Vectibix (panitumumab)

Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

From an initial pool of 1345 articles, 11 relevant studies were selected for inclusion, encompassing a diverse range of systemic treatments, including panitumumab combined with FOLFOX4 and FOLFIRI, irinotecan paired with panitumumab, regorafenib followed by cetuximab ± irinotecan and vice versa, and panitumumab as a maintenance therapy post-induction...Notably, cetuximab + FOLFIRI was associated with a median survival of 25.7 months versus 16.4 months for FOLFIRI alone, emphasizing the potential benefits of integrating targeted therapies with chemotherapy. In conclusion, the review underscores the significant impact of systemic treatments, particularly targeted therapies and their combinations with chemotherapy, on survival outcomes and QoL in patients with RAS-positive stage IV colorectal cancer, and the need for personalized treatment.

P1/2, N=1126, Recruiting, Amgen | Trial primary completion date: Sep 2026 --> Dec 2026

P=N/A, N=647, Completed, iOMEDICO AG | Active, not recruiting --> Completed

P3, N=408, Recruiting, ECOG-ACRIN Cancer Research Group | Not yet recruiting --> Recruiting

The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

P2, N=71, Recruiting, University of Wisconsin, Madison | N=110 --> 71

P1, N=30, Recruiting, Vanderbilt-Ingram Cancer Center | Initiation date: Apr 2024 --> Aug 2023

Patients received anti-EGFR rechallenge therapy, including cetuximab plus avelumab, trifluridine-tipiracil plus panitumumab, irinotecan plus cetuximab, or panitumumab monotherapy. Within the limitation of a subgroup analysis, the absence of liver metastases was associated with significant improved survival. ClinicalTrials.gov Identifiers: NCT02296203; NCT04561336; NCT03227926; NCT05468892.

According to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.

P2, N=75, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

P2, N=25, Recruiting, University of Alabama at Birmingham | Trial primary completion date: Dec 2025 --> Dec 2026

P1/2, N=107, Completed, NuCana plc | Recruiting --> Completed | N=225 --> 107 | Trial completion date: Nov 2023 --> Mar 2024 | Trial primary completion date: Nov 2023 --> Mar 2024

Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation...In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

P2, N=46, Recruiting, Gruppo Oncologico del Nord-Ovest

P1, N=64, Recruiting, MapKure, LLC | Not yet recruiting --> Recruiting

These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

P3, N=464, Active, not recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Recruiting --> Active, not recruiting | Trial completion date: Jun 2021 --> Dec 2024 | Trial primary completion date: Jun 2021 --> Jul 2023

Promising inhibitors such as sotorasib and adagrasib targeting KRASG12C mutations have demonstrated efficacy...Treatment with FOLFIRINOX and bevacizumab, and later FOLFIRI and bevacizumab, with surgeries and local interventions resulted in partial responses...This case highlights the remarkable outcome of a heavily treated KRAS G12C mutant mCRC patient. The combination of sotorasib and panitumumab, along with multidisciplinary approaches including surgery and local interventions, played an important role in our patient's survival.

We evaluated the relative efficacy and safety of first-line EGFRIs plus doublet chemotherapy (FOLFIRI or FOLFOX) vs. bevacizumab plus doublet chemotherapy for patients with RAS WT left-sided mCRC, as well as in all- and right-sided tumors...Safety was available in 6 trials for all-sided tumors and 1 trial for left-sided tumors, each demonstrating typical class-specific adverse events. This most comprehensive meta-analysis indicates a benefit for first-line EGFRI plus chemotherapy over bevacizumab plus chemotherapy in patients with left-sided RAS WT mCRC.

The pivotal trials of cetuximab in combination with BRAF/ MEK inhibitor for BRAF V600E mutant mCRC, and panitumumab with KRAS G12C inhibitor in KRAS(G12C)-mutant mCRC have been practice-changing. The non-invasive monitoring of molecular resistance to targeted therapies using Next Generation Sequencing analysis of circulating tumor-derived DNA (ctDNA) and captured sequencing of tumors have improved patient selection for targeted therapies. This review will focus on how latest advances, challenges and future directions in the development of targeted therapies in mCRC.

P2, N=15, Not yet recruiting, Nicholas DeVito, MD

P1, N=30, Recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Aug 2029 --> Nov 2029 | Initiation date: Dec 2023 --> Apr 2024 | Trial primary completion date: Aug 2028 --> Nov 2028

P3, N=450, Not yet recruiting, Amgen

P2, N=73, Not yet recruiting, UNICANCER

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. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

P2, N=22, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

Based on the findings of molecular and pathological examinations(RAS: wild type; BRAF: wild type; MSI: negative; HER2: negative), the following chemotherapy regimens were administered: first-line, FOLFIRI plus panitumumab(PANI); second-line, mFOLFOX6; third-line, trifluridine/tipiracil; fourth- line, regorafenib...Therefore, rechallenge therapy with anti-epidermal growth factor receptor(EGFR)drugs, cetuximab(CET)and irinotecan(IRI), was administered 13 months after the final course of FOLFIRI plus PANI treatment. After 4 courses of CET plus IRI, the size of the 2 metastatic tumors markedly decreased and his tumor marker levels normalized.

Because of RAS/BRAF wild type, we started the mFOLFOX6 plus panitumumab (Pmab)...After that, the chemotherapy was changed to 5-FU 80% FOLFIRI plus bevacizumab, but hyperammonemia recurred...In this case, muscle weakness due to sarcopenia was considered to be one of the causes. We believe that oral drugs containing FTD/TPI can be used relatively safely without causing hyperammonemia.

The patient underwent sigmoidectomy with D3 lymph node dissection and partial bladder resection for sigmoid colon cancer(cT4bN1M0, cStage Ⅲa), after preoperative chemotherapy with mFOLFOX plus panitumumab, and FOLFOXIRI plus bevacizumab...Although he was treated with FOLFIRI plus ramucirumab or aflibercept, resulted in progression of disease, then he received trifluridine tipiracil hydrochloride plus bevacizumab...He has received pembrolizumab for 4 years without another recurrence. Here, we report a case of MSI-high sigmoid colon cancer in which long-term survival was achieved by pembrolizumab for recurrent lesions resistant to conventional chemotherapy.

P2, N=105, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Extended molecular profiling beyond RAS may have the potential to improve of the patient selection for anti-EGFR containing maintenance regimens.

Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.

P3, N=355, Recruiting, City Clinical Oncology Hospital No 1

In our systematic review, we revised available data from clinical trials assessing anti-EGFR rechallenge activity in chemo-refractory mCRC patients, discussing as well potential future scenarios and development to implement this therapeutic approach. Particularly, we discussed the role of ctDNA as a safe, timely and comprehensive tool to refine patient's selection and the therapeutic index of anti-EGFR rechallenge.

KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.

P1, N=5, Completed, Rutgers, The State University of New Jersey | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Feb 2023 | Trial primary completion date: Sep 2024 --> Feb 2023

P1/2, N=12, Not yet recruiting, Stanford University | Trial primary completion date: Aug 2023 --> Aug 2024

P1, N=64, Not yet recruiting, MapKure, LLC

Anti-EGF VacAbs enhance the antiproliferative effects of drugs targeting the ERK/MAPK and PIK3CA/Akt pathways. Our data provide a rationale for clinical trials testing anti-EGF vaccination combined with inhibitors selected according to the patient's genetic profile.

Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .

This activity is supported by educational grants from Natera Inc and Pfizer Inc. Frequency and clinical relevance of HER2 aberrations among patients with mCRC Published data from the pivotal Phase II MOUNTAINEER trial evaluating tucatinib/trastuzumab for previously treated HER2-positive mCRC; recent FDA approval and optimal incorporation into practice Available efficacy and safety findings with trastuzumab deruxtecan (T-DXd) for patients with HER2-expressing mCRC (eg, from the DESTINY-CRC01 and DESTINY-CRC02 trials); current and potential nonresearch role Incidence of KRAS G12C mutations in patients with mCRC; early data with sotorasib and adagrasib monotherapy Biological rationale for combining KRAS G12C inhibitors with EGFR antibodies Recently presented results from the Phase III CodeBreaK 300 study evaluating sotorasib with panitumumab versus standard therapy for chemorefractory mCRC with KRAS G12C mutations; implications for clinical practice Early data with and ongoing evaluations of other targeted strategies for mCRC