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Current Problems in Cancer Dec 2021
Topics: Antineoplastic Agents, Immunological; Genes, ras; Humans; Hypertrichosis; Male; Middle Aged; Panitumumab; Rectal Neoplasms
PubMed: 33933278
DOI: 10.1016/j.currproblcancer.2021.100748 -
Nature Medicine Jan 2024The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the...
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
Topics: Humans; Panitumumab; Proto-Oncogene Proteins p21(ras); Antibodies, Monoclonal; Colorectal Neoplasms; ErbB Receptors; Mutation; Antineoplastic Combined Chemotherapy Protocols; Piperazines; Pyridines; Pyrimidines
PubMed: 38177853
DOI: 10.1038/s41591-023-02717-6 -
Nature Medicine Aug 2022Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the...
Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Circulating Tumor DNA; Colonic Neoplasms; Colorectal Neoplasms; Humans; Mutation; Panitumumab; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms
PubMed: 35915157
DOI: 10.1038/s41591-022-01886-0 -
JAMA Oncology Jul 2023Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR)... (Randomized Controlled Trial)
Randomized Controlled Trial
Panitumumab Plus Trifluridine-Tipiracil as Anti-Epidermal Growth Factor Receptor Rechallenge Therapy for Refractory RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.
IMPORTANCE
Current third-line therapies for patients with metastatic colorectal cancer (MCRC) have limited efficacy. Rechallenge with epidermal growth factor receptor (EGFR) inhibitors for RAS wild-type (WT) MCRC may be valuable for these patients.
OBJECTIVE
To compare the anti-EGFR monoclonal antibody panitumumab plus standard-of-care trifluridine-tipiracil with trifluridine-tipiracil alone as third-line therapy for RAS WT MCRC.
DESIGN, SETTING, AND PARTICIPANTS
This phase 2 randomized clinical trial (RCT) was conducted in 7 Italian centers from June 2019 to April 2022. Patients with refractory RAS WT MCRC who had a partial or complete response to first-line chemotherapy plus an anti-EGFR monoclonal antibody and an anti-EGFR drug-free interval of 4 or more months during second-line therapy were included.
INTERVENTIONS
Patients were randomized 1:1 to receive panitumumab plus trifluridine-tipiracil or trifluridine-tipiracil alone.
MAIN OUTCOMES AND MEASURES
The primary end point was progression-free survival (PFS). Circulating tumor DNA (ctDNA) extended sequence variation analysis was performed in a subgroup of patients.
RESULTS
Of 62 included patients, 31 received panitumumab plus trifluridine-tipiracil (19 [61.3%] male; median age, 65 years [range, 39-81 years]) and 31 received trifluridine-tipiracil alone (17 [54.8%] male; median age, 66 years [range, 32-82 years]). The primary end point was met. Median PFS was 4.0 months (95% CI, 2.8-5.3 months) in the panitumumab plus trifluridine-tipiracil arm vs 2.5 months (95% CI, 1.4-3.6 months) in the trifluridine-tipiracil only (hazard ratio [HR], 0.48; 95% CI, 0.28-0.82; P = .007). Pretreatment plasma RAS/BRAF WT ctDNA identified patients obtaining prolonged clinical benefit with panitumumab plus trifluridine-tipiracil compared with trifluridine-tipiracil, with PFS rates at 6 months of 38.5% vs 13.0% and at 12 months of 15.4% vs 0%. A ctDNA liquid-biopsy extended mutation analysis by FoundationOne Liquid CDx (profiling 324 genes) was performed in a subgroup of patients with baseline plasma RAS/BRAF WT ctDNA; in 15 of 23 patients (65.2%) whose tumors were WT for KRAS, NRAS, BRAFV600E, EGFR, ERBB2, MAP2K1, and PIK3CA, median PFS was 6.4 months (95% CI, 3.7-9.2 months). Within this group of 15 patients, 2 (13.3%) had partial response, 11 (73.3%) had stable disease, and 2 (13.3%) had disease progression as best response.
CONCLUSIONS AND RELEVANCE
In this RCT, third-line treatment with the anti-EGFR monoclonal antibody panitumumab plus the standard-of-care trifluridine-tipiracil resulted in improved PFS compared with treatment with trifluridine-tipiracil alone among patients with refractory RAS WT MCRC. The findings support the clinical utility of liquid biopsy-guided anti-EGFR rechallenge therapy for refractory RAS WT MCRC.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05468892.
Topics: Aged; Female; Humans; Male; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Panitumumab; Proto-Oncogene Proteins B-raf; Trifluridine
PubMed: 37200022
DOI: 10.1001/jamaoncol.2023.0655 -
Journal of Oncology Pharmacy Practice :... Jul 2022The addition of panitumumab to chemotherapy in wild-type metastatic colon cancer contributes to survival. While the skin related side effects of panitumumab are well...
INTRODUCTION
The addition of panitumumab to chemotherapy in wild-type metastatic colon cancer contributes to survival. While the skin related side effects of panitumumab are well known, we wanted to present a case where it was a possible cause of acute pancreatitis.
CASE REPORT
The FOLFOX regimen was started in a 67-year-old patient with sigmoid colon cancer and multiple liver metastases. After 2 cycles, genetic tests were concluded and panitumumab 6 mg/kg was added to the treatment. The patient who presented with abdominal pain 2 days after the treatment was hospitalized with acute pancreaatitis.
MANAGEMENT & OUTCOME
Abdominal tomography of the patient was compatible with acute pancreatitis. Oral intake was stopped, IV hydration was started. The patient, whose complaints regressed, was discharged on the 3rd day of hospitalization.
DISCUSSION
Skin side effects related to panitumumab are observed quite frequently. Although panitumumab related gastrointestinal side effects have been reported, there is no data on acute pancreatitis. Panitumumab was added to the chemotherapy regimen he received, and it was thought that panitumumab might be the etiological factor in the case who developed pancreatitis.
Topics: Male; Humans; Aged; Panitumumab; Antibodies, Monoclonal; Acute Disease; Pancreatitis; Fluorouracil; Colonic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms
PubMed: 35037780
DOI: 10.1177/10781552221073997 -
Current Oncology (Toronto, Ont.) Oct 2019Mutations in have been implicated in the pathogenesis of various types of cancer, and therefore antibody therapy directed against the epidermal growth factor receptor...
Mutations in have been implicated in the pathogenesis of various types of cancer, and therefore antibody therapy directed against the epidermal growth factor receptor (egfr) is increasingly being used in the management of various cancers. Currently, anti-egfr antibodies are used mainly in the management of cancers of the head and neck and metastatic colorectal cancers. Because of this increasing use, we would like to inform the oncology community in North America of a rare, but life-threatening, toxicity associated with anti-egfr antibody therapy. Although cases in white and Japanese men have been documented, we present the first known North American report of panitumumab-induced pulmonary toxicity in a white woman.
Topics: Antineoplastic Agents, Immunological; Colonic Neoplasms; ErbB Receptors; Female; Humans; Lung; Middle Aged; Panitumumab; Respiratory Distress Syndrome
PubMed: 31708664
DOI: 10.3747/co.26.5399 -
Biomedicine & Pharmacotherapy =... Apr 2023The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative....
The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.
Topics: Humans; Animals; Mice; Photosensitizing Agents; Cell Line, Tumor; Phototherapy; Immunotherapy; Panitumumab; Bone Neoplasms; Xenograft Model Antitumor Assays
PubMed: 36791566
DOI: 10.1016/j.biopha.2023.114390 -
Nature Medicine Mar 2024Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic...
Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .
Topics: Humans; Panitumumab; Bevacizumab; Antibodies, Monoclonal; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 38347302
DOI: 10.1038/s41591-023-02791-w -
Pharmacokinetic and pharmacodynamic evaluation of panitumumab in the treatment of colorectal cancer.Expert Opinion on Drug Metabolism &... 2015Integration of targeted therapy and additional chemotherapy options has improved median overall survival (OS) in patients with unresectable metastatic colorectal cancer... (Review)
Review
INTRODUCTION
Integration of targeted therapy and additional chemotherapy options has improved median overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC). Cetuximab and panitumumab are examples of targeted therapies, specifically against the epidermal growth factor receptor (EGFR). This review focuses on Panitumumab, a fully human IgG2 monoclonal antibody, which inhibits key oncogenic downstream cell signalling pathways. Panitumumab and cetuximab have improved tumour response rate, progression-free survival, and OS in mCRC patients in whom the RAS (Rat Sarcoma) gene is of Wild Type (WT) status.
AREAS COVERED
The EGFR signalling pathway and preclinical, Phase I and Phase II clinical studies on the pharmacokinetic, pharmacodynamic and safety evaluation of panitumumab are presented. Phase III studies utilising panitumumab in the first, second and third line setting in mCRC are also described.
EXPERT OPINION
Panitumumab exhibits excellent pharmacokinetics and pharmacodynamics by way of uncomplicated dosing, non-existent drug interactions, minimal infusion reactions and manageable side effects, making it a suitable target for combination treatments. However, innate and acquired resistances are still obstacles. To overcome this, experimented strategies are ongoing, particularly in patients with Her-2 and BRAF gene alterations. Novel biomarkers to improve patient selection and second-generation targeted antibodies are in development.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Humans; Molecular Targeted Therapy; Panitumumab; Patient Selection; Survival Rate
PubMed: 26572750
DOI: 10.1517/17425255.2015.1112787 -
Cancer Discovery Jan 2024To boost KRASG12C inhibitor efficacy and counter cancer cells' ability to mount resistance, combination strategies are being utilized. Findings from the phase III...
To boost KRASG12C inhibitor efficacy and counter cancer cells' ability to mount resistance, combination strategies are being utilized. Findings from the phase III CodeBreaK 300 trial indicate that adding the EGFR inhibitor panitumumab to sotorasib bests standard care for chemorefractory KRASG12C colorectal cancer. Joint SHP2 blockade is another approach that shows signs of activity in reversing acquired KRASG12C inhibitor resistance, according to preliminary phase I data.
Topics: Humans; Antibodies, Monoclonal; Colorectal Neoplasms; ErbB Receptors; Panitumumab; Mutation; Proto-Oncogene Proteins p21(ras)
PubMed: 37921413
DOI: 10.1158/2159-8290.CD-ND2023-0015