ESMO 2016 conference highlights
Dr Bishal Gyawali - Nagoya University, Nagoya, Japan
The first study that I’m talking about is about niraparib maintenance therapy in ovarian cancer, in platinum sensitive recurrent ovarian cancer. This was a very important study because niraparib is a PARP inhibitor and this study found that it significantly reduces the risk of progression free survival. The most intriguing thing about this study was we usually know PARP inhibitors to be effective in those cancers that have germline BRCA mutations but in this study we found that niraparib was effective regardless of the presence or the absence of a BRCA mutation. But there are some caveats to implement this study into your clinical practice: number one, we don’t have data on overall survival, these positive findings are only regarding progression free survival. The progression free survival is quite substantial in this case so most likely it can translate into overall survival benefit. But another thing to consider is the increasing toxicity with the use of this agent was not negligible, it was substantial. So we need to have a proper discussion with the patient and the absolute increase in benefit is, of course, higher in the case of those who have a BRCA mutation compared to those who don’t. So maybe for patients who have a BRCA mutation this is a very, very good treatment considering the balance of risks and benefit but for those who don’t have a BRCA mutation we need to have a proper evaluation of the risks and benefit of this agent.
The second study was, of course, was about immune checkpoint inhibitor, the famous thing in all major oncology meetings. This is a study of adjuvant ipilimumab for melanoma and this is a positive study again. The use of adjuvant ipilimumab significantly improved the recurrence free survival and this is quite an exciting study for melanoma because in melanoma in the adjuvant setting we do not have a good study that shows proper benefit and the only agent we have is interferon which has a lot of toxicities and is very difficult to use. But in this study I am disappointed with a few things. The most important thing that I didn’t like about this study is the duration of treatment because ipilimumab is approved for metastatic melanoma and even in the case of metastatic melanoma we use only four courses of ipilimumab. But this is an adjuvant study so these are patients whose primary tumour has already been treated with a local therapy and you are giving adjuvant, supplementary treatment in the hope of reducing the risk of recurrence. They have used this agent for three years in this case, so you can imagine a person who has metastatic disease who has disease you give it only for four courses and then stop and it is effective, it is an approved agent. But in this adjuvant setting they are giving it for three years and then they are finding a little bit of benefit. So in my case I would not be very comfortable prescribing this agent for three years. And it has substantial toxicities, ipilimumab is not an easy to use drug. You need to be very careful about all the auto-immune side effects that this agent brings and I would definitely not be comfortable using it for three years on anyone.
The third study is from breast cancer and it’s the study of ribociclib and this was again a positive study. This study found that with the use of ribociclib in the setting of hormone receptor positive advanced breast cancer the risk of progression free survival was significantly improved with the use of this drug. So this is a positive study and the hazard ratio is also pretty good but again there are a few caveats. The first thing to understand is we don’t have the survival data yet, the overall survival data are not matured, and it’s more important in the case of breast cancer because from past experience, although it was a different setting, we have seen that bevacizumab also substantially improved PFS but later on it showed that there was no improvement in the overall survival. In the setting of hormone receptor but second line we have everolimus. Everolimus also significantly improved progression free survival, it has quite a big margin of improvement, but later again the overall survival was not improved. So it’s still open whether the use of ribociclib is going to improve the OS or not. This is more important because the increase in toxicity is quite high, especially haematological toxicity. Neutropenia, grade 3 or higher neutropenia, with this agent was nearly 59% compared to only 1% in the control group. So whether or not the patient is ready to accept a 58% increase in the risk of neutropenia compared to taking a drug that is not yet known to improve survival.
The next study is of pembrolizumab, it’s a KEYNOTE-024 study, and this was a positive study again and this was a good study in the sense that it also improved overall survival with the use of pembrolizumab in the first line setting of non-small cell lung carcinoma with significant improvement in overall survival with the use of this immunotherapy drug. One important thing is that this drug in this trial was used only for those patients who had a PDL1 positivity of more than 50%. So we do not know whether it will be effective in those patients who have a PDL1 positivity of less than 50% or who are PDL1 negative so we do not know that yet. But for patients who have PDL1 positivity of more than 50% now this should be a practice changing drug in the first line setting. It’s a very good study and in this setting ipilimumab has failed so pembro has captured the market in the first line setting of lung cancer, non-small cell lung cancer. But, as I said, it is only for those patients who have a PDL1 positivity of more than 50%.
For nivolumab also there was good news because there was another study in head and neck cancer in the second line metastatic setting in which nivolumab showed positive results. This study, what I liked about this nivolumab study, is maybe the long duration and they used a primary endpoint of overall survival and not progression free survival. Because with the use of immunotherapy agents and we have heard a lot about pseudo-progression and progression free survival benefit not being captured well by the RECIST criteria, so it’s always important for any immunotherapy drug in a phase III clinical trial to have a primary endpoint of overall survival because the immunotherapy benefits are seen a little bit later and after a period of pseudo-progression in some patients. So they did a beautiful thing, they used a primary endpoint of overall survival and it was a significant benefit. But if you see PFS, progression free survival, in fact there was no significant benefit so if they had used a primary endpoint of PFS it should have been called a negative study so it was a good thing that they used OS as the primary endpoint. This should also be practice changing.
The last study is of adjuvant sunitinib for renal cell carcinoma. This is a very intriguing study and it really captured my interest because we have seen a lot of studies of targeted agents in the adjuvant setting in a variety of cancers and most of them are negative. So the interesting thing about targeted agents is they work in the case of metastatic setting but if you try to use the same drug in the adjuvant setting after surgery they don’t do very well. So we do not exactly know why and this study was hailed as a positive study in the adjuvant setting for renal cell carcinoma and this is the first time that has happened for a targeted agent and it is very interesting. But again because all of these studies of targeted agents in the adjuvant setting have been negative, I’m a bit reluctant to yet incorporate this or recommend this for clinical practice because, number one, we don’t have survival data yet, this is just the data on disease free survival. Number two, they have used sunitinib for one year and sunitinib is a highly toxic drug, it is very toxic and the patients don’t have a good time having this drug. It’s easy for a patient who has cancer, who has metastatic disease, to convince that the benefit is higher so you need to take this drug. Even in the metastatic setting they usually take it for six or seven months by which time they have progression of disease, they have significant toxicities and they try to escape this agent and switch to a different agent. So how can I convince a patient who doesn’t have cancer because it has already been rejected, so he doesn’t have cancer inside his body and I’m trying to ask him to take a drug as toxic as sunitinib for one year in the hope of prolonging his recurrence free survival and I do not know about overall survival yet. So I don’t think this should be a practice changing thing but let’s see.