New antibody drug, MPDL3280A, in non-small cell lung cancer
Prof Jean-Charles Soria - Institut Gustave Roussy, Paris, France
The data we presented is a very large phase I trial with a monoclonal antibody that blocks a compound, let’s say an antigen, that is called PDL1. PDL1 is, if you want, a diplomatic immunity that is used by the cancer cells to avoid their destruction by infiltrating activated T-cells. When you have a cancer cell, the cancer cells when they die they release antigens that in theory will induce an immune response that will activate T-cells that should be able to destroy the remaining cancer cells. But in reality these cancer cells avoid destruction by up-regulating and expressing either themselves or their microenvironment PDL1 that will prevent the activity of the immune infiltrating cells. So it works like a diplomatic immunity, you’re a bad guy, the police come, want to take you but you have a diplomatic passport and so he goes back. So an anti-PDL1 is a compound that will take away the diplomatic immunity and allow the cops, the immune cells, to do the job and take the bad guys away. By blocking PDL1 you will block two interactions that are important – the PDL1/PD1 interaction and the PDL1/B7-H1 interaction that will allow not only T-cell priming but also the restoration of a strong anti-immune response. So your own lymphocytes will be doing the job of fighting the cancer cells.
What was the design of the study?
In reality this was a study, a very large phase I study, as many of the on-going phase I studies today that have hundreds of patients. So we have left the era where phase I was about thirty patients and only toxicity, we are in an era where phase Is are hundreds of patients, also for activity. In that study we deliver the MPDL3280A, that’s a long name, let’s call it MPDL for monoclonal PDL, IV as a monotherapy every three weeks up to one year of therapy. This was given to many different tumour types – breast, colorectal, gastric, melanoma, renal cell carcinoma, non-small cell lung cancer, lymphomas – and in every single one of these tumour types objective responses were seen. The data that I presented was specifically focussed on the 85 non-small cell lung cancers that were enrolled in that trial; in that population, which was heavily pre-treated because over 55% of those metastatic non-small cell lung cancers got at least three lines of previous therapy, in that population the global objective response rate was 23%, that’s very significant when you are on fourth line and beyond of therapy.
What was the toxicity?
Phase I, as I told you, is not only about toxicity that is a 20th century definition. In the 21st century phase I is both about defining toxicity and acquiring data regarding activity. So you generally need to change your paradigm or your software. But, indeed, toxicity was carefully and thoroughly evaluated in this trial and the profile of the criticity of MPDL was extremely favourable, mainly grade 1 and 2 adverse events with no need for an intervention, no pneumonitis, this is important because PD1 antibodies have been related to pneumonitis, we saw none, one single immune-related severe adverse event with diabetes. So a good safety profile.
What was the response rate in patients who smoke?
We know that lung tumours are among those solid tumours with the highest mutational load in the tumour cells. We also know that smokers among lung cancers have more mutations than never smokers so we hypothesised that maybe the mutational load will be related to the immunogenicity of the tumour and therefore the activity of the compound. Indeed we had 80% of current or former smokers and only 20% of never smokers but the response rate in the current and former smokers was higher, 26% as compared to 10% in the never smokers. This is the first time in the last ten years that a molecular targeted agent brings more hope for smokers than for never smokers. I’m not saying you should keep smoking, the best you can do is to stop smoking, but if you are a lung cancer that has arisen from smoking, usually most of the innovation, the tyrosine kinase inhibitors for EGFR mutation, ALK and others, were only for the never smokers where most of the oncogenic mutations happen. Here we have great news, we have the smoking people who have the possibility to benefit from a new compound with mild toxicity and clear activity.
What potential does this hold for treatments in the future?
As I said, I have been a strong member of the immuno-skeptical clinicians, those who have seen over the last fifteen years huge investments in immunology, at least in the lung cancer setting, with zero results. But this is clearly a game changer; there is no waiving the data here. Really, whether it is PD1 data already presented with compounds from BMS or this PDL1 antibody from Genentech, and we look forward to today’s presentation of the PDL1 from MedImmune and the PD1 from Merck that will be presented in lung cancer, these compounds have as monotherapies. So it’s a single IV shot of an hour, correct, in an outpatient setting every three weeks can change your life. A quarter of the patients will have a response and, on top of that, in our trial we demonstrated that the level of expression of the target, PDL1, in the tumour immune infiltrating cells was predicted for higher efficacy. The higher the level of PDL1 the higher the response rate so this is really exciting times.
Would combination therapy be possible with this agent?
When you have something that is so powerful, so well tolerated, you want to partner it with other important cornerstones of anti-cancer therapy. Obviously combining it with other targeted agents makes a lot of sense; I personally believe that combination with oncogene kinase inhibitors like EGFR tyrosine kinase inhibitors or ALK inhibitors is very important. On the other hand, obviously chemotherapy remains the cornerstone of therapy in systemic stage 4 non-small cell lung cancer and there are combinations that are being tested but you need to bear in mind the fact that when you combine an immune checkpoint modulator, like a PDL1 or PD1 antibody, with chemotherapy one of the problems is that chemotherapy needs steroids otherwise you vomit too much and you have too much side effects. Well steroids are an antidote to building an anti-immune response, that’s going to be the challenge of the future.
Does this impact clinicians now?
The good news is that in non-small cell lung cancer in smokers and notably in squamous we have a very promising compound. These compounds are not commercially available yet so clinicians who have patients in good performance status 0,1, metastatic who fail standard of care should be referring their patients to the cancer centres or university hospitals that are currently testing these compounds through specific clinical trials.
Were there responses in other tumour types?
I cannot comment since I do not develop PDL1 for Genentech, I’m an investigator from an academic centre, but I am sure that beyond non-small cell lung cancer, as you know, there is already a huge development in the melanoma world where not only PD1 and PDL1 but also their combinations have already been tested. In renal cell carcinoma there are huge investments. A question mark whether the pharma is going to go full speed beyond these three tumour types, melanoma, renal and lung, to other tumour types where some responses have been seen.
What is your final message to clinicians and researchers?
Immunology really works in lung cancer. This is new. This is changing the paradigm. We used to consider that these were very expensive initiatives with zero results, now we know that these initiatives can lead to 25% objective response rate as a monotherapy, that’s high. So immunology has entered the thoracic world, immunology is working, immunology brings promise.