Metronomic Methotrexate Regimen Proposed For Platinum-Refractory Oral Cancer
Patients with treatment-refractory squamous cell carcinoma of the oral cavity may respond to a metronomic schedule of oral methotrexate, erlotinib and celecoxib
Date: 25 Sep 2019
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Head and Neck Cancers / Anticancer Agents
medwireNews: Phase I/II trial results suggest that an oral metronomic regimen of methotrexate, erlotinib and celecoxib may have activity against platinum-refractory squamous cell cancer of the oral cavity.
The researchers describe their findings as “exciting” when compared against historical response rates of up to 13.6% and progression-free survival (PFS) of up to 2.3 months for cytotoxic chemotherapy agents and nivolumab.
The optimal biological dose of methotrexate 9 mg/m2 per week was identified in phase I and this was given once per week alongside erlotinib 150 mg/day and celecoxib 200 mg twice daily to 76 patients in phase II.
The participants had all progressed within 1 month of surgery or radiation, or within 6 months of receiving platinum-based systemic treatment, explain Kumar Prabhash and colleagues, from the Tata Memorial Centre in Mumbai, India.
After a median follow-up of 6.8 months, the median PFS was 4.6 months, with 3- and 6-month PFS rates of 71.1% and 34.5%, respectively. And at data cutoff, the median overall survival (OS) duration was 7.2 months with a 6-month rate of 61.2%.
At 2 months, 37.4% of patients achieved a response to treatment and this increased to 42.9% over follow-up. The median response durations in these two groups were 2.1 and 4.4 months, respectively.
Safety analysis of 88 patients indicated the most common adverse events were fatigue (85.2%), rash (80.7%) and anaemia (80.7%), while other less common events included grade 3–4 hyponatremia (14.8%) and elevated alanine transaminase (5.7%). Overall, 13.6% of patients required a dose reduction, most commonly for the methotrexate treatment (11.4%).
“In conclusion, the combination of erlotinib, [methotrexate], and celecoxib in platinum-insensitive oral cancer results in promising [response rates], PFS, and OS”, Kumar Prabhash and co-authors conclude in the Journal of Clinical Oncology.
And they recommend that “[i]ts activity needs to be confirmed in a phase III randomized study.”
Reference
Patil VM, Noronha V, Joshi A, et al. Phase I/II study of palliative triple metronomic chemotherapy in platinum-refractory/early-failure oral cancer . J Clin Oncol; Advance online publication 20 September 2019. DOI: 10.1200/JCO.19.01076
miércoles, 9 de octubre de 2019
Third-line Cabazitaxel Benefit Demonstrated For metastatic CRPC Patients
Cabazitaxel Benefit Demonstrated For metastatic CRPC Patients
Patients with metastatic castration-resistant prostate cancer have better outcomes with third-line cabazitaxel than with receipt of a second androgen signalling-targeted agent
Date: 08 Oct 2019
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Anticancer Agents
medwireNews: For men with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel and use of enzalutamide or abiraterone, cabazitaxel offers significantly better survival than treatment with the alternative androgen signalling-targeted agent, research suggests.
The CARD trial findings were presented at the ESMO Congress 2019 in Barcelona, Spain and simultaneously reported in The New England Journal of Medicine.
After a median of 9.2 months, imaging-based progression or death had occurred in 73.6% of the metastatic CRCP 129 patients who were randomly assigned to receive cabazitaxel 25 mg/m2 every 3 weeks, alongside prednisone 10 mg/day and granulocyte colony-stimulating factor therapy at each cycle.
This rate was significantly lower than the 80.2% reported for the 126 patients who instead were randomly assigned to receive enzalutamide or abiraterone, according to which agent they had previously received, giving a significant hazard ratio (HR) for progression or death of 0.54 in favour of the taxane.
Post hoc analyses confirmed that this superior outcome with cabazitaxel was true regardless of whether the second androgen signalling-targeted inhibitor was enzalutamide or abiraterone, reported presenting author Ronald de Wit, from Erasmus Medical Center in Rotterdam, the Netherlands, and co-workers.
Patients using cabazitaxel also achieved a significantly longer duration of overall survival than those given a second androgen signalling-targeted agent (median 13.6 vs 11.0 months, HR=0.64) as well as better progression-free survival when including prostate-specific antigen (PSA) and pain progression (median 4.4 vs 2.7 months, HR=0.52).
These benefits with cabazitaxel were accompanied by higher rates of PSA response (35.7 vs 13.5%) and tumour response (36.5 vs 11.5%), the researchers say.
Of note, there was a comparable incidence of serious adverse events (AEs) in the cabazitaxel and second androgen signalling-inhibitor trial arms (38.9 vs 38.7%), although cabazitaxel was associated with a higher rate of discontinuation because of AEs (19.8 vs 8.9%).
Cabazitaxel-treated patients were more likely than those given enzalutamide or abiraterone to experience grade 3 and more severe asthenia/fatigue (4.0 vs 2.4%), diarrhoea (3.2 vs 0%), peripheral neuropathy (3.2 vs 0%), and febrile neutropenia (3.2 vs 0%), but were less likely to develop renal disorders (3.2 vs 8.1%), musculoskeletal pain (1.6 vs 5.6%), cardiac disorders (0.8 vs 4.8%) and spinal cord or nerve root disorders (2.4 vs 4.0%).
“The results of the CARD trial are in agreement with those of previous studies that have shown poor outcomes with a second androgen-signaling–targeted inhibitor”, de Wit and co-workers note.
“This is probably due to the fact that these agents target the same pathway and thus share common mechanisms of resistance” whereas “taxanes, owing to their different mechanism of action, are able to overcome several mechanisms of resistance to androgen-signaling-targeted inhibitors”, they hypothesise.
References
de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer . N Engl J Med; Advance online publication 30 September 2019. DOI: 10.1056/NEJMoa1911206
de Wit R, Kramer G, Eymard J-C, et al. CARD: Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). ESMO Congress 2019 ; Barcelona, Spain: 27 September–1 October. LBA13
Patients with metastatic castration-resistant prostate cancer have better outcomes with third-line cabazitaxel than with receipt of a second androgen signalling-targeted agent
Date: 08 Oct 2019
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Anticancer Agents
medwireNews: For men with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel and use of enzalutamide or abiraterone, cabazitaxel offers significantly better survival than treatment with the alternative androgen signalling-targeted agent, research suggests.
The CARD trial findings were presented at the ESMO Congress 2019 in Barcelona, Spain and simultaneously reported in The New England Journal of Medicine.
After a median of 9.2 months, imaging-based progression or death had occurred in 73.6% of the metastatic CRCP 129 patients who were randomly assigned to receive cabazitaxel 25 mg/m2 every 3 weeks, alongside prednisone 10 mg/day and granulocyte colony-stimulating factor therapy at each cycle.
This rate was significantly lower than the 80.2% reported for the 126 patients who instead were randomly assigned to receive enzalutamide or abiraterone, according to which agent they had previously received, giving a significant hazard ratio (HR) for progression or death of 0.54 in favour of the taxane.
Post hoc analyses confirmed that this superior outcome with cabazitaxel was true regardless of whether the second androgen signalling-targeted inhibitor was enzalutamide or abiraterone, reported presenting author Ronald de Wit, from Erasmus Medical Center in Rotterdam, the Netherlands, and co-workers.
Patients using cabazitaxel also achieved a significantly longer duration of overall survival than those given a second androgen signalling-targeted agent (median 13.6 vs 11.0 months, HR=0.64) as well as better progression-free survival when including prostate-specific antigen (PSA) and pain progression (median 4.4 vs 2.7 months, HR=0.52).
These benefits with cabazitaxel were accompanied by higher rates of PSA response (35.7 vs 13.5%) and tumour response (36.5 vs 11.5%), the researchers say.
Of note, there was a comparable incidence of serious adverse events (AEs) in the cabazitaxel and second androgen signalling-inhibitor trial arms (38.9 vs 38.7%), although cabazitaxel was associated with a higher rate of discontinuation because of AEs (19.8 vs 8.9%).
Cabazitaxel-treated patients were more likely than those given enzalutamide or abiraterone to experience grade 3 and more severe asthenia/fatigue (4.0 vs 2.4%), diarrhoea (3.2 vs 0%), peripheral neuropathy (3.2 vs 0%), and febrile neutropenia (3.2 vs 0%), but were less likely to develop renal disorders (3.2 vs 8.1%), musculoskeletal pain (1.6 vs 5.6%), cardiac disorders (0.8 vs 4.8%) and spinal cord or nerve root disorders (2.4 vs 4.0%).
“The results of the CARD trial are in agreement with those of previous studies that have shown poor outcomes with a second androgen-signaling–targeted inhibitor”, de Wit and co-workers note.
“This is probably due to the fact that these agents target the same pathway and thus share common mechanisms of resistance” whereas “taxanes, owing to their different mechanism of action, are able to overcome several mechanisms of resistance to androgen-signaling-targeted inhibitors”, they hypothesise.
References
de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer . N Engl J Med; Advance online publication 30 September 2019. DOI: 10.1056/NEJMoa1911206
de Wit R, Kramer G, Eymard J-C, et al. CARD: Randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). ESMO Congress 2019 ; Barcelona, Spain: 27 September–1 October. LBA13
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