Immunotherapy is making its mark in the management of lung cancer – the leading cause of cancer deaths in Australia. Survival is being extended for many patients and new agents have just been added to the PBS for patients who have progressed after chemotherapy.

The limbic spoke to Dr Leora Horn, Ingram Associate Professor of Medicine and Clinical Director of the Thoracic Oncology Research Program at the Vanderbilt Ingram Cancer Center in Nashville. Dr Horn was an invited speaker at the recent post-MOGA Immuno-Oncology Forum sponsored by several pharmaceutical companies.

Where does immunotherapy currently fit in our toolkit for the management of patients with lung cancer?

In Australia, the immune checkpoint inhibitors are currently approved in the second line setting for lung cancer patients. In the US, there are three drugs approved – atezolizumab, pembrolizumab and nivolumab. Nivolumab and atezolizumab are approved in all patients; pembrolizumab, in the second line setting, is only approved in patients with PD-L1 expression greater than 1%.

With all three drugs, I personally think we are seeing very similar results; there is no huge distinguisher in terms of efficacy. We are seeing a benefit in about 15-20% of NSCLC patients and in those responders we are seeing a benefit that is often durable that can last for years.

In the first line setting, we have seen two negative studies and we have one positive study with pembrolizumab in patients that in tumours that are strongly PD-L1 positive, >50% expression. And that’s about 25% of NSCLC patients who are now getting a checkpoint inhibitor in the first line setting.

We’ve also seen data with carboplatin and pemetrexed with or without pembrolizumab in an all-comer patient population with nonsquamous NSCLC, which showed higher response rates and a trend towards PFS benefit but no overall survival benefit from the combination of chemotherapy and pembrolizumab. So that has received FDA approval in the US but I‘m personally still waiting for data from phase 3 trials before I start adopting a combination of chemotherapy plus a checkpoint inhibitor.

 How do we identify which patients will benefit from immunotherapy?

The reality is for most of these drugs, they are working in a subset of NSCLC patients – they don’t work in everyone – and one of the things we need to focus on is selecting the right patients.

Never smokers and the patients who have tumours with EGFR mutations and ALK rearrangements seem to have lower response rates and are definitely better off getting treatment with a targeted therapy and if that targeted therapy is not working then they are potentially better off getting chemotherapy.

In the lung cancer world, I think we’re a little biomarker obsessed. The problem is there are different assays and each has different cut points and what defines PD-L1 positivity. These assays are not good discriminators. For example, if someone is EGFR mutated and we give them an oral targeted therapy, then the chance of them responding is about 70% but if they are EGFR wild type, the chance of responding is about 1%.

If a patient is PD-L1 positive, the response rate is 20-40% but if they are PD-L1 negative, there is still a 10% chance of them responding. I don’t think that is a good enough discriminator in helping us select therapy.

There is some interesting data suggesting that a high mutation burden is a potential predictor of response to pembrolizumab, nivolumab and atezolizumab. The problem with mutation burden is it is all done by whole exome sequencing which is expensive, takes too long and you don’t get the results back soon enough to help you select therapy.

How long do we treat patients for? What is the goal of immunotherapy?

I personally don’t allow patients to go beyond two years off study but there are many folk who think that two years is too long. We all have patients who we gave 2-3 doses of therapy and then they have to come off therapy for one reason or another and these patients are maintaining a response to their checkpoint inhibitor years later.

You can’t keep patients on these drugs indefinitely. First of all, if you are on treatment five to six years later, do you really still want to come to the cancer centre every two to three weeks for therapy? And the other issue is these drugs are expensive and we are still learning about the potential short and long-term toxicities. With time we will sort out how long we’ve got to give the drug for. Maybe they only need six months or four doses similar to ipilimumab in melanoma patients.

What are some of the other key challenges with immunotherapy?

A key challenge is managing the toxicities. This is a whole new realm of toxicity management that oncologists have not traditionally been accustomed to.

Managing patient expectations is also important. While I am a big believer in these drugs and I think they are phenomenal, the reality is they do not work in everybody. And so while we are hopeful of a response, when I start therapy I tell patients this works in about 1 in 6 people and we don’t exactly know who this is going to work in.

And we’re still figuring out who to use them in and when to use them. Right now we’re moving them into the adjuvant setting, we’re moving them after concurrent chemo or radiation. For sure they are effective in stage IV disease, but are they going to be as effective in early stage? We don’t know yet; the data is not there yet.

Where do we stand on using combination therapies?

Oncologists are pretty simple. If one drug works, add it to another drug and see if it works better. Immune therapy combinations with chemotherapy have shown higher responses but what we haven’t seen yet is the overall survival benefit. That is an important question with the phase 3 trials because should you give everything at once or should you give sequential therapy?

One of the reasons for giving immune therapy up front with chemotherapy is in lung cancer about 1/3 of patients don’t even get second line therapy. So 1/3 of patients are potentially missing out on drugs. But if a patient develops toxicity, do you stop the chemotherapy or do you stop the checkpoint inhibitor? How do you know which drug the patient is deriving benefit from?

Combinations with immune therapy and targeted therapy have also seen higher toxicities that are unexpected. A trial with durvalumab and osimertinib was discontinued because of a toxicity concern.

I think one of the more interesting areas is the combination of a checkpoint inhibitor with another immune agent. Can we attack two parts of the immune system and potentially take a patient who didn’t respond to a single agent and either upregulate the T-cells through a different mechanism or affect the tumor microenvironment so that we can increase the likely hood of response.

Is immunotherapy a game changer for lung cancer?

I think we’ve seen that it is. 10 years ago, if you had all comers with lung cancer from stage I to stage IV, the overall survival was 15-16% at five years. Data that was presented this year at AACR from Checkmate 003 in stage IV patients, many of them who’ve had multiple prior therapies, shows an overall survival of 16%. And these patients aren’t just living; they actually have a good quality of life.