Advanced Mesothelioma Treatment: Chemotherapy and Immunotherapy Options

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• Historical Chemotherapy Standard
• Immunotherapy Breakthrough
• Treatment by Subtype
• Combination Therapy Trials
• Key Immunotherapy Agents
• Relapse Treatment Options
• Full Transcript

Historical Chemotherapy Standard

For many years, pemetrexed combined with cisplatin or carboplatin was the only licensed systemic treatment for mesothelioma. Dr. Dean Fennell, MD, notes this chemotherapy regimen provided a progression-free survival benefit of approximately six months. The original trial reported a 40% response rate. This treatment offered good symptom control and a demonstrable improvement in survival compared to single-agent therapy.

Immunotherapy Breakthrough

The treatment landscape for mesothelioma changed dramatically in 2020. The CheckMate 743 clinical trial was a pivotal study. It compared the combination immunotherapy of ipilimumab and nivolumab against standard chemotherapy. Dr. Dean Fennell, MD, explains the trial demonstrated a superior overall survival benefit. The hazard ratio was approximately 0.74. This significant result led to rapid FDA, European, and UK MHRA approval for this immunotherapy combination as a frontline treatment.

Treatment by Subtype

Choosing the best first-line treatment for mesothelioma depends heavily on the histological subtype. Dr. Dean Fennell, MD, states that for patients with non-epithelioid mesothelioma, the decision is clear. The hazard ratio for overall survival with immunotherapy was less than 0.5. This represents a major survival advantage over chemotherapy. For the epithelioid subtype, the overall survival benefit between immunotherapy and chemotherapy was similar, at around six months. This creates a critical decision point for oncologists and patients.

Combination Therapy Trials

Researchers are actively working to improve outcomes for epithelioid mesothelioma. The strategy involves combining immunotherapy with chemotherapy. Dr. Dean Fennell, MD, points to the success of this approach in lung cancer. Several phase three trials are now underway for mesothelioma. These include the DREAM3R trial, testing durvalumab with chemotherapy. The BEAT-meso trial is investigating bevacizumab and atezolizumab added to chemotherapy. The results of these studies will determine if combination therapy becomes a new standard.

Key Immunotherapy Agents

The approved immunotherapy regimen for mesothelioma consists of two agents. Nivolumab targets the PD-1 immune checkpoint. Ipilimumab targets the CTLA-4 checkpoint. Dr. Dean Fennell, MD, emphasizes that ipilimumab did not show activity as a single agent in the DETERMINE study. However, the combination with nivolumab creates a powerful synergistic effect. This synergy is also seen in other cancers like melanoma and renal cancer. These two drugs are now the main licensed immunotherapy agents for mesothelioma.

Relapse Treatment Options

Treatment options exist for patients whose mesothelioma progresses after initial platinum-based chemotherapy. Dr. Dean Fennell, MD, was directly involved in the CONFIRM trial. This was a placebo-controlled, double-blind study. It provided the only evidence of a drug improving survival in the relapse setting. The study confirmed that single-agent nivolumab can improve survival by approximately 30%. This agent is available for certain patients within systems like the UK's National Health Service.

Full Transcript

Dr. Anton Titov, MD: What is the classical approach to the systemic medical chemotherapeutic treatment of mesothelioma?

Dr. Anton Titov, MD: Where does the targeted therapy and immunotherapy fit into the current treatment options for patients with mesothelioma?

Dr. Dean Fennell, MD: Up until last year, about August of last year, we only really had one systemic treatment option for patients with mesothelioma that was licensed. That was pemetrexed with cisplatin or carboplatin.

Combination of pemetrexed with cisplatin or carboplatin is associated with about six months of progression-free survival benefit for patients with mesothelioma. It's not really great when looking across the board. Response rates in the original trial are quoted at 40% of patients.

We see overall good symptom control with chemotherapy. There is an improvement in survival from this original trial that compared pemetrexed, cisplatin to pemetrexed.

We have to wait maybe for the Checkmate 743 trial. There are a number of single-arm studies and combination studies, including ipilimumab and nivolumab in the relapse of mesothelioma. It had shown promising results.

We highlight the MAPS2 clinical study showing the benefit of ipilimumab and nivolumab in the relapse of mesothelioma. This treatment was randomized against chemotherapy. It demonstrated superiority overall, with respect to the hazard ratio. It was around about 0.74 for overall survival.

This led last year to FDA approval, swiftly followed by European approval and UK approval as well by MHRA body. When you look at the data in more detail, the reflex decision to offer immunotherapy is one that the physician has to perhaps think about.

It is so because we have no doubt. I would imagine every physician out there would agree that we're looking at non-epithelioid mesothelioma with the hazard ratio of less than 0.5 for overall survival. This is partly due to the worst performance, the sort of the less favorable performance in this group of patients with mesothelioma with chemotherapy.

But immunotherapy is absolutely without question what these patients should be receiving. So that's not an issue.

The main question at the moment that's on people's minds is this.

Dr. Anton Titov, MD: What to do for patients with epithelioid malignant mesothelioma?

Dr. Dean Fennell, MD: I mentioned six months of benefit. That's what we see with chemotherapy. That's what we see with combination immunotherapy.

Indeed, we are looking at overall survival in the epithelioid mesothelioma subgroup. We do not see a significant superiority or difference between combination immunotherapy and chemotherapy.

So really, what we have then is an opportunity. I see this as really improving upon outcomes in the epithelioid mesothelioma group. This approach is being used by many investigators around the world.

It is to combine immunotherapy with chemotherapy. We have seen it as the new standard of care in lung cancer, for example. That includes small cell lung cancer as well as non-small cell lung cancer.

We are augmenting the effects of the chemotherapy with immunotherapy or vice versa. So these results from phase three trials such as 227, BEAT-meso clinical trials. The most recent clinical trial in mesothelioma is DREAM3R.

These clinical trials will tell us for the epithelioid mesothelioma whether or not a superiority can be achieved with the addition of a single medication (Durvalumab). In BEAT-meso clinical trial, Bevacizumab and Atezolizumab are added to chemotherapy.

If we look at lung cancer, that was absolutely barnstorming activity that we saw. And, of course, we hope for that with mesothelioma. But only time will tell.

Dr. Anton Titov, MD: What kind of immunotherapeutic agents are currently being used for mesothelioma?

Dr. Anton Titov, MD: What are the top agents, and how to choose between them?

Dr. Dean Fennell, MD: That's an easy one because the FDA approval was given for the nivolumab. If we move on, so targeting the PD-1 immune checkpoint, inhibitory checkpoint, essentially removing that shield with which the tumor has to protect itself from immune surveillance from the immune system.

And then CTLA-4, which is the target of Ipilimumab. Ipilimumab did not show activity in a randomized phase 2 study called DETERMINE as a single agent.

In the relapse of mesothelioma, ipilimumab can be combined with the nivolumab. As we have seen in melanoma and in renal cancer, the synergy that occurs between these two agents seems to be very important.

Those are the two medications now that are licensed. They are really the main mesothelioma immunotherapy agents for use in mesothelioma.

I might add, because I was directly involved in this clinical study. We have shown the only evidence of a drug to improve survival in relapse of mesothelioma after platinum-based therapy is nivolumab.

Nivolumab in the placebo-controlled double-blind study, we confirmed, we published again last year, that nivolumab is an agent that can improve survival by about 30 or so percent. So in the UK, for example, there are certain patients who are able to receive this on National Health Service.

However, as we've seen with lung cancer, the expectation is that immunotherapies will always move from the relapse setting effectively to the frontline treatment. That's precisely what we've seen with ipilimumab and nivolumab.