The potential of combination immunotherapy

The potential of combination immunotherapy

SciTech Europa spoke to ESMO’s Spokesperson Dr Marina Garassino about the potential benefits of combination immunotherapy and some of the challenges involved in realising this potential.

Combination immunotherapy has a lot of potential when it comes to the treatment of metastatic non-small cell lung cancer (NSCLC) patients. Indeed, there have been numerous clinical trials investigating different combinations of immunotherapy agents and chemotherapy. However, challenges remains.

SciTech Europa asked the European Society for Medical Oncology’s (ESMO) Spokesperson, Dr Marina Garassino, the head of the Thoracic Pulmonary Medical Oncology Unit at the Fondazione IRCCS Istituto Nazionale dei Tumori of Milan, Italy, about the potential benefits of combination immunotherapies, including some of the results from the aforementioned clinical trials, and how she would like to see a move towards a more personalised medicine in the context of immune-oncology.

While not a panacea, it does seem that combination immunotherapies can have significant benefits. What are your thoughts, then, on the use of combination immunotherapies?

Currently, there are two kinds of combinations; the first and most popular combination in 2018 was the combination of chemotherapy with immunotherapy. Indeed, there are numerous clinical trials taking place combining immunotherapy with chemotherapy, with the most relevant being the KEYNOTE-189 trial, This was a randomised phase III study that compared platinum/pemetrexed versus platinum/pemetrexed plus pembrolizumab in nonsquamous histology (while there is also a twin trial for the squamous population).

In addition, there is also a group of trials exploring the combination of atezolizumab plus chemotherapy, as well as another trial of nivolumab plus chemotherapy, although this is only in patients with PDL 1 negative, which is quite different from the trials of atezolizumab and pembrolizumab.

In total, these trials involve some 5,000 patients, which means that they are generating a lot of important data on the combination of chemotherapy plus immunotherapy and, so far, the trials have all been consistent in demonstrating that the combination of chemotherapy plus immunotherapy in terms of improving progression free survival and, in the majority of the trials (although not in all) in terms of overall survival.

In the future, there is a real possibility that the treatment of advanced metastatic non-small cell lung cancer (NSCLC) in patients with PDL 1 of more than 50% will be possible with either pembrolizumab as a monotherapy (which is the standard of care at the moment), or with the combination of chemotherapy plus immunotherapy.

However, currently there are no trials taking place to determine the superiority of chemotherapy plus immunotherapy compared to single agents. As such, academic research is now exploring what the best treatment for patients with PDL 1 of more than 50% actually is – i.e. if it is a single agent – and so if this demonstrates less toxicity etc. – or the combination of chemotherapy with immunotherapy.

Moving forwards, it may emerge that patients who have a very good prognosis are treated with the single agent, while patients with a very large tumour and a very large burden of disease (patients with less than 50% PDL 1) will be treated with chemotherapy plus immunotherapy.

There are two other trials which have taken place which, rather than looking at a combination of chemotherapy plus immunotherapy, instead explored a combinations of two immunotherapy agents. One of these is the durvalumab with or without tremelimumab versus platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer (MYSTIC) trial, which was recently presented at the ESMO Immuno-Oncology Congress on 13-16 December 2018 in Geneva, Switzerland.

The MYSTIC trial enrolled 1,118 patients with metastatic NSCLC who were randomly allocated to durvalumab alone, durvalumab plus tremelimumab, or chemotherapy. The primary endpoints were overall survival for durvalumab versus chemotherapy, and overall survival and progression free survival for durvalumab plus tremelimumab versus chemotherapy in patients with 25% or greater PD-L1 expression in tumour cells.

An exploratory analysis examined survival according to high or low tumour mutational burden (TMB) in the blood – 16 or more mutations per megabase was defined as ‘high’ and less than 16 as ‘low’. TMB evaluation was performed in more than 70% of patients, of whom 40% had high TMB.

In patients with high TMB, overall survival was 16.5 months with durvalumab plus tremelimumab versus 10.5 months with chemotherapy, with a hazard ratio of 0.64. Overall survival with durvalumab alone was 11 months. The proportion of high TMB patients alive at two years was 39% with durvalumab plus tremelimumab, 30% with durvalumab, and 18% with chemotherapy. In those with low TMB, overall survival was 8.5 months with durvalumab plus tremelimumab, 12.2 months with durvalumab, and 11.6 months with chemotherapy.

The second was the CheckMate 227 trial, the results of which were published in the New England Journal of Medicine in March 2018.

Unfortunately, while the results in terms of increase in progression free survival were positive for patients with high a tumour mutational burden, the overall survival results was negative for both the CheckMate 227 and MYSTIC trials, unlike what was shown in the other trials I have mentioned.

As such, more research needs to be done in this area, while we need to identify which patients really stand to benefit from these kind of combination therapies, and while the tumour mutational burden can be an important biomarker we still do not have a cut off to define what is ‘high’, ‘low’, or ‘intermediate’. Furthermore, because many tests are quite unreliable, we also need new trials to properly demonstrate benefits in terms of overall survival.

There is thus a lot of work that needs to be done by both the academic research and pharmaceutical communities to better understand, for example, the best way to test the tumour mutational burden, what the best cut off is, and whether the tests should be done on blood or on tissue.

An important point to be made by the MYSTIC trial was that when it comes to the use of single agent monotherapy, durvalumab is very similar to pembrolizumab in patients with PDL 1 of more than 50%. Elsewhere, the BIRCH trial has also shown that atezolizumab in another trial, all three drugs for patients PDL 1 more than 50% have been explored and although we do not have a direct comparison, the results are very similar.

For patients with PDL 1 of more than 50%, pembrolizumab is the only approved drug. Moving forwards, however, we hope to see regulatory agencies also approve durvalumab and atezolizumab.

The combination of immune checkpoint inhibitors and chemotherapy has been successfully tested in different trials as first line therapy for metastatic non-small cell lung cancer (NSCLC) while the use of two immunotherapy drugs without chemotherapy has been addressed in very few studies. How would you like to see this change? Are there any efforts already taking place?

This is a very controversial issue, and the community is often divided about whether the combination of two immunotherapies is better in some patients, with some calling for proper randomised controlled trials in the population in which we think that there could be an effect.

I think that we need more research, and that we are far from arriving at a final solution.

How do you feel the challenges involved in using combination immunotherapies (such as perhaps the cost of the drugs and the fact that immunotherapies can potentially trigger dangerous autoimmune reactions that combination treatments can exacerbate) could be addressed moving forwards?

Many oncologists would like to remove chemotherapy from the treatment pathway, but for the time being this is the only agent that is able to enhance the immune system and to thus increase the response to immunotherapy.

There are many combinations now being tested in clinical trials but, currently, they are not enough to increase the overall survival of the patients. At the moment, only chemotherapy plus immunotherapy is able to do that.

There is thus a need now for academic research to try to find the right quantity of the chemotherapy that needs to be administered in order to achieve this effect; we need to find the right balance of immunotherapy with the toxic effect of chemotherapy.

Can ESMO play a role here?

There is a good amount of contribution that a professional society like ESMO can offer: in the first place by educating clinicians and keeping them updated with the latest advances.

But also by supporting the importance of academic research. Several trials are being launched, trying to reduce the amount of chemotherapy being used, and to better understand what is the best chemotherapy agent to be added, what the right duration of chemotherapy is, how much chemotherapy needs to be administered in combination, and more. These are critical questions that must be asked but not typically addressed by pharmaceutical companies; they are academic questions.

Is the pharma industry engaging as well as it could/should with the academic community to do the research that is needed?

As we move into 2019, an increasing amount of research is being conducted as a collaborative effort between the academic sphere and the pharmaceutical industry, and this is necessary – pharma needs the support of academia, and vice versa.

While, of course, the main objective of the pharmaceutical industry is to get drugs to market, this also involves helping the patient, and so there is not such a large division between pharma and academia as some would perhaps argue; their objectives remain essentially the same.

As such, I am certainly not opposed to the pharmaceutical industry supporting an academic trial in an effort to answer the questions around the duration of chemotherapy or on the right chemotherapy to be added. We have many questions which need to be answered, and for us to do this quickly and effectively all actors should work together so that we can provide better treatment to our patients.

As researchers, we have to join forces with the others involved in this area and try to forge the path towards precision medicine with immunotherapy. Indeed, in a paper recently published in Cell the term ‘individualised medicine’ was used in this context, and that is something which really has significance.

As we move into a future where artificial intelligence will come to play an increasing role in the healthcare sector, and as biobanking becomes increasingly important, we are reaching the stage where we may soon be able to tailor treatment to the individual patient, and this will be crucial because we must always remember that a patient will not only have a tumour that is unique to them, but we also need to take into consideration the other unique factors – the patient’s microbiome, their genealogy, their co-morbidity and so on; each patient needs to be treated as an individual.

Dr Marina Garassino
European Society for Medical Oncology (ESMO)
Head, Thoracic Pulmonary Medical Oncology Unit
Fondazione IRCCS Istituto Nazionale dei Tumori
Tweet @myESMO

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