FDA Modifies Indication for Erlotinib in NSCLC
The use is limited to patients whose tumours have specific EGFR mutations
Date: 24 Oct 2016
Topic: Lung and other thoracic tumours / Anticancer agents & Biologic therapy
On 18 October, 2016, the US Food and Drug Administration (FDA) modified the indication for erlotinib (TARCEVA, Astellas Pharm Global Development Inc.) for treatment of non-small cell lung cancer (NSCLC) to limit use to patients whose tumours have specific epidermal growth factor receptor (EGFR) mutations.
The labelling change applies to patients with NSCLC receiving maintenance or second or greater line treatment. These indications will be limited to those patients whose tumours have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test.
The first-line indication previously was limited to patients with EGFR exon 19 deletions or exon 21 substitution mutations.
This labelling supplement is based on the results of the IUNO trial, a randomised, double-blind, placebo-controlled, trial of erlotinib administered as maintenance therapy in 643 patients with advanced NSCLC who had not experienced disease progression or unacceptable toxicity during four cycles of platinum-based first-line chemotherapy. Patients whose tumours harboured activating EGFR mutations (exon 19 deletions or exon 21 L858R mutations) were excluded from this trial.
Patients were randomised 1:1 to receive erlotinib or placebo orally once daily (322 erlotinib, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. In total, 50% of patients randomised to erlotinib entered the open-label phase and received chemotherapy, while 77% of patients randomised to placebo entered the open-label phase and received erlotinib.
The trial’s primary endpoint was overall survival. Results demonstrated that survival following treatment with erlotinib was not better than placebo administered as maintenance in patients with metastatic NSCLC tumours not harbouring EGFR-activating mutations. No difference in progression-free survival between the erlotinib arm and the placebo arm was observed.
FDA will not require new post-marketing requirements or request post-marketing commitments based on the results of the IUNO trial.
miércoles, 26 de octubre de 2016
Chemoradiotherapy Alone in Inferior Rectal Cancer.
Inferior Rectal Cancer OS With Chemoradiotherapy Alone
Real-world data suggest that foregoing surgery after chemoradiotherapy may not be the best option for patients with stage II or III rectal adenocarcinoma
Date: 21 Oct 2016
Author: By Shreeya Nanda, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Rectal Cancer / Surgery and/or Radiotherapy of Cancer
medwireNews: Treatment with chemoradiotherapy alone results in significantly reduced overall survival (OS) compared with when it is followed by surgery in patients with rectal adenocarcinoma, according to a research letter published in JAMA Oncology.
Using the National Cancer Database, the researchers identified 1655 patients who received chemoradiotherapy alone for stage II or III rectal cancer, while their 14,207 counterparts underwent “conventional treatment” comprising chemoradiotherapy and proctectomy.
OS was shorter for patients in the chemoradiotherapy alone group than for those who also received surgery, with 3- and 5-year survival rates of 71.34% versus 88.29% and 58.21% versus 77.12%, respectively. This equated to a significant 1.90-fold increased risk of death for patients given chemoradiotherapy alone.
The elevated risk with chemoradiotherapy alone persisted after adjustment for confounding factors, such as race, insurance status, comorbidity score and tumour grade, with an adjusted hazard ratio of 1.69, reports the team from the University of North Carolina at Chapel Hill in the USA.
Highlighting that their results are contrary to previous single-institution and clinical trial results, C Tyler Ellis and co-researchers say: “This finding is likely because chemoradiotherapy only can be viewed at once as both an innovative treatment paradigm in some settings and low-quality care in others.
“Although [nonoperative management] is an intentional approach for some patients, it is likely that many individuals forgoing surgery in the community are doing so as a result of systematic barriers. Our results point to disparities in the process of rectal cancer care where historically disadvantaged groups receive suboptimal care and experience worse outcomes.”
The authors point out that they could not determine whether patients responded completely to chemoradiotherapy or whether they failed to receive surgery for other reasons.
However, given that the use of chemoradiotherapy alone “has doubled among individuals with nonmetastatic rectal adenocarcinoma”, they find the results “concerning”.
The team concludes: “As [nonoperative management] becomes an increasingly accepted treatment approach, more comparative effectiveness studies evaluating outcomes in the real-world setting will be needed.”
Reference
Ellis CT, Dusetzina SB, Sanoff H, Stitzenberg KB. Long-term survival after chemoradiotherapy without surgery for rectal adenocarcinoma: a word of caution. JAMA Oncol; Advance online publication 20 October 2016. doi:10.1001/jamaoncol.2016.3424
lunes, 24 de octubre de 2016
Adjuvant Ipi Improves Survival in Melanoma
Medscape Oncology
Big News: Adjuvant Ipi Improves Survival in Melanoma
Caroline Robert, MD, PhD
Disclosures | October 17, 2016
Breakthrough in Adjuvant Therapy
Hello. I am Dr Caroline Robert, chief of dermatology at the Institut Gustave Roussy in France. Welcome to Medscape Oncology Insights. At the 2016 meeting of the European Society for Medical Oncology (ESMO), we heard exciting data in melanoma. I will share with you some of the highlights.
In melanoma, we have been living through a revolution for the past 6 years. We have two winning strategies: targeted agents for BRAF-mutant melanoma, which is about half of the patients that we take care of, and immunotherapy. Until this meeting, progress was mostly in the field of metastatic melanoma. We had not yet improved the management of patients with a high risk for relapse, and we had not really gone into the field of adjuvant therapy. Now, things have changed.
First, at this meeting, we heard the overall survival results of the EORTC trial,[1] which evaluated ipilimumab, an anti-CTLA-4 antibody, versus placebo. This trial was for patients with stage III melanoma, patients who have had a resection of their metastatic lymph nodes and who were at high risk for relapse. In this population of patients, we already knew that the duration before relapse had been significantly prolonged with ipilimumab. This actually gave rise to the authorization of ipilimumab in the United States. We have learned that we also have an overall survival benefit with ipilimumab. This is significant. The risk for death was decreased by 28%. At 5 years, there was a difference of 11% between the two arms: 65% in the patients who received ipilimumab versus 54%.
This is big news because, until now, we had only interferon for this population of patients, and the improvement in overall survival was not very consistent across all of the trials. We knew that we prolonged the duration before relapse, but we did not know that with interferon we could have an influence on overall survival. This [improvement in overall survival from ipilimumab] is a very important result. However, there were adverse events, with five deaths in the arm with patients treated with ipilimumab. This was due to immune-related adverse events. They occurred in close to 42% of the patients with a grade 3 or above. This is something that has to be prescribed by physicians who are used to treating patients with melanoma and who are used to managing these immune-related adverse events.
Metastatic Melanoma: Survival Still Climbing
Targeted Agents Yield 3-Year Survival of 45%
In the metastatic field, we have had two very important pieces of news—one in the field of targeted agents and one in the field of immunotherapy.
Targeted agents: Here, we talk about patients with BRAF-mutant melanoma. As I said before, it concerns about half of the population of patients with melanoma. We already knew that the combination of an anti-BRAF plus anti-MEK is much more effective than anti-BRAF monotherapy. We have the results of the 3-year overall survival of patients who were included in the phase 3 trial[2] evaluating the combination of dabrafenib plus trametinib, anti-BRAF plus anti-MEK, compared with vemurafenib, an anti-BRAF single agent.
We can now announce that after a median 28 months of follow-up of the patients in the combination arm, we have 45% of patients alive. This is a very significant improvement over vemurafenib, with only 32% of patients alive. This is the highest percentage of patients alive at 3 years in a randomized trial of patients with metastatic melanoma.
This is very important to note because, right now, a lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true. Combination targeted agents give the same ratio. For anti-PD-1 single agents, we will very soon have the 3-year overall survival results, and we think that it will also probably be around 40%-45%.
A lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true.
We also have patients with complete response, which was 19% in this trial of dabrafenib plus trametinib with a median duration of response of 39 months. We have long-term responses with the combination and the same percentage of patients alive at 3 years.
What is going to be extremely important is to follow these patients and to see if we arrive at a plateau. The follow-up of these patients in this arm is going to be very important. It is quite promising because we have 66 patients still on therapy who are censored in the arm of dabrafenib plus trametinib. It is always important in the Kaplan-Meier curve to look at the number of censored patients in each of the arms, especially the ones who are still on the active treatment. It is 66 patients in the dabrafenib-plus-trametinib arm and only 10 patients in the vemurafenib arm. Probably, the top curve will remain much flatter than the [vemurafenib arm].
Immunotherapy: Ipilimumab Dose Provides Unexpected Results
In the field of immunotherapy, the results that we are all looking forward to having are from the combination of anti-CTLA-4 plus anti-PD-1. We know that in terms of response and progression-free survival, it is better than an anti-PD-1 single agent,[3] but we still have to wait some months to have the overall survival results.
At this meeting, we learned some quite unexpected results. It was very interesting. Paolo Ascierto, our colleague from Italy, presented the results of ipilimumab 3 mg versus 10 mg.[4] I forgot to tell you that in the adjuvant trial, ipilimumab was given at 10 mg/kg, which is not the dose that is approved for metastatic melanoma. So it was very important to know the results of 3 mg versus 10 mg in the metastatic setting.
This trial with a long follow-up allowed us to get 3-year overall survival rates. In the 10-mg/kg arm, the benefit in terms of survival at 3 years was 31% of patients alive compared with 23% in the 3-mg/kg arm. There was significant improvement: The hazard ratio showed that the risk for death was decreased by 16%.
It actually came as a surprise to see the significant difference. We don't know today how it will impact the future, because now we all think that ipilimumab will probably more or less always be combined with an anti-PD-1 antibody. Nevertheless, this may be something that is important for other combinations. There is a dose effect of ipilimumab, with 10 mg being more effective than 3 mg in the metastatic setting.
It was quite rich in information for melanoma this year at ESMO. Thank you for joining me for this edition of Medscape Oncology Insights. This is Caroline Robert, reporting from ESMO 2016.
Big News: Adjuvant Ipi Improves Survival in Melanoma
Caroline Robert, MD, PhD
Disclosures | October 17, 2016
Breakthrough in Adjuvant Therapy
Hello. I am Dr Caroline Robert, chief of dermatology at the Institut Gustave Roussy in France. Welcome to Medscape Oncology Insights. At the 2016 meeting of the European Society for Medical Oncology (ESMO), we heard exciting data in melanoma. I will share with you some of the highlights.
In melanoma, we have been living through a revolution for the past 6 years. We have two winning strategies: targeted agents for BRAF-mutant melanoma, which is about half of the patients that we take care of, and immunotherapy. Until this meeting, progress was mostly in the field of metastatic melanoma. We had not yet improved the management of patients with a high risk for relapse, and we had not really gone into the field of adjuvant therapy. Now, things have changed.
First, at this meeting, we heard the overall survival results of the EORTC trial,[1] which evaluated ipilimumab, an anti-CTLA-4 antibody, versus placebo. This trial was for patients with stage III melanoma, patients who have had a resection of their metastatic lymph nodes and who were at high risk for relapse. In this population of patients, we already knew that the duration before relapse had been significantly prolonged with ipilimumab. This actually gave rise to the authorization of ipilimumab in the United States. We have learned that we also have an overall survival benefit with ipilimumab. This is significant. The risk for death was decreased by 28%. At 5 years, there was a difference of 11% between the two arms: 65% in the patients who received ipilimumab versus 54%.
This is big news because, until now, we had only interferon for this population of patients, and the improvement in overall survival was not very consistent across all of the trials. We knew that we prolonged the duration before relapse, but we did not know that with interferon we could have an influence on overall survival. This [improvement in overall survival from ipilimumab] is a very important result. However, there were adverse events, with five deaths in the arm with patients treated with ipilimumab. This was due to immune-related adverse events. They occurred in close to 42% of the patients with a grade 3 or above. This is something that has to be prescribed by physicians who are used to treating patients with melanoma and who are used to managing these immune-related adverse events.
Metastatic Melanoma: Survival Still Climbing
Targeted Agents Yield 3-Year Survival of 45%
In the metastatic field, we have had two very important pieces of news—one in the field of targeted agents and one in the field of immunotherapy.
Targeted agents: Here, we talk about patients with BRAF-mutant melanoma. As I said before, it concerns about half of the population of patients with melanoma. We already knew that the combination of an anti-BRAF plus anti-MEK is much more effective than anti-BRAF monotherapy. We have the results of the 3-year overall survival of patients who were included in the phase 3 trial[2] evaluating the combination of dabrafenib plus trametinib, anti-BRAF plus anti-MEK, compared with vemurafenib, an anti-BRAF single agent.
We can now announce that after a median 28 months of follow-up of the patients in the combination arm, we have 45% of patients alive. This is a very significant improvement over vemurafenib, with only 32% of patients alive. This is the highest percentage of patients alive at 3 years in a randomized trial of patients with metastatic melanoma.
This is very important to note because, right now, a lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true. Combination targeted agents give the same ratio. For anti-PD-1 single agents, we will very soon have the 3-year overall survival results, and we think that it will also probably be around 40%-45%.
A lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true.
We also have patients with complete response, which was 19% in this trial of dabrafenib plus trametinib with a median duration of response of 39 months. We have long-term responses with the combination and the same percentage of patients alive at 3 years.
What is going to be extremely important is to follow these patients and to see if we arrive at a plateau. The follow-up of these patients in this arm is going to be very important. It is quite promising because we have 66 patients still on therapy who are censored in the arm of dabrafenib plus trametinib. It is always important in the Kaplan-Meier curve to look at the number of censored patients in each of the arms, especially the ones who are still on the active treatment. It is 66 patients in the dabrafenib-plus-trametinib arm and only 10 patients in the vemurafenib arm. Probably, the top curve will remain much flatter than the [vemurafenib arm].
Immunotherapy: Ipilimumab Dose Provides Unexpected Results
In the field of immunotherapy, the results that we are all looking forward to having are from the combination of anti-CTLA-4 plus anti-PD-1. We know that in terms of response and progression-free survival, it is better than an anti-PD-1 single agent,[3] but we still have to wait some months to have the overall survival results.
At this meeting, we learned some quite unexpected results. It was very interesting. Paolo Ascierto, our colleague from Italy, presented the results of ipilimumab 3 mg versus 10 mg.[4] I forgot to tell you that in the adjuvant trial, ipilimumab was given at 10 mg/kg, which is not the dose that is approved for metastatic melanoma. So it was very important to know the results of 3 mg versus 10 mg in the metastatic setting.
This trial with a long follow-up allowed us to get 3-year overall survival rates. In the 10-mg/kg arm, the benefit in terms of survival at 3 years was 31% of patients alive compared with 23% in the 3-mg/kg arm. There was significant improvement: The hazard ratio showed that the risk for death was decreased by 16%.
It actually came as a surprise to see the significant difference. We don't know today how it will impact the future, because now we all think that ipilimumab will probably more or less always be combined with an anti-PD-1 antibody. Nevertheless, this may be something that is important for other combinations. There is a dose effect of ipilimumab, with 10 mg being more effective than 3 mg in the metastatic setting.
It was quite rich in information for melanoma this year at ESMO. Thank you for joining me for this edition of Medscape Oncology Insights. This is Caroline Robert, reporting from ESMO 2016.
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