factors associated with each grade ≥ 2 skin symptoms were assessed. Incidence of total grade ≥ 2 skin toxicity symptoms was 61.2%, and those of grade ≥ 2 rash, dry skin, fissures, and paronychia were 34.5%, 25.9%, 20.7%, and 25.0%, respectively. Multivariate logistic regression analyses revealed that liver metastasis was an independent risk factor for overall grade ≥ 2 skin toxicities (adjusted odds ratio [OR], 2.88; 95% confidence interval [CI], 1.22-6.78; P = 0.02) and prophylactic administration of antibiotics as a preventive factor (OR 0.10; 95%CI 0.01-0.91; P = 0.04). For grade ≥ 2 rash, prophylactic use of systemic antibiotics and topical steroid ointment was a preventive factor (OR 0.37; 95%CI 0.16-0.89; P = 0.03). Moreover, liver metastasis (OR 8.37; 95%CI 1.98-35.47; P = 0.004) and prophylactic administration of antibiotics (OR 0.15; 95%CI 0.03-0.76; P = 0.02) were significantly associated with grade ≥ 2 paronychia. Liver metastasis was suggested to be a risk factor for the incidence of overall grade ≥ 2 skin toxicities; moreover, preemptive systemic antibiotic administration drastically decreased this risk during all periods of anti-EGFR treatment for mCRC.

A multicenter, phase II trial of GC1118, a novel anti-EGFR antibody, for recurrent glioblastoma patients with EGFR amplification.

We evaluated the therapeutic efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in recurrent glioblastoma (GBM) patients with EGFR amplification. This study was a multicenter, open-label, single-arm phase II trial. Recurrent GBM patients with EGFR amplification were eligible: EGFR amplification was determined using fluorescence in situ hybridization analysis when a sample had both the EGFR/CEP7 ratio of ≥2 and a tight cluster EGFR signal in ≥10% of recorded cells. GC1118 was administered intravenously at a dose of 4 mg/kg once weekly. The primary endpoint was the 6-month progression-free survival rate (PFS6). Next-generation sequencing was performed to investigate the molecular biomarkers related to the response to GC1118. Between April 2018 and December 2020, 21 patients were enrolled in the study and received GC1118 treatment. Eighteen patients were eligible for efficacy analysis. The PFS6 was 5.6% (95% confidence interval, 0.3%-25.8%, Wilson method). The median progression-free survival was 1.7 months (range: 28 days-7.2 months) and median overall survival was 5.7 months (range: 2-22.0 months). GC1118 was well tolerated except skin toxicities. Skin rash was the most frequent adverse event and four patients experienced Grade 3 skin-related toxicity. Genomic analysis revealed that the immune-related signatures were upregulated in patients with tumor regression. This study did not meet the primary endpoint (PFS6); however, we found that immune signatures were significantly upregulated in the tumors with regression upon GC1118 therapy, which signifies the potential of immune-mediated antitumor efficacy of GC1118.

Treatment outcome comparisons of first-line targeted therapy in patients with KRAS wild-type metastatic colorectal cancer: A nationwide database study.

The first-line systemic therapy for metastatic colorectal cancer (mCRC) is a combination of one targeted therapy agent and a chemotherapy doublet. Whether bevacizumab or anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (mAb) is the more effective addition to a chemotherapy doublet as the first-line treatment for inoperable KRAS wild-type mCRC remains controversial in prior clinical trials. Moreover, the association between the sidedness of primary tumors and the efficacy of anti-EGFR mAb needs to be addressed. We established a cohort of patients with KRAS wild-type mCRC who were treated with first-line targeted therapy plus doublet chemotherapy between 2013 and 2018 using Taiwan's National Health Insurance Research Database. Secondary surgery was defined as either resection of primary tumors, liver metastases, lung metastases, or radiofrequency ablation. A total of 6482 patients were included; bevacizumab and anti-EGFR mAb were the first-line targeted therapies in 3334 (51.4%) and 3148 (48.6%) patients, respectively. Compared with those who received bevacizumab, patients who received anti-EGFR mAb exhibited significantly longer overall survival (OS; median, 23.1 vs. 20.2 months, p = 0.012) and time to treatment failure (TTF; median, 11.3 vs. 10 months, p < 0.001). Among left-sided primary tumors, the OS and TTF benefits of anti-EGFR mAb remained. Among right-sided primary tumors, the OS and TTF were similar regardless of the type of targeted therapy. In multivariate analyses, first-line anti-EGFR mAb therapy remained an independent predictor of longer OS and TTF for left-sided primary tumors. Patients who received anti-EGFR mAb were more likely to receive secondary surgery (29.6% vs. 22.6%, p < 0.0001) than patients who received bevacizumab. For patients who received first-line doublet chemotherapy for KRAS wild-type mCRC, adding anti-EGFR mAb was associated with significantly longer OS and TTF, especially for left-sided primary tumors.

Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer.

Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance. This multicenter, randomized, noncomparative phase II study evaluated ficlatuzumab, an antihepatocyte growth factor mAb, with or without cetuximab in recurrent/metastatic HNSCC. The primary end point was median progression-free survival (PFS); an arm met significance criteria if the lower bound of the 90% CI excluded the historical control of 2 months. Key eligibility criteria were HNSCC with known human papillomavirus (HPV) status, cetuximab resistance (progression within 6 months of exposure in the definitive or recurrent/metastatic setting), and resistance to platinum and anti-PD-1 mAb. Secondary end points included objective response rate (ORR), toxicity, and the association of HPV status and cMet overexpression with efficacy. Continuous Bayesian futility monitoring was used. From 2018 to 2020, 60 patients were randomly assigned and 58 were treated. Twenty-seven versus 33 patients were allocated to monotherapy versus combination. Arms were balanced for major prognostic factors. The monotherapy arm closed early for futility. The combination arm met prespecified significance criteria with a median PFS of 3.7 months (lower bound 90% CI, 2.3 months; P = .04); the ORR was 6 of 32 (19%), including two complete and four partial responses. Exploratory analyses were limited to the combination arm: the median PFS was 2.3 versus 4.1 months (P = .03) and the ORR was 0 of 16 (0%) versus 6 of 16 (38%; P = .02) in the HPV-positive versus HPV-negative subgroups, respectively. cMet overexpression was associated with reduced hazard of progression in HPV-negative but not HPV-positive disease (P interaction = .02). The ficlatuzumab-cetuximab arm met significance criteria for PFS and warrants phase III development. HPV-negative HNSCC merits consideration as a selection criterion.

Treatment Protocols in the Efficacy and Safety of Anti-EGFR Medicines in Combination with Standard Therapy for Patients with Nasopharyngeal Cancer: A Meta-Analysis.

This study was conducted to compare the efficacy of standard therapy (radiotherapy/RT/CT) with that of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody (NPC) therapy in patients with advanced nasopharyngeal cancer. A meta-analysis was performed to meet the objective of this study. The English databases PubMed, Cochrane Library, and Web of Science were searched. The literature review compared anti-EGFR-targeted therapy with conventional therapy practices. The main outcome measure was overall survival (OS). Secondary goals were progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and adverse events (grade 3). The database search resulted in 11 studies, with a total of 4219 participants. It was found that combining an anti-EGFR regimen with conventional therapy did not enhance OS (hazard ratio [HR] = 1.18; 95%confidence interval [CI] = 0.51-2.40; p = 0.70) or PFS appreciably (HR = 0.95; 95%CI = 0.51-1.48; p = 0.88) in patients with nasopharyngeal carcinoma. While LRRFS increased considerably (HR = 0.70; 95%CI = 0.67-1.00; p = 0.01), the combined regimen did not improve DMFS (HR = 0.86; 95%CI = 0.61-1.12; p = 0.36). Treatment-related adverse events included haematological toxicity (RR = 0.2; 95%CI = 0.08-0.45; p = 0.01), cutaneous reactions (RR = 7.05; 95%CI = 2.15-23.09; p = 0.01), and mucositis (RR = 1.96; 95%CI = 1.58-2.09; p = 0.01). Individuals who have nasopharyngeal cancer do not have an increased chance of surviving until a local recurrence of their disease if they get normal therapy in addition to an anti-EGFR regimen. However, this combination does not enhance overall survival. On the other hand, this factor adds to an increase in the number of adverse effects.

Rechallenge with anti-EGFR therapy to extend the continuum of care in patients with metastatic colorectal cancer.

In patients with RAS wild-type metastatic colorectal cancer (mCRC), an anti-epidermal growth factor receptor (EGFR) monoclonal antibody plus chemotherapy is a standard option for treatment in the first-line setting. Patients who progress while on treatment with anti-EGFR-based therapy can be resistant to further anti-EGFR treatment, but evidence suggests that the anti-EGFR-resistant clones decay, thereby opening the potential for rechallenge or reintroduction in later lines of treatment. Results from recent clinical studies have shown that some patients with mCRC who are rechallenged with anti-EGFR monoclonal antibodies exhibit durable responses. While other therapies have demonstrated improved overall survival in chemorefractory mCRC over the past decade, rechallenge with anti-EGFR monoclonal antibodies in later lines of treatment represents a new option that deserves further investigation in clinical trials. In this review, we summarize the molecular rationale for rechallenge or reintroduction in patients with mCRC who have progressed on earlier-line anti-EGFR treatment and examine the current evidence for using liquid biopsy as a method for selecting rechallenge as a therapeutic option. We also provide an overview of published trials and trials in progress in this field, and outline the potential role of rechallenge in the current clinical setting.