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
martes, 6 de agosto de 2019
Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer
Enzalutamide Could Have Pivotal Role in Metastatic Hormone-Sensitive Prostate Cancer
Ellie Leick
Published: Friday, Jul 12, 2019
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Christopher J. Sweeney, MBBS
Christopher J. Sweeney, MBBS Results of the ENZAMET trial showed that enzalutamide (Xtandi) significantly improved overall survival (OS) when added to the standard of care for patients with metastatic hormone-sensitive prostate cancer, although the benefits were lower for those slated to receive early docetaxel, explained Christopher Sweeney, MBBS.
In the phase III study, investigators randomized 1125 patients to receive testosterone suppression plus either enzalutamide or a nonsteroidal antiandrogen, such as bicalutamide (Casodex), nilutamide (Nilandron), or flutamide (Eulexin).
Interim findings showed that the 3-year OS rate was 80% in patients with metastatic hormone-sensitive prostate cancer who received the enzalutamide regimen compared with 72% of those who received a standard nonsteroidal antiandrogen agent.
Additionally, a subgroup of patients received early doses of docetaxel or abiraterone acetate (Zytiga) with testosterone suppression. In this group, the OS rates were similar between the 2 arms (HR, 0.90; 0.62-1.31).
The addition of enzalutamide, however, did exacerbate docetaxel-related adverse events (AEs). Docetaxel-related AEs in the enzalutamide versus nonsteroidal antiandrogen arms included neutropenic fever (14% vs 13%, respectively), grade 2 sensory neuropathy (9% vs 3%), nail discoloration (10% vs 5%), grade 1 or 2 watery eyes (20% vs 6%), and grade 2 fatigue (20% vs 14%).
“We need longer follow-up, but it is possible we will see that adding enzalutamide to docetaxel will have a clinical benefit. We can't say that yet because we've got to do the quality-of-life analysis to see if delaying progression improves the patient's quality of life. There were some extra side effects with adding the enzalutamide to docetaxel,” said Sweeney, a medical oncologist at Dana-Farber Cancer Institute.
In an interview with OncLive, Sweeney discussed the results of the ENZAMET trial and the next steps for researching the efficacy of enzalutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.
OncLive: Could you provide an overview of the ENZAMET trial design?
Sweeney: This is a study in the metastatic hormone-sensitive setting of prostate cancer. It's asking whether enzalutamide, which we know improved the survival of men with castration-resistant disease, is more effective when given at the start of hormonal therapy—testosterone suppression. In this hormone-sensitive setting, patients with a high volume of disease also benefit from getting docetaxel. That result came out in the CHAARTED study, which was not too long after we wrote, designed, and activated the ENZAMET study. We quickly activated an amendment that allowed patients to receive docetaxel based on physician and patient choice. The patients could either get testosterone suppression with a standard nonsteroidal—either bicalutamide, nilutamide, or flutamide—as an active control or enzalutamide. Then, patients were stratified by whether they received docetaxel. What ultimately happened is 50% of the patients received docetaxel, many of them with high-volume disease. Half of the patients received enzalutamide and half were treated with the nonsteroidal antiandrogen.
We saw that enzalutamide prolonged OS in both patients with high-volume and low-volume disease. We also saw that patients had a longer time to progression; the study was very positive. We get the readout early from the interim analysis, [but] we need longer follow-up.
Although early enzalutamide prolonged the time to progression for those who got docetaxel, there is not a big treatment effect yet. We will hopefully see a bigger treatment effect soon with longer follow-up. It's possible to do sequential therapy as long as patients get docetaxel and enzalutamide at some stage.
On the other hand, patients who did not get docetaxel had a clear improvement in time to progression and a significant improvement in OS—a very clear treatment effect. However, we've got a lot of work to do. We often need the longer follow-up to see if it translates into longer survival. Hopefully patients who have a longer time to progression get other agents and compound the early cancer control, resulting in a longer survival, but we haven't seen it yet at the early analysis.
Could you expand upon the safety findings with enzalutamide?
It's very important when we counsel patients on the efficacy benefits and the AEs. There is the same degree of enzalutamide-associated AEs that we expected; there is fatigue, increased concentration impairment, and falls. About 5% of patients experienced falls as an AE, which is a low number but more than we saw with patients who got the standard nonsteroidal. That's something we need to be careful about. There was also a 1% incidence of seizures in patients who received enzalutamide, despite excluding patients who had a predisposition to seizures.
The other very interesting thing is enzalutamide increased some of the AEs of docetaxel. There was the same grade of neutropenic fever, but there was also grade 2 sensory neuropathy at about 9%; there was only 3% who experienced sensory neuropathy with the standard nonsteroidal. We also saw some increasing eye tearing and nail discoloration—AEs we have learned to see with docetaxel. Enzalutamide seemed to increase their frequency.
What can you share regarding the quality-of-life (QoL) analysis for enzalutamide?
Stay tuned for the QoL analysis. The ENZAMET team who worked with the clinical trial center based in Sydney, Australia has done an amazing job of getting these data out and getting the publication within 3 months of the interim analysis, which is unheard of. We focused on the efficacy endpoints and the AE endpoints. The next part is to focus on the QoL analysis because it is important for us to describe the total patient experience.
What is your takeaway message for those who are treating patients with metastatic hormone-sensitive prostate cancer?
I look at their risk category: do they high-volume or low-volume [disease]? Are they fit? Are they fit enough for chemotherapy? Then, I'll lay out the options: hormone suppression and docetaxel; hormone suppression and enzalutamide, abiraterone, or apalutamide (Erleada). [The docetaxel/hormone suppression option is] based on the different side effect profiles and if the patient has some problems being on enzalutamide for 3 years or longer. [In that case], you can get the docetaxel out of the way and maybe you add the other agents at progression until we find out that there is a clear benefit for doing it all concurrently. That is to be determined.
Otherwise, if the patient is not fit for chemotherapy and has low-volume disease, they can choose from testosterone suppression with abiraterone, enzalutamide, or apalutamide.
Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl; abstr LBA2).
Ellie Leick
Published: Friday, Jul 12, 2019
Print Button
Christopher J. Sweeney, MBBS
Christopher J. Sweeney, MBBS Results of the ENZAMET trial showed that enzalutamide (Xtandi) significantly improved overall survival (OS) when added to the standard of care for patients with metastatic hormone-sensitive prostate cancer, although the benefits were lower for those slated to receive early docetaxel, explained Christopher Sweeney, MBBS.
In the phase III study, investigators randomized 1125 patients to receive testosterone suppression plus either enzalutamide or a nonsteroidal antiandrogen, such as bicalutamide (Casodex), nilutamide (Nilandron), or flutamide (Eulexin).
Interim findings showed that the 3-year OS rate was 80% in patients with metastatic hormone-sensitive prostate cancer who received the enzalutamide regimen compared with 72% of those who received a standard nonsteroidal antiandrogen agent.
Additionally, a subgroup of patients received early doses of docetaxel or abiraterone acetate (Zytiga) with testosterone suppression. In this group, the OS rates were similar between the 2 arms (HR, 0.90; 0.62-1.31).
The addition of enzalutamide, however, did exacerbate docetaxel-related adverse events (AEs). Docetaxel-related AEs in the enzalutamide versus nonsteroidal antiandrogen arms included neutropenic fever (14% vs 13%, respectively), grade 2 sensory neuropathy (9% vs 3%), nail discoloration (10% vs 5%), grade 1 or 2 watery eyes (20% vs 6%), and grade 2 fatigue (20% vs 14%).
“We need longer follow-up, but it is possible we will see that adding enzalutamide to docetaxel will have a clinical benefit. We can't say that yet because we've got to do the quality-of-life analysis to see if delaying progression improves the patient's quality of life. There were some extra side effects with adding the enzalutamide to docetaxel,” said Sweeney, a medical oncologist at Dana-Farber Cancer Institute.
In an interview with OncLive, Sweeney discussed the results of the ENZAMET trial and the next steps for researching the efficacy of enzalutamide in the treatment of patients with metastatic hormone-sensitive prostate cancer.
OncLive: Could you provide an overview of the ENZAMET trial design?
Sweeney: This is a study in the metastatic hormone-sensitive setting of prostate cancer. It's asking whether enzalutamide, which we know improved the survival of men with castration-resistant disease, is more effective when given at the start of hormonal therapy—testosterone suppression. In this hormone-sensitive setting, patients with a high volume of disease also benefit from getting docetaxel. That result came out in the CHAARTED study, which was not too long after we wrote, designed, and activated the ENZAMET study. We quickly activated an amendment that allowed patients to receive docetaxel based on physician and patient choice. The patients could either get testosterone suppression with a standard nonsteroidal—either bicalutamide, nilutamide, or flutamide—as an active control or enzalutamide. Then, patients were stratified by whether they received docetaxel. What ultimately happened is 50% of the patients received docetaxel, many of them with high-volume disease. Half of the patients received enzalutamide and half were treated with the nonsteroidal antiandrogen.
We saw that enzalutamide prolonged OS in both patients with high-volume and low-volume disease. We also saw that patients had a longer time to progression; the study was very positive. We get the readout early from the interim analysis, [but] we need longer follow-up.
Although early enzalutamide prolonged the time to progression for those who got docetaxel, there is not a big treatment effect yet. We will hopefully see a bigger treatment effect soon with longer follow-up. It's possible to do sequential therapy as long as patients get docetaxel and enzalutamide at some stage.
On the other hand, patients who did not get docetaxel had a clear improvement in time to progression and a significant improvement in OS—a very clear treatment effect. However, we've got a lot of work to do. We often need the longer follow-up to see if it translates into longer survival. Hopefully patients who have a longer time to progression get other agents and compound the early cancer control, resulting in a longer survival, but we haven't seen it yet at the early analysis.
Could you expand upon the safety findings with enzalutamide?
It's very important when we counsel patients on the efficacy benefits and the AEs. There is the same degree of enzalutamide-associated AEs that we expected; there is fatigue, increased concentration impairment, and falls. About 5% of patients experienced falls as an AE, which is a low number but more than we saw with patients who got the standard nonsteroidal. That's something we need to be careful about. There was also a 1% incidence of seizures in patients who received enzalutamide, despite excluding patients who had a predisposition to seizures.
The other very interesting thing is enzalutamide increased some of the AEs of docetaxel. There was the same grade of neutropenic fever, but there was also grade 2 sensory neuropathy at about 9%; there was only 3% who experienced sensory neuropathy with the standard nonsteroidal. We also saw some increasing eye tearing and nail discoloration—AEs we have learned to see with docetaxel. Enzalutamide seemed to increase their frequency.
What can you share regarding the quality-of-life (QoL) analysis for enzalutamide?
Stay tuned for the QoL analysis. The ENZAMET team who worked with the clinical trial center based in Sydney, Australia has done an amazing job of getting these data out and getting the publication within 3 months of the interim analysis, which is unheard of. We focused on the efficacy endpoints and the AE endpoints. The next part is to focus on the QoL analysis because it is important for us to describe the total patient experience.
What is your takeaway message for those who are treating patients with metastatic hormone-sensitive prostate cancer?
I look at their risk category: do they high-volume or low-volume [disease]? Are they fit? Are they fit enough for chemotherapy? Then, I'll lay out the options: hormone suppression and docetaxel; hormone suppression and enzalutamide, abiraterone, or apalutamide (Erleada). [The docetaxel/hormone suppression option is] based on the different side effect profiles and if the patient has some problems being on enzalutamide for 3 years or longer. [In that case], you can get the docetaxel out of the way and maybe you add the other agents at progression until we find out that there is a clear benefit for doing it all concurrently. That is to be determined.
Otherwise, if the patient is not fit for chemotherapy and has low-volume disease, they can choose from testosterone suppression with abiraterone, enzalutamide, or apalutamide.
Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl; abstr LBA2).
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