It’s almost a decade since Bristol-Myers Squibb (BMS) ushered in the cancer immunotherapy revolution with the first approval of Yervoy (ipilimumab) in melanoma.
Since then, BMS and rivals, such as Merck & Co and Roche, have redefined care standards in both solid and blood cancers, and this year’s ASCO showed how industry is refining treatment with existing therapies, as well as finding new ways to unleash the power of the immune system against cancer.
Like many other events, this year’s ASCO went virtual due to the COVID-19 pandemic, but this enforced change did not prevent the emergence of some exciting new science, with immunotherapy a major focus for research.
Since the approval of CTLA4-class Yervoy, PD-1/L1 checkpoint inhibitors have become standard of care in many forms of cancer, showing greater efficacy than chemotherapy and with fewer side-effects.
Cell therapies followed in their wake when CAR-T drugs were first approved in blood cancer – and pharma companies are continuing to raise standards with new approaches and new ways to improve on results with established therapies.
Jennifer Harris, vice president of immuno-oncology at Syneos Health Clinical Solutions, notes progress was on display at this year’s event with a new kind of checkpoint inhibitor targeting TIGIT, short for T cell immunoreceptor with Ig and ITIM domains.
Roche’s tiragolumab data showed that the tiragolumab/Tecentriq combination met both primary endpoints in the intention-to-treat population.
Compared with just Tecentriq there was an improvement in the objective response rate – 31.3% vs 16.2% – and an improvement in progression free survival (PFS) with a 43% reduction in risk of disease worsening or death.
An exploratory analysis showed that in people where at least half of tumour cells were expressing the PD-L1 biomarker, there was a clinically meaningful improvement in overall response rate (ORR) – 55.2% compared with 17.2%.
The improvement in PFS was also more marked in this group, with a 67% reduction in the risk of disease worsening or death – not reached versus 3.9 months – with the combination compared with Tecentriq alone.
The theory behind TIGIT is that targeting this checkpoint as well as PD-L1 will produce a stronger immune response than with a single therapy, something that Harris thinks has happened here.
The data from the CITYSCAPE may suggest that the PD-L1 and TIGIT combination could have an advantage in terms of safety compared with the CTLA-4 and PD-1/PD-L1 dual therapies already on the market.
Bispecific antibodies, where the different ends of the giant “Y” shaped molecule target a different receptor, are also gaining in traction in clinical trials.
Macrogenics’ MGD013, which targets both LAG-3 and PD-1, is addressing patients who had progressed following treatment with other checkpoint inhibitors, a group Harris says should be prioritised.
MGD013 has managed to produce responses in patients who had already failed to make headway with other checkpoint inhibitors.
The study also included a group where MacroGenics’ antibody margetuximab was added to the regimen.
Margetuximab is essentially the antibody from Roche’s Herceptin (trastuzumab), but with the “tail” of the Y-shaped molecule tweaked to produce a strong immune response.
At last year’s ASCO it produced a marginal improvement over Herceptin in HER2-positive disease, but this trial suggests that it could work well as a way of priming the immune response produced from the checkpoint inhibitor.
According to Harris, this year’s ASCO also demonstrated how the industry is making a steady approach towards therapies targeted at tumours or blood cancers based on their genetic characteristics rather than their place of origin in the body.
The key to this is identifying biomarkers found in cancer tissues but not elsewhere in the body – something that has already been achieved in a couple of approved drugs.
Merck & Co’s Keytruda produced some intriguing results in colorectal cancer at ASCO, and other biomarkers are coming into play.
Those results were in tumours with a biomarker known as MSI-High, which is already targeted by Keytruda and is included on its FDA label.
But science is guiding pharma towards other biomarkers that have not yet been exploited: POLE/POLD1 is another potential target, which has attracted attention from a team at MD Anderson.
Another biomarker that was of interest at ASCO was LRP1B, which is the subject of research by a team at Duke University.
There’s also the possibility of using biomarkers found in the blood, with research at ASCO highlighting circulating stromal cells, or CAMLs, as a way of detecting cancer.
Soluble biomarkers are very attractive as they negate the need for invasive tissue biopsies. Companies such as GRAIL are exploring the potential of other blood-borne biomarkers, such as cell-free DNA circulating in the blood plasma.
Harris says: “We can’t keep biopsying these patients over and over, especially if they have metastases in difficult-to-biopsy sites such as the brain or the liver.”
The FDA also presented intriguing data about the role of the gut in effectiveness of checkpoint inhibitor regimes.
This trial involving 1,600 patients looked at four approved checkpoint inhibitor regimes and looked at whether use of antibiotics affected outcomes.
A control group with the same endpoints used standard chemotherapy or targeted therapies, and findings showed a statistically significant reduction in overall survival compared with those in the control group receiving the chemo or targeted therapy.
“Their conclusion was that – while they weren’t recommending that antibiotics be withheld from patients that need them – antibiotics do induce negative outcomes for patients on immunotherapy, specifically checkpoint inhibitors,” Harris says.
“They went so far as to say that they were advocating for antibiotic use to be used as a stratification factor in checkpoint inhibitor studies going forward.”
In the future we may see more investigation into other factors that could be causing checkpoint inhibitors and immunotherapies to fail, such as differences in the area surrounding the tumours that could be preventing the immune system from mounting its attack.
This so-called tumour microenvironment has been a common topic of discussion at ASCO for the last few years, and according to Harris could play an increasing role in trial design in the future.
“We need to really look at negative predictors of checkpoint, not just positive predictors,” she says.
Trial designs themselves also became a talking point in the oncology community during this year’s meeting, as doctors navigate increasingly complex studies and findings that can be far more complex than the top-line summaries seen on the drug’s label.
While simple trials with a control and a treatment group still do exist, in diseases such as lung cancer patients need to be stratified into different subgroup studies and often have several arms of treatment.
The case in point at ASCO 2020 was the CheckMate-227 trial, which was used to test BMS’ combination of Opdivo and Yervoy in first line non-small cell lung cancer.
This trial had four different treatment arms, and produced results that, while supportive of the therapy, showed the drug combination was only working in a certain subsection of the population studied.
So on top of the complexity of a four-arm parallel trial there are also nuances regarding the drug’s use that clinicians will have to take into account.
At the same time, patients continue to become more informed about results of trials through online searching. While this can prove beneficial in learning about novel treatments, clinicians must be wary of a potential digital divide and the implications it has for the quality of care patients receive.
“The patients that benefit are the ones that are savvy enough to go out and do their own research and ask the probing questions that lead the clinicians to dive a little deeper into the data,” says Harris.
To read additional oncology perspectives from Harris and her colleagues at Syneos Health visit syneoshealth.com/collaborate-for-a-cure/
Jennifer Harris serves as head for the Immuno-Oncology (IO) business at Syneos Health.
In this role, Harris is responsible for IO strategy and scientific support for the project portfolio. Throughout her 25 year career focused in oncology, Harris has also held clinical positions at major academic centre, the NIH clinical centre and has held scientific roles within biotech and large pharma – focusing primarily on the rapidly expanding field of immuno-oncology.
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.
Syneos Health is the only fully integrated biopharmaceutical solutions organisation. The company, including a contract research organisation (CRO) and contract commercial organisation (CCO), is purpose-built to accelerate customer performance to address modern market realities. Created through the merger of two industry-leading companies – INC Research and inVentiv Health – it brings together approximately 24,000 clinical and commercial minds to help its biopharmaceutical customers shorten the distance from lab to life. Learn more at syneoshealth.com