First-line lung cancer: Merck & Co dominates with Keytruda

  • Keytruda’s overall survival benefit continues to give it an edge over rival therapies
  • BMS is trying a new approach with its competitor Opdivo, looking for tumours with a biomarker known as ‘tumour mutation burden’
  • Merck & Co may also set the benchmark for NSCLC therapy in first-line squamous disease, but the full picture there has yet to emerge

Merck & Co is dominating the first-line lung cancer landscape with Keytruda (pembrolizumab). Richard Staines was at the ASCO 2018 conference in Chicago to find out more and hear how rivals are trying to compete.

There was a telling moment at ASCO when oncologist Thomas Stinchcombe was asked to give his verdict on the best drug to use in front-line lung cancer.

After taking delegates through various figures in an oral presentation, the message from the Duke Cancer Institute professor was clear for this highly lucrative indication for pharma companies. In non-squamous non-small cell lung cancer (NSCLC), which makes up the majority of cases, Merck & Co’s Keytruda is the go-to drug. In some cases, the preferred option includes some chemotherapy agents to improve the response in patients with low or intermediate levels of the biomarker PD-L1.

Stinchcombe’s message to the conference in Chicago was that lung cancer therapies have to show overall survival benefit, and this is where PD-1 inhibitor Keytruda currently has the edge over its rivals. The drug, a checkpoint inhibitor, works on tumours that have been hiding behind a protein their cell surfaces known as PD-L1 and tells T-cells to ignore them.

According to Stinchcombe, patients with non-squamous NSCLC with more than half their tumour cells expressing PD-L1 should receive Keytruda monotherapy. And in those with 1–49% of tumour cells expressing PD-L1 the best option is still Keytruda, plus carboplatin and pemetrexed chemotherapy. For those with PD-L1 levels below 1%, the Keytruda and double chemotherapy combination is still an option, as is chemotherapy alone.

The only drug that has a reasonable chance of outperforming Keytruda is Roche’s combination of Tecentriq (atezolizumab) and Avastin (bevacizumab) plus double chemotherapy, and this would be restricted to patients with middling levels of PD-L1 biomarker on their tumours, said Stinchcombe.

Roche is asking the FDA to review findings of the Impower 150 trial, which compared the combination of Tecentriq, Avastin, carboplatin and paclitaxel (ABCP), with Avastin and the two chemotherapies. Results presented at ASCO showed that in patients with wild-type mutations the four-drug ABCP combo increased overall survival compared with the three-drug regimen by several months. With ABCP, overall survival was 19.2 months, compared with 14.7 months in patients treated with the three-drug regimen, reducing chances of death by 22%.

Stinchcombe said that this could begin to make inroads into Keytruda’s dominance in first-line disease if the FDA agrees an expanded label.

There was no mention of AstraZeneca’s durvalumab and tremelimumab, which failed to show progression-free survival (PFS) benefit in first-line NSCLC and does not expect overall survival data until later this year.

BMS results ‘pedestrian’

So far Bristol-Myers Squibb has been left behind in first-line NSCLC, after failing to produce results with its rival PD-1 drug Opdivo (nivolumab) as monotherapy back in 2016. Since then it has been trying to play catch up and combine Opdivo with various other agents in a bid to try and get it to work.

The latest strategy from BMS is to try a different approach and look for tumours with a biomarker known as ‘tumour mutation burden’, or TMB. Put simply, TMB is the number of different mutations present in a tumour, and the thinking is that a higher TMB score will be predictive of success with an immunotherapy such as Opdivo.

BMS unveiled at ASCO an exploratory analysis, from the early phase of the already published phase III CheckMate-227 study, suggesting Opdivo and its CTLA-4 stablemate Yervoy (ipilimumab) extend PFS in NSCLC patients with high TMB but less than 1% of cells expressing PD-L1.

Those treated with Opdivo and chemo had a one-year PFS rate of 27%, while those on chemo alone had a PFS rate of 8%. In patients with low TMB and PD-L1 below 1%, the one-year PFS rate was 18% with both Opdivo plus low-dose Yervoy and Opdivo plus chemotherapy, and was 16% with chemotherapy.

BMS hopes that one day TMB will be another regularly used test that doctors could employ to decide what to prescribe to their patients. But Stinchcombe said that results so far are “pedestrian”, although he agreed they are a potential avenue of research for BMS.

Squamous disease

Keytruda also looks to be setting the benchmark for NSCLC therapy in first-line squamous disease too, which accounts for 25–30% of patients. The picture is not as complete, but once again things seem to be going in Merck & Co’s favour – it has data from the phase III KEYNOTE-407 study with better numbers than Roche’s PD-L1 competitor Tecentriq, which was tested in the IMpower131 study.

Keytruda and chemotherapy significantly improved PFS and cut risk of disease progression or death by 44% – while Tecentriq and chemo cut risk of disease worsening or death by 29%. The two studies should not be directly compared, but it would be very tempting to predict Merck & Co’s drug will win out once overall survival data becomes available.

Merck & Co has already submitted the KEYNOTE-407 data to the FDA and is asking for a swift approval in the new indication. In an interview with pharmaphorum, Roy Baynes, Merck & Co’s head of global clinical development, gave his own assessment of the situation.

He said:

“What it boils down to is that if you have first-line NSCLC, for the best PFS outcomes are obtained with pembro and low dose chemotherapy in squamous and non-squamous disease.”

He noted that Keytruda monotherapy remains an option for patients who are not fit enough to take on a chemotherapy regime because of co-morbidities. “If your PD-L1 is greater than 1%, monotherapy is a reasonable option,” Baynes said.

Next steps

Merck & Co is now investing in trials to ensure Keytruda maintains its advantage over rivals in lung cancer, which is becoming a fast-moving and highly competitive market. A major goal for Merck & Co is to find out more about why certain patients are not responding to Keytruda.

Baynes said: “There are a lot of patients dying early, not responding adequately, and we are looking to improve that response. What we are trying to do is address that mechanism using a multitude of approaches. This is a substantial area of work.”

Merck & Co this year joined with Eisai to investigate whether the Japanese pharma company’s Lenvima (lenvatinib) will boost Keytruda’s performance in a range of solid tumours, including lung cancer. Baynes described the results of trials involving Keytruda and Lenvima, which targets blood vessel formation in cancer cells, as “encouraging”.

But there are a whole host of other approaches also being considered, such as STING agonists, LAG3 drugs, Amgen’s oncolytic virus T-vec, and cancer-killing viruses from the oncolytic virus firm Viralytics that Merck & Co recently-acquired. Baynes noted that Merck & Co also has more than 20 small molecules that could be used in combination with Keytruda.

And the company is even going as far as testing Keytruda in combination with BMS’ Yervoy to see if PD-1 and CTLA-4 therapy can outperform CTLA-4 monotherapy. In December, Merck & Co began work on the KEYNOTE-598 study to see whether a combination of Keytruda and Yervoy would beat Yervoy alone in untreated patients with high PD-L1 levels. “We will answer that question definitively in front-line NSCLC,” said Baynes.

Keytruda has transformed Merck & Co’s fortunes in cancer and it looks like Roche is the only company that could pose any serious threat in the lucrative first-line indication.

After Baynes’ admission that Keytruda’s full potential may not have yet been realised in lung cancer, competitors will have to produce something revolutionary to establish a new standard of care.

About the Author

Richard Staines is Senior Reporter at pharmaphorum. He has been a journalist since the 1990s and has written for websites, newspapers and magazines. He has always had an interest in health, and has been focusing on the pharma industry since 2010, interviewing industry leaders and covering stories on topics including regulation, mergers and acquisitions, and the latest clinical developments.

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