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Promising immune checkpoint inhibitor data for lung cancer

ung cancer is the most common form of cancer in Ireland and approximately 2,300 new cases are diagnosed each year. On average, 1,888 people die from lung cancer every year, causing over 20 per cent of all cancer deaths in Ireland. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for around 80 per cent of all cases. For those with advanced disease, just 25 per cent will survive for at least one year after diagnosis, while 12 per cent will survive for at least five years. However, there have been positive recent advances in treatment options for these patients, with Irish patients participating in a number of trials, a major Dublin oncology meeting heard recently.

Recent trials of checkpoint inhibitors have proved promising and were ‘big news’ at this year’s European Society for Medical Oncology (ESMO) meeting, Dr Emer Hanrahan, Consultant Medical Oncologist, St Vincent’s University Hospital, Dublin, told the Gathering Around Cancer 2016 meeting in Dublin.

The data presented at ESMO largely focused on anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab, she said.

The KEYNOTE-010 study was a randomised trial in which patients with PDL-1 positive NSCLC received either pembrolizumab or paclitaxel. There was an improved survival in patients with pembrolizumab, said Dr Hanrahan, and this led to it being further studied in the KEYNOTE-024 study, the findings of which were presented at ESMO and published in the New England Journal of Medicine (NEJM) in a paper titled ‘Pembrolizumab versus chemotherapy for PDL-1 positive non-small cell lung cancer’.

Dr Sinead Cuffe, Medical Oncologist, St James’s Hospital, Dublin, was one of the Principal Investigators on the pembrolizumab paper that appeared in the NEJM and this was a good achievement for a small country, commented Dr Hanrahan.

KEYNOTE-024 was a randomised, phase 3 trial and to be eligible for inclusion, patients had to have untreated stage IV NSCLC and high expression of  PD-L1. To qualify for the study, a patient’s tumours had to have a higher PD-L1 expression than what was required to gain access to the KEYNOTE-10 study, said Dr Hanrahan.

The study patients were randomised to be administered 200mg of pembrolizumab intravenously for three weeks or a platinum-based doublet chemotherapy regimen. It was the choice of the clinician running the trial to do a number of standard platinum-based doublet regimes, she explained, and patients who made progress with chemotherapy were permitted to go on to receive pembrolizumab.

“The primary end-point of this study was well met,” said Dr Hanrahan, with “significant progression-free survival advantage with this use of pembrolizumab over chemotherapy. At six months, the progression-free survival rate was 62 per cent with pembrolizumab and 50 per cent with chemotherapy.”

There were less treatment-related adverse events using pembrolizumab, reported Dr Hanrahan, and the most common treatment-related toxicities in the study came from traditional chemotherapy. It was not a study for “all comers”, however, she pointed out, because only those patients who had PD-L1 expression greater than or equal to 50 per cent were permitted to take part, which constituted about one-third of patients.

Further data on pembrolizumab in the first-line setting was also presented at ESMO, said Dr Hanrahan. There was a study on the use of carboplatin/pemetrexed, with or without pembrolizumab, for advanced non-squamous NSCLC. The study was carried out as a randomised phase 2 study, the KEYNOTE-021 study, and the findings were published in The Lancet Oncology on the same weekend it was presented at ESMO.

There are several different reasons for combining chemotherapy with immunotherapy, noted Dr Hanrahan, and these include evidence that chemotherapy can induce the expression of PD-L1 on tumour cells. To participate in KEYNOTE-021, patients did not have to have PD-L1 positive disease, but they did have to have tissue available for researchers to test for PD-L1 status, she explained.

The patients that participated in KEYNOTE-021 were previously untreated for non-squamous NSCLC and they were randomised to either pemetrexed and carboplatin, or pemetrexed and carboplatin in combination with pembrolizumab. Again, said Dr Hanrahan, only patients who progressed on chemotherapy were permitted to progress onto pembrolizumab.

“The primary end-point in this study was response rate,” said Dr Hanrahan, “and the response rate was significantly improved with the addition of pembrolizumab to chemotherapy. The response rate was 55 per cent compared to 29 per cent.

“There was also a significant improvement in progression-free survival with the addition of pembrolizumab to chemotherapy; you can see a median progression-free survival of 13 months versus 8.9 months.”

The KEYNOTE-189 study, which is a randomised, double-blind, phase 3 study of platinum pemetrexed chemotherapy, with or without pembrolizumab in the first-line setting for metastatic, non-squamous NSCLC is open in Ireland through Cancer Trials Ireland, said Dr Hanrahan.

“I would encourage you, if you have potentially eligible patients, to refer them on to the study,” Dr Hanrahan told delegates attending the Gathering Around Cancer meeting.

Nivolumab

The latest trial data regarding nivolumab from the CheckMate 017 and CheckMate 057 studies in non-squamous NSCLC were also presented by Dr Hanrahan. These were randomised trials of nivolumab versus docetaxel, and both studies showed an overall survival advantage with the use of nivolumab. The latest data from the trials was presented at the 2016 American Society of Medical Oncology (ASCO) Annual Meeting, which showed that survival advantage was maintained with nivolumab at two years.

This initial data on nivolumab meant that everyone had high hopes for the CheckMate 026 study, a phase 3 trial of nivolumab versus the investigator’s choice of platinum-based doublet chemotherapy, as a first-line chemotherapy for stage IV PD-L1 positive NSCLC.

Recent trials of checkpoint inhibitors have proved promising and were ‘big news’ at this year’s European Society for Medical Oncology meeting

The primary end-point was progression-free survival and that was among patients who had greater than or equal to 5 per cent expression of PD-L1, so patients, when they were being randomised, were stratified according to this level of PD-L1 expression, said Dr Hanrahan.

“Unfortunately, this study did not meet its primary end-point and there was no progression-free survival advantage with the use of nivolumab over chemotherapy,” she reported. “Similarly, there was no survival advantage with the use of nivolumab over chemotherapy.” These results were unexpected, given the strongly positive second-line studies, said Dr Hanrahan, so the question is, why?

“Perhaps nivolumab is genuinely not more effective than chemotherapy in the first-line setting, or perhaps there are some issues in the design or conduct of the trial,” she commented. “If you look at the patient characteristics, there were certainly some imbalances between the treatment arms; in the chemotherapy arm, there were more females and less patients with liver metastases, which might favour better outcomes in the chemotherapy arm.

“If you look at PDL-1 expression between the two treatment arms, the patients were stratified based on PDL-1 expression greater than or equal to 5 per cent so those patients are equally represented in both treatment arms, about 75 per cent of patients in both treatment arms, but when you look at the higher expression of PDL-1, there is quite an imbalance between the treatment arms and one of the main differences between this trial and the positive KEYNOTE-024 trial with pembrolizumab was that the KEYNOTE-024 study used 50 per cent PDL-1 as a cut-off.”

This is not the end of the story with nivolumab, however, said Dr Hanrahan, as it is still being studied in the first-line setting in NSCLC in other trials such as CheckMate 027, where it is being studied as a single agent in a first-line setting, and also in combination with ipilimumab in combination with chemotherapy.

This study is also open in Ireland through Cancer Trials Ireland, said Dr Hanrahan, and she again asked those present to consider referring potentially eligible patients on to the sites that are conducting the study in Ireland, as this “is a great opportunity for patients”.

Atezolizumab

The other major new study on immune checkpoint inhibitors presented at ESMO this year was the OAK study (a phase 3, global, multi-centre, open-label, randomised, controlled study evaluating the efficacy and safety of atezolizumab compared with docetaxel in patients with locally-advanced or metastatic NSCLC whose disease progressed on or after treatment with platinum-containing chemotherapy), said Dr Hanrahan. This study differs from the previous two studies mentioned, she explained, because it was conducted in previously-treated patients and the agent in this study has a slightly different mechanism of action, as it is a PD-L1 antibody.

This phase 3 study followed a positive phase 2 randomised study in which patients with previously-treated NSCLC were randomised to either atezolizumab or docetaxel, where a survival advantage had been reported with the use of atezolizumab.

In OAK, patients with any PDL-1 status  — they did not have to be PDL-1 positive — were randomised to receive either atezolizumab at a fixed dose of 1,200mg every three weeks or docetaxel at the standard dose.

“Overall survival among the first 850 patients randomised was the primary end-point and that was met,” said Dr Hanrahan. “There was a significant survival advantage with the use of atezolizumab.” The survival at 18 months with atezolizumab was 40 per cent compared to 27 per cent with docetaxel, she reported.

The overall survival was also looked at among the patients with PD-L1 positive tumours and among these patients, there was also a survival advantage with the use of atezolizumab. Furthermore, an analysis was done on this study, looking at overall survival at different levels of PDL-1 expression, said Dr Hanrahan, and those patients with a high level of PDL-1 expression seemed to have a particularly marked survival advantage with the use of atezolizumab.

“It is interesting that even in the patients with PDL-1 negative tumours, there was a survival advantage with the use of atezolizumab,” said Dr Hanrahan. “In this study, similar to analogous studies with nivolumab and pembrolizumab, atezolizumab was better tolerated — it did have less toxicities than docetaxel.”

The OAK data represents the first phase 3 results for atezolizumab, which shows improved survival in all patients, said Dr Hanrahan. There was a median survival of 13.8 months versus 9.6 months, with atezolizumab well tolerated and the rate of immune-mediated adverse events was low.

In summary, said Dr Hanrahan, there was some really exciting data (KEYNOTE-024) on first-line pembrolizumab regarding overall survival, progression-free survival response rate and toxicity presented at ESMO. Furthermore, she said, it is also really encouraging that there is data suggesting that the addition of pembrolizumab to chemotherapy may be superior to chemotherapy alone. “That is currently undergoing phase 3 evaluation in the KEYNOTE-189 study. Open in Ireland, currently open at Limerick, it is going to be open in St Vincent’s University Hospital, Dublin, in about two or three weeks’ time, so please try to send eligible patients.”

References on request

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