Nivolumab Monotherapy Tolerability For Advanced Melanoma Confirmed
Analysis of data from four clinical trials shows that the side effects of nivolumab monotherapy are generally low grade and resolvable
Date: 22 Nov 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Cancer Immunology and Immunotherapy / Melanoma and other Skin Tumours / Complications of Treatment
medwireNews: Pooled safety data for nivolumab monotherapy in advanced melanoma patients confirm that most treatment-related adverse events (AEs) are low grade and can be treated with immune-modulating agents.
The research published in the Journal of Clinical Oncology included 102 patients enrolled in two phase I trials and 474 patients enrolled in two phase III trials; all patients received at least one dose of nivolumab given at a dose of 3 mg/kg every 2 weeks, over a median duration of 3.7 months.
The majority (71.0%) of patients experienced at least one treatment-related AE apparent in at least 5% of patients, most commonly fatigue (24.8%), pruritus (17.2%), diarrhoea (12.7%), rash (12.7%) and nausea (12.0%). Almost half (49.0%) of the patients had at least one AE with a possible immunological aetiology, most commonly affecting the skin (34.0%) and gastrointestinal tract (GI; 13.4%).
In addition, 9.9% of patients had a grade 3 or 4 treatment-related AE, with diarrhoea, fatigue and rash again the most commonly reported side effects. Possible grade 3 or 4 AEs associated with immunological reactions were reported most commonly in the GI tract (1.2%), liver (1.0%) and skin (0.7%).
However, the authors note that a further five patients experienced grade 3 neurological AEs including dizziness, autoimmune neuropathy, central demyelination, involuntary muscle contractions and Guillain–Barré syndrome, the last of which was unresolved 16 weeks later at time of database lock.
In all, 3.0% of patients discontinued study treatment because of AEs, with most (2.1%) discontinuing because of grade 3 or 4 side effects, the researchers add.
Time to onset of treatment-related AEs with an immunological aetiology varied from a median of 5.0 weeks for skin complaints to 7.3 weeks for GI side effects and 10.4 weeks for endocrine AEs to 15.1 weeks for renal events.
“An awareness of the typical timing of onset of immune-related select AEs may aid in their early recognition and management in clinical practice”, say Jeffrey Weber, from the H Lee Moffitt Cancer Center in Tampa, Florida, USA, and co-workers.
The time to resolution of these immunological-related AEs ranged from 1.2 weeks for GI AEs and 6.0 weeks for pulmonary side effects to 18.0 weeks for skin events and 28.0 weeks for endocrine AEs.
A quarter (24.0%) of patients in the phase III trials were given systemic corticosteroids to manage immunological-related AEs, with topical and inhaled corticosteroids given to 16.0% and 1.0%, respectively. Another 0.6% of patients were treated with secondary immunosuppressive agents.
The researchers note that median progression-free survival was 4.7 months and this did not correlate with the presence or number of treatment-related AEs.
By contrast, the objective response rate (ORR) for nivolumab monotherapy was 31.4% and analysis showed that ORR was significantly higher in patients who reported treatment-related AEs of any grade than those who did not (48.6 vs 17.8 %).
The highest ORRs found in those with three or more events of any grade, or those with one or two events, than those with none (84.6 and 46.7 vs 17.8%), although ORR was independent of the number of grade 3 or 4 events.
Nor did ORR vary between patients who were and were not given systemic immune-modulating therapy.
“Appropriate management of select AEs is essential to reduce the risk for severe toxicity and enable nivolumab therapy to be continued where possible, maximizing its potential benefits”, Jeffrey Weber et al emphasize.
“Using the nivolumab safety management guidelines, involving the use of [immune-modulating agents] (primarily systemic corticosteroids), all but one grade 3 to 4 select AE resolved.”
However, the authors caution that “because these data were from clinical trials excluding patients with autoimmune disease, organ dysfunction, and active brain metastases, safety in these contexts requires further study.”
Reference
Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol; Advance online publication 14 November 2016. DOI: 10.1200/JCO.2015.66.1389
martes, 27 de diciembre de 2016
Pancreatic Cancer: Dual Targeted Molecular Therapy Fails To Improve Cancer OS
Dual Targeted Molecular Therapy Fails To Improve Metastatic Pancreatic Cancer OS
Selumetinib plus MK-2206 therapy does not extend overall survival in metastatic pancreatic adenocarcinoma compared with modified FOLFOX chemotherapy
Date: 19 Dec 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Pancreatic Cancer
medwireNews: Dual targeting of the MEK and Akt pathways downstream of KRAS has failed to lengthen the overall survival (OS) of patients with metastatic pancreatic adenocarcinoma compared with that achieved by conventional chemotherapy.
The phase II trial assessed the efficacy of selumetinib, a selective adenosine triphosphate uncompetitive inhibitor of MEK 1/2, when used in combination with MK-2206, the first allosteric inhibitor of AKT.
“Because there are currently no drugs that directly target mutant RAS, inhibiting its downstream canonical RAF/MEK/ERK and [PIK3]/AKT signaling pathways was a rational alternate treatment strategy”, explain Vincent Chung, from City of Hope National Medical Center in Duarte, California, USA, and co-investigators.
In all, 58 patients who had failed gemcitabine-based chemotherapy were randomly assigned to receive selumetinib 100 mg/day plus MK-2206 135 mg/week, while 62 patients were treated with the modified FOLFOX regimen.
There was a trend towards shorter median OS in the patients given selumetinib plus MK-2206, at 3.9 months versus 6.7 months with modified FOLFOX, giving a nonsignificant hazard ratio of 1.37, the researchers report in JAMA Oncology.
There was also a trend for poorer progression-free survival with selumetinib plus MK-2206 than modified FOLFOX, at 1.9 versus 2.0 months. And fewer patients given the novel treatment combination achieved a partial response (0 vs 5) or stable disease (12 vs 14), the researchers add.
Furthermore, selumetinib plus MK-2206 was associated with a higher rate of grade 3 or more severe adverse events (39 vs 23 patients) and a higher rate of treatment discontinuation because of side effects (13 vs 7 patients).
“A major contributing factor to the lack of benefit was the frequency of toxicity-related treatment delays and dose reductions in the experimental arm, undermining sustained signaling inhibition”, the authors comment, noting that delays affected 45% versus 10% of those given mFOLFOX.
Discussing the need for better understanding of signalling network pathways in this patient population, the investigators emphasize that "the role of preclinical models of pancreatic cancer and the optimal translation of preclinical successes into trial design must be improved."
“Moreover, clinical testing of targeted agents must include validation of target modulation in treated patients. Obtaining tissue samples before and after treatment is challenging for this population of patients, but the recent advances in liquid biopsies may help to remove the hurdles of serial tissue sampling”, they conclude.
Reference
Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy. SWOG S115 study randomized clinical trial. JAMA Oncol; Advance online publication 15 December 2016. doi:10.1001/jamaoncol.2016.5383
Selumetinib plus MK-2206 therapy does not extend overall survival in metastatic pancreatic adenocarcinoma compared with modified FOLFOX chemotherapy
Date: 19 Dec 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Pancreatic Cancer
medwireNews: Dual targeting of the MEK and Akt pathways downstream of KRAS has failed to lengthen the overall survival (OS) of patients with metastatic pancreatic adenocarcinoma compared with that achieved by conventional chemotherapy.
The phase II trial assessed the efficacy of selumetinib, a selective adenosine triphosphate uncompetitive inhibitor of MEK 1/2, when used in combination with MK-2206, the first allosteric inhibitor of AKT.
“Because there are currently no drugs that directly target mutant RAS, inhibiting its downstream canonical RAF/MEK/ERK and [PIK3]/AKT signaling pathways was a rational alternate treatment strategy”, explain Vincent Chung, from City of Hope National Medical Center in Duarte, California, USA, and co-investigators.
In all, 58 patients who had failed gemcitabine-based chemotherapy were randomly assigned to receive selumetinib 100 mg/day plus MK-2206 135 mg/week, while 62 patients were treated with the modified FOLFOX regimen.
There was a trend towards shorter median OS in the patients given selumetinib plus MK-2206, at 3.9 months versus 6.7 months with modified FOLFOX, giving a nonsignificant hazard ratio of 1.37, the researchers report in JAMA Oncology.
There was also a trend for poorer progression-free survival with selumetinib plus MK-2206 than modified FOLFOX, at 1.9 versus 2.0 months. And fewer patients given the novel treatment combination achieved a partial response (0 vs 5) or stable disease (12 vs 14), the researchers add.
Furthermore, selumetinib plus MK-2206 was associated with a higher rate of grade 3 or more severe adverse events (39 vs 23 patients) and a higher rate of treatment discontinuation because of side effects (13 vs 7 patients).
“A major contributing factor to the lack of benefit was the frequency of toxicity-related treatment delays and dose reductions in the experimental arm, undermining sustained signaling inhibition”, the authors comment, noting that delays affected 45% versus 10% of those given mFOLFOX.
Discussing the need for better understanding of signalling network pathways in this patient population, the investigators emphasize that "the role of preclinical models of pancreatic cancer and the optimal translation of preclinical successes into trial design must be improved."
“Moreover, clinical testing of targeted agents must include validation of target modulation in treated patients. Obtaining tissue samples before and after treatment is challenging for this population of patients, but the recent advances in liquid biopsies may help to remove the hurdles of serial tissue sampling”, they conclude.
Reference
Chung V, McDonough S, Philip PA, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy. SWOG S115 study randomized clinical trial. JAMA Oncol; Advance online publication 15 December 2016. doi:10.1001/jamaoncol.2016.5383
martes, 8 de noviembre de 2016
Early Prostate Cancer: Treatment or Monitoring?
Editorial
Treatment or Monitoring for Early Prostate Cancer
Anthony V. D’Amico, M.D., Ph.D.
N Engl J Med 2016; 375:1482-1483October 13, 2016DOI: 10.1056/NEJMe1610395
The “best” initial approach to early (low-risk or intermediate-risk)1 prostate cancer remains unknown. Specifically, does active monitoring with the use of prostate-specific antigen (PSA) testing as opposed to treatment lead to increased metastasis and death from prostate cancer? If yes, then which treatment, radical prostatectomy or radiation with or without short-term (3 to 6 months) androgen-suppression therapy, minimizes metastasis and death from prostate cancer?
Hamdy and colleagues now report in the Journal the results of a randomized comparison of three of these four approaches after a median follow-up of 10 years,2 and Donovan and colleagues present data on patient-reported health-related quality of life at 6 years of follow-up.3 Men were screened with PSA testing and presented at a median age of 62 years with favorable clinical characteristics: 76% had stage T1c (PSA-detected) disease, 77% and 21% had tumors with Gleason scores of 6 and 7, respectively (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and the median PSA level was 4.6 ng per milliliter. Although a median follow-up of 10 years was too short to evaluate the primary outcome of prostate-cancer mortality in this favorable cohort (death from prostate cancer occurred in 8 of the 545 men assigned to active monitoring, 5 of the 553 men assigned to surgery, and 4 of the 545 men assigned to radiotherapy), it was adequate to evaluate the secondary outcome of the incidence of metastatic disease, defined as bony, visceral, or lymph-node metastasis on imaging or a PSA level above 100 ng per milliliter.
Several important observations were made. First, men assigned to active monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P=0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring.
Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was established. The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which are not inconsequential.4
Second, within the prerandomization stratum of age, a near-significant interaction (P=0.09 for interaction) was observed given that men 65 years of age or older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment.
This finding probably reflects the fact that advancing age is associated with higher-grade disease than disease identified at an initial biopsy5 owing to sampling error, resulting in undergrading, the risk of which rises with the increasing prostate-gland volume6 that occurs with advancing age.7
Should the interaction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age or older with early prostate cancer who today are increasingly being placed on active surveillance,8 given that the reduction in death from prostate cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09) in the Prostate Cancer Intervention versus Observation Trial (PIVOT) only trended toward significance (P=0.09).9
However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.10
Finally, a trend favoring radiation and short-course androgen-deprivation therapy over surgery was observed. Specifically, the point estimate for the hazard ratio for death from prostate cancer when comparing these two treatments was 0.80 (95% CI, 0.22 to 2.99). If this trend becomes significant, then one may consider radiation and androgen-deprivation therapy as a preferred option for otherwise healthy men 65 years of age or older with early prostate cancer for whom treatment as compared with monitoring may be more effective (P=0.09 for interaction) in reducing death from prostate cancer.
For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis.
Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.2
In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy.
Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.
This editorial was published on September 14, 2016, at NEJM.org.
Source Information
From the Department of Radiation Oncology, Brigham and Women’s Hospital and Dana–Farber Cancer Institute, Boston.
Treatment or Monitoring for Early Prostate Cancer
Anthony V. D’Amico, M.D., Ph.D.
N Engl J Med 2016; 375:1482-1483October 13, 2016DOI: 10.1056/NEJMe1610395
The “best” initial approach to early (low-risk or intermediate-risk)1 prostate cancer remains unknown. Specifically, does active monitoring with the use of prostate-specific antigen (PSA) testing as opposed to treatment lead to increased metastasis and death from prostate cancer? If yes, then which treatment, radical prostatectomy or radiation with or without short-term (3 to 6 months) androgen-suppression therapy, minimizes metastasis and death from prostate cancer?
Hamdy and colleagues now report in the Journal the results of a randomized comparison of three of these four approaches after a median follow-up of 10 years,2 and Donovan and colleagues present data on patient-reported health-related quality of life at 6 years of follow-up.3 Men were screened with PSA testing and presented at a median age of 62 years with favorable clinical characteristics: 76% had stage T1c (PSA-detected) disease, 77% and 21% had tumors with Gleason scores of 6 and 7, respectively (on a scale from 6 to 10, with higher scores indicating a worse prognosis), and the median PSA level was 4.6 ng per milliliter. Although a median follow-up of 10 years was too short to evaluate the primary outcome of prostate-cancer mortality in this favorable cohort (death from prostate cancer occurred in 8 of the 545 men assigned to active monitoring, 5 of the 553 men assigned to surgery, and 4 of the 545 men assigned to radiotherapy), it was adequate to evaluate the secondary outcome of the incidence of metastatic disease, defined as bony, visceral, or lymph-node metastasis on imaging or a PSA level above 100 ng per milliliter.
Several important observations were made. First, men assigned to active monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P=0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring.
Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was established. The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which are not inconsequential.4
Second, within the prerandomization stratum of age, a near-significant interaction (P=0.09 for interaction) was observed given that men 65 years of age or older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment.
This finding probably reflects the fact that advancing age is associated with higher-grade disease than disease identified at an initial biopsy5 owing to sampling error, resulting in undergrading, the risk of which rises with the increasing prostate-gland volume6 that occurs with advancing age.7
Should the interaction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age or older with early prostate cancer who today are increasingly being placed on active surveillance,8 given that the reduction in death from prostate cancer (hazard ratio, 0.63; 95% CI, 0.36 to 1.09) in the Prostate Cancer Intervention versus Observation Trial (PIVOT) only trended toward significance (P=0.09).9
However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.10
Finally, a trend favoring radiation and short-course androgen-deprivation therapy over surgery was observed. Specifically, the point estimate for the hazard ratio for death from prostate cancer when comparing these two treatments was 0.80 (95% CI, 0.22 to 2.99). If this trend becomes significant, then one may consider radiation and androgen-deprivation therapy as a preferred option for otherwise healthy men 65 years of age or older with early prostate cancer for whom treatment as compared with monitoring may be more effective (P=0.09 for interaction) in reducing death from prostate cancer.
For today, we can conclude on the basis of level 1 evidence2 that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis.
Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.2
In addition, given no significant difference in death due to prostate cancer with surgery versus radiation and short-course androgen-deprivation therapy, men with low-risk or intermediate-risk1 prostate cancer should feel free to select a treatment approach using the data on health-related quality of life3 and without fear of possibly selecting a less effective cancer therapy.
Disclosure forms provided by the author are available with the full text of this editorial at NEJM.org.
This editorial was published on September 14, 2016, at NEJM.org.
Source Information
From the Department of Radiation Oncology, Brigham and Women’s Hospital and Dana–Farber Cancer Institute, Boston.
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