Short-course radiotherapy followed by delayed surgery becomes a validated alternative to treat intermediate-risk localised rectal cancer
The full publication in Lancet Oncology of the Stockholm III trial helps us to understand that short-course radiotherapy in patients with localised rectal cancer could also be followed by delayed surgery.1
During more than 14 years, more than 800 patients with rectal cancer not showing unresectable features were randomised in a two-arm versus three-arm study with a non-inferiority design.
Patients could be randomised to short-course radiotherapy (5×5 Gy) and immediate (within a week) versus delayed (4–8 weeks) surgery.
In the three-arm randomisation patients could also be allocated to a long course of concurrent chemoradiation (25×2 Gy), with surgery performed 6–8 weeks thereafter.
Time to local recurrence was established as the primary endpoint.
Interestingly, short-course radiotherapy followed by delayed surgery was proven to have less acute toxicity and a lower postoperative complication rate compared with immediate surgery.Oncological results were similar among the three arms.
The authors conclude that short-course radiotherapy with surgery delayed for 4–8 weeks might have certain advantages over immediate surgery in rectal cancer treatment.
Another interesting fact observed in this study is that tumour regression and downstaging is seen in the delayed surgery arm, achieving a pathological complete response rate of 11.8%, while tumour regression is rarely appreciated in the immediate surgery group.2 Moreover, delayed surgery allows the integration of chemotherapy after short-course radiation in patients with locally advanced tumours. This strategy has been further developed in the RAPIDO trial, which already completed accrual and whose results are to be reported in about 3 years from now.
miércoles, 17 de mayo de 2017
Metformin in Advanced Lung cancer
Results of the safety run-in part of the METAL (METformin in Advanced Lung cancer) study: a multicentre, open-label phase I–II study of metformin with erlotinib in second-line therapy of patients with stage IV non-small-cell lung cancer
Floriana Morgillo, Morena Fasano, Carminia Maria Della Corte, Ferdinando Carlo Sasso, Federica Papaccio, Giuseppe Viscardi, Giovanna Esposito, Raimondo Di Liello, Nicola Normanno, Annalisa Capuano, Liberato Berrino, Giovanni Vicidomini, Alfonso Fiorelli, Mario Santini, Fortunato Ciardiello
DOI: 10.1136/esmoopen-2016-000132 Published 2 May 2017
Abstract
Purpose Our previous works demonstrated the ability of metformin to revert resistance to gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in non-small-cell lung cancer (NSCLC) EGFR/LKB1 wild-type (WT) cell lines. However, the optimal dose of metformin to be used in non-diabetic patients still remains to be defined. The phase I–II trial METformin in Advanced Lung cancer (METAL) was designed to identify the maximum tolerated dose and to evaluate safety and activity of metformin combined with erlotinib in second-line treatment of patients with stage IV NSCLC, whose tumours harbour the WT EGFR gene.
Patients and methods
We report results from the safety run-in part designed to detect acute toxicities, to study pharmacokinetics and to identify the recommended phase II dose (RPD) to be used for the following phase of the study. In the run-in phase, metformin treatment was administered according to a dose escalation scheme and, subsequently, combined with erlotinib.
Results
Twelve patients were enrolled. Common adverse events were diarrhoea, decreased appetite, abdominal pain, vomiting and skin toxicity, mostly reversible with symptomatic medical treatment. Dose-limiting toxicities were vomiting and diarrhoea registered in the initial cohort receiving metformin 2000 mg plus erlotinib at 150 mg die, which was declared the maximum administered dose. Only one of nine patients treated at the next lower dose of 1500 mg of metformin plus erlotinib at 150 mg experienced G3 gastrointestinal toxicity. Metformin plasma-concentration profile confirmed the trend already observed in non-diabetic population. Glycemic profiles showed stability of the blood glucose level within the physiological range for non-diabetic subjects. At a follow-up of 30 weeks, six (50%) patients experienced a disease control (5 SD and 1 partial response).
Conclusions
The RP2D of metformin dose was defined at 1500 mg/day to be combined with erlotinib 150 mg.
Trial registration number EudraCT number: 2014-000349-59.
Key messages
What is already known about this subject?
A series of epidemiological evidences suggested a reduced incidence of cancer in patients treated with metformin compared with those taking other therapies.
In our preclinical model, the combination of metformin with an epidermal growth factor receptor (EGFR) inhibitor resulted synergistic in terms of inhibition of proliferation and induction of apoptosis, in particular in those cell lines harbouring wild-type LKB1 gene.
What does this study add?
This phase I/II dose-escalation study evaluated the combination of metformin and erlotinib in second line treatment of stage IV non-small-cell lung cancer EGFR wild type.
The safety profile was clinically acceptable and maximum tolerated dose was identified.
Preliminary activity data were obtained.
How might this impact on clinical practice?
This clinical experience demonstrated a therapeutic role of metformin in non-diabetic people affected by non-small-cell lung cancer.
The phase II of the trial, by enrolling a higher number of patients, will probably provide more information on the activity of the combination and more instruments for the identification of patient to be treated.
Floriana Morgillo, Morena Fasano, Carminia Maria Della Corte, Ferdinando Carlo Sasso, Federica Papaccio, Giuseppe Viscardi, Giovanna Esposito, Raimondo Di Liello, Nicola Normanno, Annalisa Capuano, Liberato Berrino, Giovanni Vicidomini, Alfonso Fiorelli, Mario Santini, Fortunato Ciardiello
DOI: 10.1136/esmoopen-2016-000132 Published 2 May 2017
Abstract
Purpose Our previous works demonstrated the ability of metformin to revert resistance to gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in non-small-cell lung cancer (NSCLC) EGFR/LKB1 wild-type (WT) cell lines. However, the optimal dose of metformin to be used in non-diabetic patients still remains to be defined. The phase I–II trial METformin in Advanced Lung cancer (METAL) was designed to identify the maximum tolerated dose and to evaluate safety and activity of metformin combined with erlotinib in second-line treatment of patients with stage IV NSCLC, whose tumours harbour the WT EGFR gene.
Patients and methods
We report results from the safety run-in part designed to detect acute toxicities, to study pharmacokinetics and to identify the recommended phase II dose (RPD) to be used for the following phase of the study. In the run-in phase, metformin treatment was administered according to a dose escalation scheme and, subsequently, combined with erlotinib.
Results
Twelve patients were enrolled. Common adverse events were diarrhoea, decreased appetite, abdominal pain, vomiting and skin toxicity, mostly reversible with symptomatic medical treatment. Dose-limiting toxicities were vomiting and diarrhoea registered in the initial cohort receiving metformin 2000 mg plus erlotinib at 150 mg die, which was declared the maximum administered dose. Only one of nine patients treated at the next lower dose of 1500 mg of metformin plus erlotinib at 150 mg experienced G3 gastrointestinal toxicity. Metformin plasma-concentration profile confirmed the trend already observed in non-diabetic population. Glycemic profiles showed stability of the blood glucose level within the physiological range for non-diabetic subjects. At a follow-up of 30 weeks, six (50%) patients experienced a disease control (5 SD and 1 partial response).
Conclusions
The RP2D of metformin dose was defined at 1500 mg/day to be combined with erlotinib 150 mg.
Trial registration number EudraCT number: 2014-000349-59.
Key messages
What is already known about this subject?
A series of epidemiological evidences suggested a reduced incidence of cancer in patients treated with metformin compared with those taking other therapies.
In our preclinical model, the combination of metformin with an epidermal growth factor receptor (EGFR) inhibitor resulted synergistic in terms of inhibition of proliferation and induction of apoptosis, in particular in those cell lines harbouring wild-type LKB1 gene.
What does this study add?
This phase I/II dose-escalation study evaluated the combination of metformin and erlotinib in second line treatment of stage IV non-small-cell lung cancer EGFR wild type.
The safety profile was clinically acceptable and maximum tolerated dose was identified.
Preliminary activity data were obtained.
How might this impact on clinical practice?
This clinical experience demonstrated a therapeutic role of metformin in non-diabetic people affected by non-small-cell lung cancer.
The phase II of the trial, by enrolling a higher number of patients, will probably provide more information on the activity of the combination and more instruments for the identification of patient to be treated.
Artificial intelligence and Oncology
A new era of oncology through artificial intelligence
Alessandra Curioni-Fontecedro
DOI: 10.1136/esmoopen-2017-000198 Published 15 May 2017
ArticleeLettersInfo & Metrics
PDF
Patients’ care, from diagnosis to treatment, has radically changed; however, the awareness about the ongoing revolution has not yet spread through the oncology community.
To date, due to technical advances, cancer research is producing information at an incredibly rapid pace challenging even the most tech-competent physicians to use these data to significantly improve patient care. An example is the current information about the cancer’s genome: millions of molecular alterations that might impact the growth of cancer cells have been discovered and might also influence the response to treatment.
It has been estimated that a physician should read 29 hours per working day in order to stay updated about new medical research. Moreover, every year, the medical literature increases by doubling the amount of information every 3 years. The result is that it is only going to get harder for several generations of oncologists, like me, who have spent hours searching in the literature an answer to a medical question. Several times this ended up in a long process of reading from one article to the next one and possibly missing the answer to the initial problem. There must be a better way to integrate the current knowledge and give to our patients the best possible care.
One such solution was born in 1956 with artificial Intelligence or AI. One of the leading AI or cognitive technologies is IBM Watson, which can learn reason and understand the enormous corpus of the literature available to the scientific community. Such technology will help us make connections among all the data needed to answer a complex medical question in a very short time. Moreover, these technologies can ingest all of the published scientific knowledge, including clinical data of every single patient, ending up with evidence-based and personalised treatment options. For example, Watson for Genomics ingests approximately 10 000 scientific articles and 100 new clinical trials every month.
In one scenario, the clinician may train Watson with the tumours characteristics, the patients’ comorbidities and also add any specific wishes from the patient, for example, if the patient does not want hair loss. Based on these notions and any national and international guidelines, a cognitive computer will be able to generate a ranked list of therapeutical options, including the evidence. Moreover, it will be possible to adapt the suggestions based on the specific constrains of a country. For example, in India, it can take anywhere from 4 months to 2 years for a new product to enter the country1. Finally, such a technology could also evaluate inclusion and exclusion criteria of all possible clinical trials for each patient and find a matching list of studies in which the patient can be included.
These capacities and many others have been made possible, thanks to the collaboration between the IBM researchers and the Memorial Sloan Kettering who have also trained Watson on how a decision is made at a tumour board. Recently, at the San Antonio Conference 2016, the results of a double-blind study with 638 patients were presented comparing the decisions made by the tumour board at the Manipal Comprehensive Cancer Center (India) and the ones made by Watson for Oncology. Incredibly, 90% of Watson for Oncology’s recommendations for standard treatment or consideration were concordant with the recommendations of the tumour board.2
This tumour board was concerning patients with breast cancer and enlightens a great opportunity for big cancer centres where not all patients can be discussed due to time limitations. It is very interesting that the investigators from India, who have been working with Watson, explained how the collaboration between them and Watson was uncomplicated as they entered the electronic patients’ charts and asked Watson for an evaluation of the case. All clinical data, laboratory results and physicians’ notes were analysed. In about 40 s, Watson gave a treatment suggestion as well as the scientific evidence for each suggestion. How long would it take a physician to carefully evaluate the same data without any omission or bias?
These results have been met with great enthusiasm, but also fear between physicians: when will we all be able to use such a tool and are we still going to be fundamental for patients?
Several cancer centres, mainly in the USA, are already working with these platforms and further developing the capacities of such cognitive computers. Indeed, Watson is very young, growing at an incredible speed through the development of new abilities as the cancer genomic project. This is a partnership with the Broad Institute of the Massachusetts Institute of Technology and Harvard with IBM, by which the cancer genome of patient will be fully analysed and all data will be evaluated by the computer for treatment options.
In my opinion, we are entering a new era of oncology and the current generation of physicians must be ready to approach such an evolution with the curiosity that characterises us in this profession. The incredible potential of these technologies is that they can further learn and improve based on the physicians’ needs and as new data are ingested.
Indeed, cognitive computing has only just begun. In addition to oncology, such technologies also have applications in radiology where Watson can ingest thousands of radiological scans and detect the pathological findings. Moreover, Watson can help the pathologist in distinguishing a single tumour cell in several histological samples and in supporting the dermatologists, being able to make the diagnosis of melanoma from a smartphone. This is exactly the function of AI: to help physicians in our repetitive daily work to give us more time for our patients and research.
All of these advances do imply that physicians are aware of the capacities and limits of such technologies and are able to keep a critical attitude. Moreover, the physician will stay as the one responsible for decision-taking and further on will always be the reference for the patient at all timepoints.
Some centres already working with cognitive computers are growing a new generation of oncologists. I, for one, am looking forward to have access to such platforms in order to give to our patients more evidence-based therapeutical options and possibly inclusion into new clinical trials; we should all be ready to say: ‘Hello Watson!’.
Alessandra Curioni-Fontecedro
DOI: 10.1136/esmoopen-2017-000198 Published 15 May 2017
ArticleeLettersInfo & Metrics
Patients’ care, from diagnosis to treatment, has radically changed; however, the awareness about the ongoing revolution has not yet spread through the oncology community.
To date, due to technical advances, cancer research is producing information at an incredibly rapid pace challenging even the most tech-competent physicians to use these data to significantly improve patient care. An example is the current information about the cancer’s genome: millions of molecular alterations that might impact the growth of cancer cells have been discovered and might also influence the response to treatment.
It has been estimated that a physician should read 29 hours per working day in order to stay updated about new medical research. Moreover, every year, the medical literature increases by doubling the amount of information every 3 years. The result is that it is only going to get harder for several generations of oncologists, like me, who have spent hours searching in the literature an answer to a medical question. Several times this ended up in a long process of reading from one article to the next one and possibly missing the answer to the initial problem. There must be a better way to integrate the current knowledge and give to our patients the best possible care.
One such solution was born in 1956 with artificial Intelligence or AI. One of the leading AI or cognitive technologies is IBM Watson, which can learn reason and understand the enormous corpus of the literature available to the scientific community. Such technology will help us make connections among all the data needed to answer a complex medical question in a very short time. Moreover, these technologies can ingest all of the published scientific knowledge, including clinical data of every single patient, ending up with evidence-based and personalised treatment options. For example, Watson for Genomics ingests approximately 10 000 scientific articles and 100 new clinical trials every month.
In one scenario, the clinician may train Watson with the tumours characteristics, the patients’ comorbidities and also add any specific wishes from the patient, for example, if the patient does not want hair loss. Based on these notions and any national and international guidelines, a cognitive computer will be able to generate a ranked list of therapeutical options, including the evidence. Moreover, it will be possible to adapt the suggestions based on the specific constrains of a country. For example, in India, it can take anywhere from 4 months to 2 years for a new product to enter the country1. Finally, such a technology could also evaluate inclusion and exclusion criteria of all possible clinical trials for each patient and find a matching list of studies in which the patient can be included.
These capacities and many others have been made possible, thanks to the collaboration between the IBM researchers and the Memorial Sloan Kettering who have also trained Watson on how a decision is made at a tumour board. Recently, at the San Antonio Conference 2016, the results of a double-blind study with 638 patients were presented comparing the decisions made by the tumour board at the Manipal Comprehensive Cancer Center (India) and the ones made by Watson for Oncology. Incredibly, 90% of Watson for Oncology’s recommendations for standard treatment or consideration were concordant with the recommendations of the tumour board.2
This tumour board was concerning patients with breast cancer and enlightens a great opportunity for big cancer centres where not all patients can be discussed due to time limitations. It is very interesting that the investigators from India, who have been working with Watson, explained how the collaboration between them and Watson was uncomplicated as they entered the electronic patients’ charts and asked Watson for an evaluation of the case. All clinical data, laboratory results and physicians’ notes were analysed. In about 40 s, Watson gave a treatment suggestion as well as the scientific evidence for each suggestion. How long would it take a physician to carefully evaluate the same data without any omission or bias?
These results have been met with great enthusiasm, but also fear between physicians: when will we all be able to use such a tool and are we still going to be fundamental for patients?
Several cancer centres, mainly in the USA, are already working with these platforms and further developing the capacities of such cognitive computers. Indeed, Watson is very young, growing at an incredible speed through the development of new abilities as the cancer genomic project. This is a partnership with the Broad Institute of the Massachusetts Institute of Technology and Harvard with IBM, by which the cancer genome of patient will be fully analysed and all data will be evaluated by the computer for treatment options.
In my opinion, we are entering a new era of oncology and the current generation of physicians must be ready to approach such an evolution with the curiosity that characterises us in this profession. The incredible potential of these technologies is that they can further learn and improve based on the physicians’ needs and as new data are ingested.
Indeed, cognitive computing has only just begun. In addition to oncology, such technologies also have applications in radiology where Watson can ingest thousands of radiological scans and detect the pathological findings. Moreover, Watson can help the pathologist in distinguishing a single tumour cell in several histological samples and in supporting the dermatologists, being able to make the diagnosis of melanoma from a smartphone. This is exactly the function of AI: to help physicians in our repetitive daily work to give us more time for our patients and research.
All of these advances do imply that physicians are aware of the capacities and limits of such technologies and are able to keep a critical attitude. Moreover, the physician will stay as the one responsible for decision-taking and further on will always be the reference for the patient at all timepoints.
Some centres already working with cognitive computers are growing a new generation of oncologists. I, for one, am looking forward to have access to such platforms in order to give to our patients more evidence-based therapeutical options and possibly inclusion into new clinical trials; we should all be ready to say: ‘Hello Watson!’.
lunes, 15 de mayo de 2017
Avelumab for Urothelial Carcinoma
FDA Grants Accelerated Approval to Avelumab for Urothelial Carcinoma
FDA granted priority review for this application for PD-L1 blocking antibody in locally advanced or metastatic urothelial carcinoma patients
Date: 10 May 2017
Topic: Genitourinary cancers / Cancer Immunology and Immunotherapy
On 9 May, 2017, the US Food and Drug Administration (FDA) granted accelerated approval to avelumab (BAVENCIO, EMD Serono, Inc.) for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
Approval was based on data from an open-label, single arm, multicentre study that enrolled 242 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed on or after platinum-based therapy or within 12 months of a platinum-containing neoadjuvant or adjuvant chemotherapy regimen.
Patients received avelumab, 10 mg/kg intravenously, every 2 weeks until radiographic or clinical progression or unacceptable toxicity. All patients received pre-medication with an anti-histamine and acetaminophen prior to each avelumab administration.
Confirmed overall response rate (ORR) in patients who had been followed for at least 13 weeks was 13.3% (n=30) (95% CI: 9.1, 18.4), and 16.1% (n=26) (95% CI: 10.8, 22.8) in patients who had been followed for at least 6 months. Median time to response was 2.0 months (range 1.3-11.0). The median response duration had not been reached in patients followed for at least 13 weeks or at least 6 months, but ranged from 1.4+ to 17.4+ months in both groups.
Deaths due to an adverse reaction occurred in 6% of patients. Serious adverse reactions were reported in 41% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, haematuria/urinary tract haemorrhage, intestinal obstruction/small intestinal obstruction, and pyrexia. The most common adverse reactions that occurred in at least 20% of patients were fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection.
The recommended dose of avelumab is 10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks. Pre-medicate with an anti-histamine and acetaminophen prior to the first four infusions of avelumab.
Full prescribing information is available here.
FDA granted this application priority review. FDA approved avelumab for this indication approximately 3 months ahead of the goal date.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.
Pegylated Liposomal Irinotecan: NICE does not recommend it for the treatment of metastatic pancreatic cancer after gemcitabine-based therapy
NICE Issues Technology Appraisal Guidance for Pegylated Liposomal Irinotecan
NICE does not recommend it for the treatment of metastatic pancreatic cancer after gemcitabine-based therapy
Date: 11 May 2017
Topic: Gastrointestinal cancers / Anticancer agents & Biologic therapy
On 26 April 2017, the NICE published technology appraisal guidance [TA440] in which it was stated that pegylated liposomal irinotecan, in combination with 5‑fluorouracil (5-FU) and leucovorin (LV), is not recommended, within its marketing authorisation, for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.
This guidance is not intended to affect the position of patients whose treatment with pegylated liposomal irinotecan was started within the NHS before this guidance was published. Treatment of these patients may continue without change to whatever funding arrangements were in place for them before this guidance was published until they and their NHS clinician consider it appropriate to stop.
Current practice
Metastatic adenocarcinoma of the pancreas that has progressed after gemcitabine treatment is associated with a poor prognosis because there are few treatments available, and survival may be less than 6 months. Current treatments are limited in efficacy so there is value in more treatment options in this area.
The technology
The appraisal committee heard from the clinical and patient experts that there were few options for treating metastatic adenocarcinoma of the pancreas and that pegylated liposomal irinotecan plus 5‑FU and LV would provide another option. However, the committee concluded that having an extra treatment option did not mean that pegylated liposomal irinotecan plus 5‑FU and LV was innovative. It also concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.
What is the position of the treatment in the pathway of care for the condition?
The appraisal committee understood from the clinical expert that oxaliplatin plus 5‑FU and LV or capecitabine monotherapy are used in clinical practice in England after gemcitabine treatment. The committee agreed with the company, evidence review group (ERG) and advice from the clinical expert that the most appropriate comparator for pegylated liposomal irinotecan plus 5‑FU and LV in NHS practice would be oxaliplatin plus 5‑FU and LV.
Adverse reactions
In NAPOLI‑1, treatment-emergent serious adverse events (that is, events that first appear during treatment, or worsen during treatment) were more common in the pegylated liposomal irinotecan plus 5‑FU and LV group than in the 5‑FU plus LV group (47.9% compared with 44.8%). The committee noted that health-related quality-of-life data were collected in NAPOLI‑1 and that the results at 6 weeks and 12 weeks showed no real differences between the groups, suggesting no negative effect of pegylated liposomal irinotecan on health-related quality of life.
Evidence for clinical effectiveness
The company's submission presented clinical-effectiveness evidence from NAPOLI-1, comparing pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV.
The company considered that a formal indirect comparison of the clinical effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV was not appropriate because the trials were too heterogeneous.
Relevance to general clinical practice in the NHS
The patients in NAPOLI‑1 were fitter than those generally seen in clinical practice.
Uncertainties generated by the evidence
The committee noted that given the uncertainties inherent in the indirect treatment comparison, the ERG reviewed the literature and concluded that, in general, the progression-free survival (PFS) and overall survival (OS) estimates appeared very similar for oxaliplatin plus 5‑FU and LV and pegylated liposomal irinotecan plus 5‑FU and LV. The committee also noted that the relative effectiveness of oxaliplatin plus 5‑FU and LV compared with pegylated liposomal irinotecan plus 5‑FU and LV was difficult to estimate.
Estimate of the size of the clinical effectiveness including strength of supporting evidence: The median extension in OS in NAPOLI‑1 for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was 1.9 months.
Both the company and the ERG were unable to produce a reliable estimate of the difference in OS between pegylated liposomal irinotecan plus 5‑FU and LV and oxaliplatin plus 5‑FU and LV, but when comparing 3 trials of oxaliplatin plus 5‑FU and LV the median OS was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.
Evidence for cost effectiveness
The company submitted a de novo economic model to estimate the cost effectiveness of pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV and with oxaliplatin plus 5‑FU and LV, in patients with metastatic adenocarcinoma of the pancreas after gemcitabine treatment.
The company used an indirect treatment comparison to estimate OS, PFS and time-on-treatment curves for the comparison with oxaliplatin plus 5‑FU and LV.
Uncertainties around and plausibility of assumptions and inputs in the economic model
The company made assumptions about the costs and survival estimates.
The committee noted that the total QALYs for oxaliplatin plus 5‑FU and LV were significantly lower than for 5‑FU plus LV in the company's analysis. It acknowledged that this result was not in agreement with comments from the clinical expert, who stated that oxaliplatin plus 5‑FU and LV is the preferred option; it is more clinically effective than 5‑FU and LV and is standard clinical practice in the NHS.
The committee concluded that because the data were complete for PFS and time on treatment, and virtually complete for OS, using the Kaplan–Meier data from NAPOLI‑1 was more appropriate than using the company's parametric modelling.
The committee concluded that it was not appropriate to assume dose reductions would always apply in the company's model and that full costing should be assumed in the base case. It also concluded that it was not appropriate to assume use of the smallest sized vials in the company's model and that the ERG's method of calculating costs was more appropriate.
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The committee concluded that although there was uncertainty about the most appropriate utility values to use for a second-line treatment population with pancreatic cancer, the values used by the company were acceptable for decision-making.
The committee concluded that there were no additional gains in health-related quality of life over those already included in the QALY calculations.
What are the key drivers of cost effectiveness?
For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with 5‑FU plus LV the committee considered that all the changes, except the ERG's preferred health state utility values, should be included in the base case. The committee therefore concluded that the incremental cost-effectiveness ratio (ICER) for pegylated liposomal irinotecan plus 5‑FU and LV, compared with 5‑FU plus LV, was over 100,000 GBP per QALY gained.
For the comparison of pegylated liposomal irinotecan plus 5‑FU and LV with oxaliplatin plus 5‑FU and LV, the ERG carried out scenarios altering the QALY difference between the 2 treatments. When taking into account these scenarios, the ICER ranged from 201,019 GBP per QALY gained (when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% less than for pegylated liposomal irinotecan plus 5‑FU and LV) to pegylated liposomal irinotecan plus 5‑FU and LV being dominated (that is, less effective and more expensive than oxaliplatin plus 5‑FU and LV) when the total QALYs for oxaliplatin plus 5‑FU and LV were 10% more.
Most likely cost-effectiveness estimate (given as an ICER)
The committee concluded that taking into account all of the ICERs presented, the ICER for pegylated liposomal irinotecan plus 5‑FU and LV compared with 5‑FU plus LV was over 100,000 GBP per QALY gained.
Additional factors taken into account
Patient access schemes
The committee considered analyses incorporating the confidential patient access scheme for pegylated liposomal irinotecan plus 5‑FU and LV.
End-of-life considerations
The committee concluded that the criterion for short life expectancy was met.
However, pegylated liposomal irinotecan plus 5‑FU and LV survival estimates from the trial and model showed that the criterion for extension to life was not met for the comparison with 5‑FU plus LV or with oxaliplatin plus 5‑FU and LV. The committee noted that when comparing 3 trials of oxaliplatin plus 5‑FU and LV, the median OS was similar to that reported for pegylated liposomal irinotecan plus 5‑FU and LV in NAPOLI‑1.
Therefore, the committee concluded that pegylated liposomal irinotecan plus 5‑FU and LV did not meet the NICE supplementary advice criteria to be considered as a life-extending, end-of-life treatment.
Pembrolizumab as First-Line Combination Therapy with Pemetrexed and Carboplatin: FDA Approves Combination Therapy
FDA Approves Pembrolizumab as First-Line Combination Therapy with Pemetrexed and Carboplatin for Metastatic Non-squamous NSCLC Irrespective of PD-L1 Expression
First approval for an anti-PD-1 therapy as a combination in metastatic non-squamous NSCLC
Date: 12 May 2017
Topic: Lung and other thoracic tumours / Cancer Immunology and Immunotherapy
On 10 May 2017, Merck, known as MSD outside the US and Canada, announced that the US Food and Drug Administration (FDA) has approved pembrolizumab (KEYTRUDA®), the anti-PD-1 therapy, in combination with pemetrexed and carboplatin (pem/carbo), a commonly used chemotherapy regimen, for the first-line treatment of metastatic non-squamous non-small cell lung cancer (NSCLC), irrespective of PD-L1 expression. Under the FDA’s accelerated approval regulations, this indication is approved based on tumour response rate and progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
The approval was based on data from KEYNOTE-021, Cohort G1, in 123 previously untreated patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumour aberrations and irrespective of PD-L1 expression. In this trial, pembrolizumab plus pem/carbo demonstrated an objective response rate (ORR) that was nearly double the ORR of pem/carbo alone (55% [95% CI: 42, 68] compared to 29% [95% CI: 18, 41], respectively; all responses were partial responses). Among patients who received pembrolizumab plus pem/carbo, 93% had a duration of response of six months or more (range 1.4+ to 13.0+ months) compared to 81% who received pem/carbo alone (range 1.4+ to 15.2+ months). In addition, findings demonstrated an improvement in PFS (HR 0.53 [95% CI, 0.31-0.91; p=0.0205]), with a median PFS of 13.0 months (95% CI, 8.3-not estimable) for patients treated with pembrolizumab plus pem/carbo compared to 8.9 months (95% CI, 4.4-10.3) with pem/carbo alone.
Immune-mediated adverse reactions occurred with pembrolizumab including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered when appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for grade 3 or 4 reactions, stop infusion and permanently discontinue pembrolizumab. Based on its mechanism of action, pembrolizumab can cause foetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a foetus.
The combination therapy indication makes pembrolizumab an option for more patients. Pembrolizumab is the only anti-PD-1 antibody approved in the first-line setting as both monotherapy and combination therapy for appropriate patients with metastatic NSCLC. Pembrolizumab is approved as monotherapy in the first-line setting for patients with metastatic NSCLC whose tumours have high PD-L1 expression (tumour proportion score [TPS] ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumour aberrations. Pembrolizumab as monotherapy is also indicated for the second-line or greater treatment of patients with metastatic NSCLC whose tumours express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumour aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
When administering pembrolizumab in combination with pem/carbo, pembrolizumab should be administered first prior to chemotherapy when given on the same day. In metastatic NSCLC, pembrolizumab is approved at a fixed dose of 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression; pemetrexed and carboplatin should be administered according to their FDA-approved labels.
The news release of Merck & Co., Inc., Kenilworth, NJ, US includes “forward-looking statements”. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful.
selumetinib and docetaxel: KRAS mutation-positive non-small-cell lung cancer patients do not benefit from a second-line
Negative SELECT-1 Results For Previously Treated KRAS-Mutated Advanced NSCLC
Advanced KRAS mutation-positive non-small-cell lung cancer patients do not benefit from a second-line combination of selumetinib and docetaxel
Date: 10 May 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Non-Small-Cell Lung Cancer, Metastatic
medwireNews: Adding selumetinib to docetaxel does not improve progression-free survival (PFS) in patients who have previously been treated for advanced KRAS-mutated non-small-cell lung cancer (NSCLC), report the SELECT-1 investigators.
The primary endpoint of median PFS was 3.9 months for the 254 patients who were randomly assigned to receive a continuous 75 mg twice daily dose of the oral MEK1/2 inhibitor alongside docetaxel 75 mg/m2 given on day 1 of a 21-day cycle.
This did not significantly differ from the 2.8 months achieved by the 254 patients given placebo plus docetaxel, write Pasi Jänne, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in JAMA.
Median overall survival was also comparable in the selumetinib–docetaxel and placebo–docetaxel groups, at 8.7 versus 7.9 months. Although the selumetinib regimen led to a significantly higher objective response rate (ORR; 20.1 vs 13.7%, odds ratio=1.61), median duration of response was similar between the arms (2.9 vs 4.5 months).
Common side effects associated with the selumetinib regimen included diarrhoea (61%), nausea (38%), rash (34%) and peripheral oedema (30%), whereas the most frequent adverse events with placebo plus docetaxel were diarrhoea (35%), fatigue (31%), Alopecia (25%) and nausea (24%).
Patients in the selumetinib–docetaxel group, compared with those given placebo–docetaxel, experienced higher rates of grade 3 or more serious side effects (67 vs 45%), serious adverse events (49 vs 32%), and adverse events leading to hospitalisation (46 vs 30%).
Dose reductions were also more common in the selumetinib–docetaxel group, affecting 28% of patients versus 6% of those given placebo, as were treatment interruptions (41 vs 21%) and discontinuation of the study treatment (23 vs 9%) and docetaxel (29 vs 15%).
The researchers note that placebo–docetaxel had greater efficacy in the current study than the earlier phase II trial, while the selumetinib–docetaxel regimen had poorer efficacy.
Hypothesizing that differences in the distribution of KRAS mutation subtypes between the phase II and III trials could partially account for this, the team compared findings for 301 SELECT-1 participants with a KRAS G12C or G12CV mutation and 195 patients with other KRAS variants.
However, PFS did not significantly correlate with mutation group or individual KRAS mutation. And while the ORR was higher in patients with a KRAS G12C or G12C mutation who were assigned to receive the selumetinib regimen compared with those given placebo–docetaxel, the researchers say that “this was not translated into a meaningful [PFS] benefit.”
Jacob Kaufman, from Duke University, and Thomas Stinchcombe, from the Duke Cancer Institute, both based in Durham, North Carolina, USA, question in an accompanying comment whether other mutations associated with response to MEK inhibition, such as concurrent loss of the LKB1 tumour suppressor Gene, may also have influenced the trial results.
They suggest it may be “premature” to rule out other MEK inhibitors in KRAS-mutated NSCLC and that other chemotherapy agents in combination with MEK inhibitors “may have more synergy than was observed with docetaxel.”
The commentators conclude: “The next generation of targeted therapies will likely focus on the primary oncogenic molecular event and the acquired resistance mechanisms, and will be more potent and specific for the oncogenic driver.
“This will ideally improve efficacy and reduce off-target toxicities,” they write, adding: “The development of a targeted therapy is critical to the future management of patients with KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations.”
References
Jänne PA, van den Heuvel MM, Barlesi F, et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer. The SELECT-1 randomized clinical trial. JAMA 2017; 317: 1844–1853, published online 9 May 2017. doi:10.1001/jama.2017.3438
Kaufman J, Stinchcombe TE. Treatment of KRAS-mutant non-small cell lung cancer. The end of the beginning for targeted therapies. JAMA 2017; 317: 1835–1837, published online 9 May 2017. doi:10.1001/jama.2017.3436
miércoles, 10 de mayo de 2017
EGFR Mutation-Positive Advanced NSCLC: Clarifying a New Standard of Care
News & Perspective > Viewpoints
COMMENTARY
The Evolving Landscape for EGFR Mutation-Positive Advanced NSCLC: Clarifying a New Standard of Care
H. Jack West, MD
Disclosures
May 03, 2017
For patients with advanced non–small cell lung cancer (NSCLC) and an activating mutation in the epidermal growth factor receptor (EGFR) gene, the management of acquired resistance now offers the potential for further EGFR-directed treatment before turning, most commonly, to conventional chemotherapy. The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib has been demonstrated to have significant activity in patients with EGFR mutation-positive acquired resistance, overwhelmingly more in the 50% to 60% who develop a T790M mutation as a mechanism of resistance.[1] The US Food and Drug Administration (FDA) has approved osimertinib for T790M mutation–positive acquired resistance based on this early phase 1/2 work.[2] Despite the availability of osimertinib and its demonstrated efficacy, testing for this marker remained limited. This is in part because osimertinib had not been compared with an active therapy in a phase 3 trial.
The AURA-3 trial randomly assigned 419 patients with EGFR T790M-positive advanced NSCLC and acquired resistance after a prior EGFR TKI in a 2:1 fashion to either the third-generation EGFR TKI osimertinib at 80 mg by mouth daily or standard cisplatin or carboplatin with pemetrexed.[3] The trial demonstrated a highly significant efficacy advantage for osimertinib over chemotherapy in terms of objective response rate (ORR, 71% vs 31%; odds ratio, 5.39; P < .001) and progression-free survival (PFS, median 10.1 vs 4.4 months; hazard ratio [HR], 0.30; P < .0001). Among the 144 patients, median PFS also strongly favored osimertinib (8.5 vs 4.2 months; HR, 0.32). Toxicity also favored osimertinib, as the rate of grade 3 toxicities was twice as high with chemotherapy as with osimertinib (47% vs 23%, respectively). The most common adverse effects (any grade) with osimertinib were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%), while those with chemotherapy were nausea (49%), diminished appetite (36%), constipation (35%), and anemia (30%).
In AURA-3, the comparator to osimertinib was the clear best alternative widely used outside of a trial, with platinum doublet therapy frequently selected in the absence of further mutation-directed therapy[4] and a platinum-pemetrexed combination commonly favored as a potential optimal choice in patients with lung adenocarcinomas. Osimertinib demonstrated a highly significant benefit in efficacy that was accompanied by an overall more favorable toxicity profile, thus adding an option not otherwise available and simply deferring platinum doublet chemotherapy until subsequent progression.
Osimertinib has now emerged as the standard of care for EGFR T790M mutation–positive NSCLC after progression on a prior EGFR TKI, making it mandatory to look for T790M once acquired resistance has developed. Of note, there is an FDA-approved plasma-based companion diagnostic, providing a noninvasive approach as an initial "first pass" when looking for T790M. However, because plasma testing is still evolving and has a sensitivity in the 60%-80% range,[5] a negative plasma test may represent a false negative and should ideally be followed by a tissue biopsy before concluding that a patient is T790M negative, especially given the very favorable efficacy and tolerability of osimertinib and with availability limited only to those positive for this marker.
With the AURA-3 phase 3 trial convincingly demonstrating the greater efficacy and tolerability of osimertinib over conventional chemotherapy for T790M mutation–positive NSCLC, it emerges as the clear standard of care in this setting. Unless it demonstrates superiority over first-line gefitinib or erlotinib in the completed but not-yet-reported FLAURA trial,[6] its use remains restricted to those patients who are tested and found to have a T790M mutation. Whether by plasma, urine, tissue, or a combination of these platforms, it is now imperative to test for this marker in EGFR mutation–positive patients with acquired resistance to provide them with an opportunity to benefit from osimertinib.
1 Comment References
Medscape Oncology © 2017 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this article: The Evolving Landscape for EGFR Mutation-Positive Advanced NSCLC: Clarifying a New Standard of Care - Medscape - May 03, 2017.
COMMENTARY
The Evolving Landscape for EGFR Mutation-Positive Advanced NSCLC: Clarifying a New Standard of Care
H. Jack West, MD
Disclosures
May 03, 2017
For patients with advanced non–small cell lung cancer (NSCLC) and an activating mutation in the epidermal growth factor receptor (EGFR) gene, the management of acquired resistance now offers the potential for further EGFR-directed treatment before turning, most commonly, to conventional chemotherapy. The third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib has been demonstrated to have significant activity in patients with EGFR mutation-positive acquired resistance, overwhelmingly more in the 50% to 60% who develop a T790M mutation as a mechanism of resistance.[1] The US Food and Drug Administration (FDA) has approved osimertinib for T790M mutation–positive acquired resistance based on this early phase 1/2 work.[2] Despite the availability of osimertinib and its demonstrated efficacy, testing for this marker remained limited. This is in part because osimertinib had not been compared with an active therapy in a phase 3 trial.
The AURA-3 trial randomly assigned 419 patients with EGFR T790M-positive advanced NSCLC and acquired resistance after a prior EGFR TKI in a 2:1 fashion to either the third-generation EGFR TKI osimertinib at 80 mg by mouth daily or standard cisplatin or carboplatin with pemetrexed.[3] The trial demonstrated a highly significant efficacy advantage for osimertinib over chemotherapy in terms of objective response rate (ORR, 71% vs 31%; odds ratio, 5.39; P < .001) and progression-free survival (PFS, median 10.1 vs 4.4 months; hazard ratio [HR], 0.30; P < .0001). Among the 144 patients, median PFS also strongly favored osimertinib (8.5 vs 4.2 months; HR, 0.32). Toxicity also favored osimertinib, as the rate of grade 3 toxicities was twice as high with chemotherapy as with osimertinib (47% vs 23%, respectively). The most common adverse effects (any grade) with osimertinib were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%), while those with chemotherapy were nausea (49%), diminished appetite (36%), constipation (35%), and anemia (30%).
In AURA-3, the comparator to osimertinib was the clear best alternative widely used outside of a trial, with platinum doublet therapy frequently selected in the absence of further mutation-directed therapy[4] and a platinum-pemetrexed combination commonly favored as a potential optimal choice in patients with lung adenocarcinomas. Osimertinib demonstrated a highly significant benefit in efficacy that was accompanied by an overall more favorable toxicity profile, thus adding an option not otherwise available and simply deferring platinum doublet chemotherapy until subsequent progression.
Osimertinib has now emerged as the standard of care for EGFR T790M mutation–positive NSCLC after progression on a prior EGFR TKI, making it mandatory to look for T790M once acquired resistance has developed. Of note, there is an FDA-approved plasma-based companion diagnostic, providing a noninvasive approach as an initial "first pass" when looking for T790M. However, because plasma testing is still evolving and has a sensitivity in the 60%-80% range,[5] a negative plasma test may represent a false negative and should ideally be followed by a tissue biopsy before concluding that a patient is T790M negative, especially given the very favorable efficacy and tolerability of osimertinib and with availability limited only to those positive for this marker.
With the AURA-3 phase 3 trial convincingly demonstrating the greater efficacy and tolerability of osimertinib over conventional chemotherapy for T790M mutation–positive NSCLC, it emerges as the clear standard of care in this setting. Unless it demonstrates superiority over first-line gefitinib or erlotinib in the completed but not-yet-reported FLAURA trial,[6] its use remains restricted to those patients who are tested and found to have a T790M mutation. Whether by plasma, urine, tissue, or a combination of these platforms, it is now imperative to test for this marker in EGFR mutation–positive patients with acquired resistance to provide them with an opportunity to benefit from osimertinib.
1 Comment References
Medscape Oncology © 2017 WebMD, LLC
Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this article: The Evolving Landscape for EGFR Mutation-Positive Advanced NSCLC: Clarifying a New Standard of Care - Medscape - May 03, 2017.
martes, 2 de mayo de 2017
FDA Approves Durvalumab for Bladder Cancer
Web Exclusives >
FDA Approves Durvalumab for Bladder Cancer
Jason M. Broderick @jasoncology
Published Online: Monday, May 01, 2017
The FDA has granted an accelerated approval to the PD-L1 inhibitor durvalumab (Imfinzi) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
A complementary diagnostic for PD-L1, the VENTANA PD-L1 (SP263) Assay, was simultaneously approved.
The approval was based on the single-arm phase I/II Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.
In the study, the objective response rate (ORR) per blinded independent central review was 17.0% (95% CI, 11.9-23.3). At the data cutoff, the median duration of response was not reached (range, 0.9+ to 19.9+ months).
Among 95 patients with high PD-L1 expression, the ORR was 26.3% (95% CI, 17.8-36.4). In the cohort of 73 patients with low or no PD-L1 expression, the ORR was 4.1% (95% CI, 0.9-11.5).
“The usual course of treatment for patients with advanced bladder cancer begins with a standard platinum-containing chemotherapy. Patients who have disease progression during or following chemotherapy are left with few other treatment options. The approval of Imfinzi to treat this population of select patients signifies hope for those who are currently suffering, or may find themselves with limited options in the future,” Nicholas J. Vogelzang, MD, clinical professor at the University of Nevada School of Medicine; SWOG GU Vice Chair; US Oncology Research GU Chair; Comprehensive Cancer Centers of Nevada, said in a statement.
The median age of patients in Study 1108 was 67 years (range, 34-88), 64% were white, and 72% were male. Two-thirds of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Forty-one percent of patients had a baseline creatinine clearance of less than 60 mL/min and 66% had an ECOG performance score of 1.
Thirty-five percent of patients had received at least 2 prior lines systemic therapy. Prior cisplatin and prior carboplatin were reported in 70% and 35% of patients, respectively. Among the overall population, 20% of patients had progressed after receiving platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy.
Patients were not eligible to enroll in the trial if they had a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg/day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection.
Expression of PD-L1 on tumor cells (TC) and immune cells (IC) was determined at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Criteria for inclusion in the PD-L1 high cohort were as follows: if ICs involve >1% of the tumor area, TC ≥25% or IC ≥25%; if ICs involve ≤1% of the tumor area, TC ≥25% or IC = 100%.
Durvalumab was administered at 10 mg/kg IV every 2 weeks for up to 1 year or until disease progression or unacceptable toxicity. Tumors were assessed at weeks 6, 12, and 16, then every 8 weeks for the first year and every 12 weeks thereafter.
At a median follow-up of 5.6 months, 31 patients achieved a response, including 5 complete responses (CRs) and 26 partial responses (PRs). Among patients with high PD-L1 expression, responses occurred in 25 patients, with 3 CRs and 22 PRs. Three patients in the PD-L1 low/none cohort had a response, including 1 CR and 2 PRs. Three responses (1 CR and 2 PRs) were also achieved in the group of patients whose PD-L1 status was not evaluable.
All-grade adverse events (AEs) occurring in 15% or more of patients included fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%).
Grade 3/4 AEs occurred in 43% of patients, the most common (≥3%) of which were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.
Infection and immune-related AEs observed with durvalumab included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes.
Forty-six percent of patients experienced serious AEs, including acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each).
AEs led to treatment discontinuation in 3.3% of patients. There were 8 patients deaths, due to cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis.
In February 2016, the FDA granted a breakthrough therapy designation to durvalumab as a treatment for patients with PD-L1–positive inoperable or metastatic urothelial bladder cancer following progression on prior treatment with a platinum-based regimen.
Durvalumab is being evaluated as a single agent and in combination with tremelimumab in the phase III DANUBE trial in the frontline setting for patients with metastatic urothelial carcinoma, regardless of their eligibility for cisplatin-based chemotherapy.
More than 30 other ongoing trials are evaluating various combinations of durvalumab with other immunotherapies and targeted agents.
The accelerated approval of durvalumab in bladder cancer is contingent upon results from a confirmatory trial.
“We are excited to offer Imfinzi as a breakthrough therapy for patients with locally-advanced or metastatic bladder cancer. Imfinzi is the cornerstone of our extensive Immuno-Oncology program, in development across many tumor types, as monotherapy and in combination. This first approval for Imfinzi is an important milestone in our return to growth and brings us another step closer to our goal of redefining the way cancer is treated,” Pascal Soriot, CEO of AstraZeneca, the manufacturer of durvalumab, said in a statement.
FDA Approves Durvalumab for Bladder Cancer
Jason M. Broderick @jasoncology
Published Online: Monday, May 01, 2017
The FDA has granted an accelerated approval to the PD-L1 inhibitor durvalumab (Imfinzi) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
A complementary diagnostic for PD-L1, the VENTANA PD-L1 (SP263) Assay, was simultaneously approved.
The approval was based on the single-arm phase I/II Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.
In the study, the objective response rate (ORR) per blinded independent central review was 17.0% (95% CI, 11.9-23.3). At the data cutoff, the median duration of response was not reached (range, 0.9+ to 19.9+ months).
Among 95 patients with high PD-L1 expression, the ORR was 26.3% (95% CI, 17.8-36.4). In the cohort of 73 patients with low or no PD-L1 expression, the ORR was 4.1% (95% CI, 0.9-11.5).
“The usual course of treatment for patients with advanced bladder cancer begins with a standard platinum-containing chemotherapy. Patients who have disease progression during or following chemotherapy are left with few other treatment options. The approval of Imfinzi to treat this population of select patients signifies hope for those who are currently suffering, or may find themselves with limited options in the future,” Nicholas J. Vogelzang, MD, clinical professor at the University of Nevada School of Medicine; SWOG GU Vice Chair; US Oncology Research GU Chair; Comprehensive Cancer Centers of Nevada, said in a statement.
The median age of patients in Study 1108 was 67 years (range, 34-88), 64% were white, and 72% were male. Two-thirds of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Forty-one percent of patients had a baseline creatinine clearance of less than 60 mL/min and 66% had an ECOG performance score of 1.
Thirty-five percent of patients had received at least 2 prior lines systemic therapy. Prior cisplatin and prior carboplatin were reported in 70% and 35% of patients, respectively. Among the overall population, 20% of patients had progressed after receiving platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy.
Patients were not eligible to enroll in the trial if they had a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg/day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection.
Expression of PD-L1 on tumor cells (TC) and immune cells (IC) was determined at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Criteria for inclusion in the PD-L1 high cohort were as follows: if ICs involve >1% of the tumor area, TC ≥25% or IC ≥25%; if ICs involve ≤1% of the tumor area, TC ≥25% or IC = 100%.
Durvalumab was administered at 10 mg/kg IV every 2 weeks for up to 1 year or until disease progression or unacceptable toxicity. Tumors were assessed at weeks 6, 12, and 16, then every 8 weeks for the first year and every 12 weeks thereafter.
At a median follow-up of 5.6 months, 31 patients achieved a response, including 5 complete responses (CRs) and 26 partial responses (PRs). Among patients with high PD-L1 expression, responses occurred in 25 patients, with 3 CRs and 22 PRs. Three patients in the PD-L1 low/none cohort had a response, including 1 CR and 2 PRs. Three responses (1 CR and 2 PRs) were also achieved in the group of patients whose PD-L1 status was not evaluable.
All-grade adverse events (AEs) occurring in 15% or more of patients included fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%), and urinary tract infection (15%).
Grade 3/4 AEs occurred in 43% of patients, the most common (≥3%) of which were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration.
Infection and immune-related AEs observed with durvalumab included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes.
Forty-six percent of patients experienced serious AEs, including acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain, and pyrexia/tumor associated fever (2.7% each).
AEs led to treatment discontinuation in 3.3% of patients. There were 8 patients deaths, due to cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis.
In February 2016, the FDA granted a breakthrough therapy designation to durvalumab as a treatment for patients with PD-L1–positive inoperable or metastatic urothelial bladder cancer following progression on prior treatment with a platinum-based regimen.
Durvalumab is being evaluated as a single agent and in combination with tremelimumab in the phase III DANUBE trial in the frontline setting for patients with metastatic urothelial carcinoma, regardless of their eligibility for cisplatin-based chemotherapy.
More than 30 other ongoing trials are evaluating various combinations of durvalumab with other immunotherapies and targeted agents.
The accelerated approval of durvalumab in bladder cancer is contingent upon results from a confirmatory trial.
“We are excited to offer Imfinzi as a breakthrough therapy for patients with locally-advanced or metastatic bladder cancer. Imfinzi is the cornerstone of our extensive Immuno-Oncology program, in development across many tumor types, as monotherapy and in combination. This first approval for Imfinzi is an important milestone in our return to growth and brings us another step closer to our goal of redefining the way cancer is treated,” Pascal Soriot, CEO of AstraZeneca, the manufacturer of durvalumab, said in a statement.
Suscribirse a:
Entradas (Atom)