Cetuximab Relative Dose Intensity (Rdi) in Recurrent/Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (Scchn): First Observational Prospective Study in Unselected Patients (Direct Trial)

Guigay, J.; Peyrade, Fréd́eric; Petre-Lazar, B.; Mornex, F.; Ceruse, P.; Digue, Laurence; Berrier, A.; Degardin, M.; Alfonsi, M.; Artignan, Xavier; Cals, L.; Faivre, Sandrine; Vuillemin, E.; Rolland, Frédéric; Timochenko, A.; Babin, E.; Prévost, Alain; Romano, O.; Chamorey, Emmanuel; Tourneau, C. Le

doi:10.1093/annonc/mdu340.11

Cited by 5 publications

(7 citation statements)

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“…In the DIRECT study, prospective data were collected for 154 patients with untreated SCCHN in the R/M setting receiving cetuximab according to the EXTREME regimen guidelines (53). The EXTREME regimen was shown to be feasible in everyday clinical practice and yielded a median time to progression of 6 months, which is in line with PFS findings in the EXTREME study (9, 11, 56).…”

Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

“…Over the past decade, retrospective and observational studies have consistently confirmed the benefits of the EXTREME regimen in patients with first-line R/M SCCHN ( 9 , 11 , 56 ). In the DIRECT study, prospective data were collected for 154 patients with untreated SCCHN in the R/M setting receiving cetuximab according to the EXTREME regimen guidelines ( 53 ). The EXTREME regimen was shown to be feasible in everyday clinical practice and yielded a median time to progression of 6 months, which is in line with PFS findings in the EXTREME study ( 9 , 11 , 56 ).…”

Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

“…Similarly, in a retrospective study of 31 patients with R/M SCCHN, cetuximab plus CT followed by maintenance with biweekly cetuximab led to a stable disease rate of 52%, partial response rate of 39%, and complete response rate of 9% ( 59 ). Furthermore, there is evidence that maintenance therapy until PD with cetuximab as a single agent following the EXTREME regimen is also well-tolerated with a good compliance (relative dose intensity = 82%) ( 53 , 59 ). Indeed, in the EXTREME trial, the frequency of severe skin reactions in the cetuximab-containing arm decreased from 9 to 5% during the cetuximab maintenance phase (median treatment duration = 29.9 weeks) ( 60 ).…”

Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

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Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

et al. 2017

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The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the “EXTREME” regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials are comparing regimens with ICIs, alone and in combination with other ICIs or CT, with the EXTREME regimen for first-line treatment of R/M SCCHN. As we eagerly await the results of these trials, the EXTREME regimen remains the standard of care for the first-line treatment of R/M SCCHN.

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Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

Section: First-line Treatment Options In R/m Scchnmentioning

confidence: 99%

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Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

et al. 2017

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“…The safety profile of the EXTREME regimen was consistent with that expected for the administered agents, including cardiac events (associated with 5-FU), anorexia, and skin reactions, except for an increase in the number of patients who developed sepsis (9 of 219 in the EXTREME arm vs. 1 of 215 in the chemotherapy-only arm) (5). The safety and efficacy of the EXTREME regimen have been consistent in the real world, as evidenced by multiple prospective, observational studies, including DIRECT, ENCORE, and SOCCER (26–28). Therefore, the EXTREME regimen is feasible for use in everyday clinical practice.…”

Section: The Continuum Of Care In R/m Scchnmentioning

confidence: 79%

“…Importantly, as 5-FU and taxanes have distinct associated toxicities, they can be used to treat different patient subgroups with R/M SCCHN with specific contraindications to chemotherapy agents while maintaining optimal efficacy. Indeed, observational studies have showed that physicians do not include 5-FU in 14–45% of therapeutic plans, indicating that 5-FU is not systematically prescribed as part of the EXTREME regimen, likely due to differences in its safety profile and administration (26, 27). The TPExtreme study results showed that replacing 5-FU with taxanes led to a better safety profile.…”

Section: Safety and Administration Differences Between Taxanes And 5-mentioning

confidence: 99%

The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Evidence, Advantages, and Future Directions

et al. 2019

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The addition of cetuximab to platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]), followed by maintenance cetuximab until disease progression (EXTREME), resulted in the first regimen to yield significantly improved survival outcomes in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in over 30 years. Currently, the EXTREME regimen is a guideline-recommended treatment in the first-line R/M setting, and, therefore, it is used as a control arm in all new first-line, phase 3 immunotherapy trials. More recently, new checkpoint inhibitor approaches have emerged and are changing the treatment landscape for PD-L1–positive patients with R/M SCCHN. Additionally, alternative chemotherapy backbones in R/M SCCHN are continually investigated. Replacing 5-FU with a taxane in the EXTREME regimen seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel. These cetuximab-, platinum-, and taxane-based treatments have demonstrated promising survival results and cytoreductive properties in single-arm studies. Thus, these combination treatments may be of importance to patients with high tumor burden and dangerous site involvements (e.g., causing bleeding, suffocation, dysphagia, or ulceration), in whom symptom relief is a key treatment goal. TPExtreme is the first large, randomized trial comparing a cetuximab, platinum, and taxane combination regimen with EXTREME. Currently, the substitution of 5-FU with a taxane is a feasible and clinically beneficial option for patients with contraindications to 5-FU. The TPEx regimen appears to be a new option in first-line R/M SCCHN, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. For patients with R/M disease in whom further cisplatin- or carboplatin-based treatment is unsuitable, or whose disease has already progressed on first-line R/M therapy, treatment options such as cetuximab plus a taxane, which capitalize on the combinative ability of the 2 agents, can be considered. Notably, it is as of yet unknown what second-line treatments may be suitable to follow a checkpoint inhibitor-based first-line therapy.

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Observational, prospective, phase 4 study in patients with first‐line recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with cetuximab and platinum‐based therapy: DIRECT

et al. 2021

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Background: Cetuximab plus platinum-based therapy (PBT) followed by cetuximab maintenance until progression (EXTREME) is a guideline-recommended first-line treatment option in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). DIRECT (Dose Intensity RElative to CeTuximab) was the first phase 4 observational study evaluating EXTREME administration in the real-world setting. Aims:The primary aim of this study was to assess the relative dose intensity of cetuximab in patients with R/M SCCHN treated with first-line cetuximab according to the EXTREME regimen.Methods and results: Patients were ≥18 years old and eligible to receive cetuximab/ PBT. Primary endpoint was cetuximab relative dose intensity (RDI). Of prospectively enrolled patients (n = 157), 119 received ≥1 cycle of EXTREME. Practices differing from the EXTREME trial were 5-fluorouracil omission (14%), maintenance cetuximab given every other week (54%), prior cetuximab, disease-free interval <6 months. 64% of patients reached cetuximab RDI ≥80%; mean cetuximab RDI was 88%. 46% of patients received maintenance cetuximab (mean RDI, 91%). Median progression-free survival and overall survival were 4.5 and 9.4 months. No new/unexpected safety findings were observed. Conclusions:The DIRECT study showed that first-line cetuximab plus PBT was a feasible, beneficial first-line treatment regimen in patients with R/M SCCHN in the realworld setting.

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Cetuximab Relative Dose Intensity (Rdi) in Recurrent/Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (Scchn): First Observational Prospective Study in Unselected Patients (Direct Trial)

Cited by 5 publications

References 0 publications

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck: Evidence, Advantages, and Future Directions

Observational, prospective, phase 4 study in patients with first‐line recurrent and/or metastatic squamous cell carcinoma of the head and neck treated with cetuximab and platinum‐based therapy: DIRECT

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