The management of metastatic colorectal cancer (mCRC) and metastatic and recurrent loco-regional squamous cell cancer of the head and neck (SCCHN) continues to evolve, not only as new agents reach the clinic but also new understandings of how best to utilize existing agents to optimize clinical outcomes for patients. One of the continuing areas of focus is use of inhibitors of the epidermal growth factor receptor (EGFR) pathway. For both mCRC and metastatic and recurrent loco-regional SCCHN, increasing attention is being placed on second-line approaches as well as first-line application in combination with radiation therapy and/or platinum-based chemotherapy.
Global Oncology Academy
Best Practices for Existing Epidermal Growth Factor Receptor (EGFR) Inhibitor Agents
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Best Practices for Existing Epidermal Growth Factor Receptor (EGFR) Inhibitor Agents
EGFR Pathway Inhibition: A History Lesson from the European Medicines Agency (EMA)
The management of metastatic colorectal cancer (mCRC) and metastatic and recurrent loco-regional squamous cell cancer of the head and neck (SCCHN) continues to evolve, not only as new agents reach the clinic but also new understandings of how best to utilize existing agents to optimize clinical outcomes for patients. One of the continuing areas of focus is use of inhibitors of the epidermal growth factor receptor (EGFR) pathway. For both mCRC and metastatic and recurrent loco-regional SCCHN, increasing attention is being placed on second-line approaches as well as first-line application in combination with radiation therapy and/or platinum-based chemotherapy.
A review of current educational modules on the Global Oncology Academy (GOA) website provides a broad background of the developmental use of inhibitors of the EGFR pathway in both mCRC and metastatic and recurrent loco-regional SCCHN, including:
- Current Treatment Paradigms in Colorectal Cancer (CRC)
- Multidisciplinary management of Metastatic Colorectal Cancer
- Treatment Options for Locally-Advanced Squamous Cell Carcinoma of the Head and Neck
- Squamous Cell Carcinoma of the Head and Neck (SCCHN): Focus on Recurrent/Metastatic Disease
- The Hypoxic Tumor Environment: From Basics to Therapeutics
- Cancer Strategies for Fertility Preservation
Additionally, topical interviews with key knowledge leaders from around the globe help crystallize and validate the focus on inhibition of the EGFR pathway as a key contributor to improved outcomes in both cancer types. Interviews held at both ESMO 2016 and ASCO 2016, and the knowledge leaders included:
- Athanassios Argiris, MD, PhD, FACP
- Tanguy Seiwert, MD
- Jan B. Vermorken, MD, PhD
- Donimik Modest, MD
- Makato Tahara, MD, PhD
- Joël Guigay.MD, PhD
Often in reviewing improvements in the management of various cancers the understanding how a particular agent came to be approved fades into memory. In many cases the failure to fully appreciate the key clinical findings as the drug agent moved through trials to approval results in a diminished understanding of how these agents continue to be useful within and often beyond their original indications, especially as combination and sequential management philosophies become more the norm. One such example is the interesting history of how cetuximab gained European Medicines Agency Assessment (EMA) approval and how this approval was fine-tuned as the understanding of KRAS wt and mutant cancers emerged as patient selection marker. This information is reported in the EMA Assessment Reports explaining how the Committee on Medicinal Products for Human Use (CHMP) reached its opinion in favor of granting marketing authorization, and follows directly.
EMA: Cetuximab in Colorectal Cancer
Cetuximab is used to treat metastatic cancer of the colon or rectum (mCRC) in patients whose tumors express epidermal growth factor receptor (EGFR) and are ‘wild-type’ (wt; non-mutated) versions ‘RAS’.
Cetuximab is utilized:
- In combination regimens containing irinotecan
- With the oxaliplatin-containing regimen FOLFOX in patients who have not been previously treated
- As monotherapy in patients failing previous treatment using oxaliplatin- and irinotecan-containing regimens, or who are intolerant of those regimens.
Cetuximab is also used to treat squamous cell carcinoma of the head and neck (SCCHN). In locally-advanced cancer cetuximab is given in combination with radiotherapy; in SCCHN that is recurrent or metastatic, cetuximab is offered with a ‘platinum-based’ regimen such as those utilizing cisplatin or carboplatin.
For mCRC, the EMA evaluated cetuximab in 6 key studies, the 5 most relevant follow:
- Two studies involved 1,535 patients who had not received chemotherapy before, looking at the effects of adding Cetuximab to a treatment combination containing either irinotecan or oxaliplatin (FOLFOX); a third study looked also at the effects of adding cetuximab to two treatment combinations containing oxaliplatin, one of which was similar to FOLFOX, in 1,630 patients.
- Three studies involved 2,199 patients whose disease progressed while on previous treatment including irinotecan, oxaliplatin, or both; or who were intolerant of these drug agents.
For SCCHN, the EMA evaluated cetuximab in 2 key studies:
- The first involved 424 patients with locally-advanced SCCHN evaluating the clinical outcomes when adding cetuximab to radiotherapy.
- The second involved 442 patients with recurrent or metastatic SCCHN evaluating the clinical outcomes when adding cetuximab to a platinum-based regimen.
All studies assessed PFS or OS as end points; and most in mCRC separated findings between patients with wt KRAS and those with mutated KRAS. One trial separated patients whose tumors carried wild-type forms of all RAS genes from those with any mutated forms of RAS gene (conversely, for SCCHN, detection of EGFR expression was not performed since more than 90% of patients with SCCHN have tumors that express EGFR (see below).
In mCRC cetuximab was demonstrated to improve either PFS or OS, for example:
- Patients who had not previously received chemotherapy and who were wt KRAS had a significantly improved PFS if receiving cetuximab in addition to irinotecan-containing chemotherapy (9.9 months compared with 8.4 months, on average). More convincingly, patients receiving cetuximab in combination with oxaliplatin-containing chemotherapy (FOLFOX) and who were wt KRAS, had a PFS of 12.0 months compared to 5.8 months for patients receiving FOLFOX alone. In the third study, patients with wt KRAS only survived overall for 16.3 months when cetuximab was added to different oxaliplatin-based treatment similar to FOLFOX, compared with 18.2 months when the oxaliplatin-based treatment was used alone. Thus chemotherapy choice makes a difference in the impact of cetuximab in these patients.
EMA: Cetuximab in Loco-regional and Recurrent/Metastatic Head and Neck Carcinoma
Cetuximab in combination with radiation therapy for locally-advanced disease:
- This randomized study compared the combination of cetuximab and radiation therapy (211 patients) with radiation therapy alone (213 patients) in patients with locally advanced SCCHN. Cetuximab was started one week before radiation therapy and administered until the end of the radiation therapy period. Trial results demonstrated that in locally advanced SCCHN the PFS of patients when cetuximab was added to radiotherapy was significantly longer, 24.4 months compared with 14.9 months, on average.
Cetuximab in combination with platinum-based chemotherapy in recurrent and/or metastatic disease:
- This randomized study included patients with recurrent and/or metastatic SCCHN who had not received prior chemotherapy, and compared the combination of cetuximab and cisplatin or carboplatin plus infusional 5-fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Treatment in the cetuximab arm consisted of up to 6 cycles of platinum-based chemotherapy in combination with cetuximab followed by cetuximab as maintenance therapy until disease progression. Trial results demonstrated that in recurrent or metastatic SCCHN, survival was longer when cetuximab was added to a platinum-based combination, 10.1 months compared with 7.4 months, on average.
If you want to know more of the specifics of these trials, and to access breaking news and news updates, timely interviews, clickable resources, and other clinical information in regard to mCRC and recurrent/metastatic and loco-regional SCCHN, please visit the Global Oncology Academy website at: https://www.globalmultiplesclerosisacademy.org/.
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The management of metastatic colorectal cancer (mCRC) and metastatic and recurrent loco-regional squamous cell cancer of the head and neck (SCCHN) co…
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