The new era of cancer treatment heralded by immunotherapies is not without its challenges.
As clinicians know all too well, patients’ experiences on immunotherapy can be wildly different.
In some minority cases, immunotherapy has replaced chemotherapy as the first-line treatment of choice and, at times, it can produce stunning results. But for most patients, it’s a last-ditch experimental therapy that comes with the risk of serious side effects.
Either way, everyone involved – specialists and their patients alike – are wrestling with the everyday uncertainty of whether immunotherapies will work, and if they do, for how long.
It’s now almost a decade since the first immunotherapy was approved, and the statistics have been stacking up. Around half of melanoma patients might respond to immune checkpoint inhibitors, but the figure falls to around 15% to 30% in bladder, head and neck cancers.
“We’ve made huge progress, but we again reach a point of asking how can we further improve that response?” says Dr Margaret Chua, a radiation oncologist at Peter MacCallum Cancer Centre in Melbourne. “Unfortunately, not all patients will respond and some will then become resistant. It’s new challenge.”
But it’s not a challenge specialists and researchers shy away from. It means trialling combination therapies to see whether adding immunotherapy agents together can enhance their effect or if radiotherapy can reinvigorate patients’ immune responses.
It also has research teams investigating ways to better predict which people are unlikely respond to immunotherapy drugs and how to support the lucky ones who do (in case their cancer suddenly returns).
“The complexity of its management is growing, which is good because it means there are more treatment options available,” says Dr Aaron Wong, a dual-trained medical oncologist and palliative care specialist, also at Peter MacCallum Cancer Centre.
“But it feels like we can do better in the discovery of a wider range of methods to treat immunotherapy-related side effects, and more clinical evidence to support the various treatments used in supportive care.”
COMBINATION THERAPIES
When it comes to immunotherapy, melanoma is still a shining beacon of possibility.
First, it was single-agent checkpoint inhibitors that had some metastatic melanoma patients living longer. Now, immunotherapies that block different immune cell pathways are being combined to great effect and oncologists are hoping these combination therapies can raise response rates in other cancer types, especially those cancers which are yet to benefit from immunotherapies. Only then will immunotherapy realise its full potential.
But melanoma is particularly immunogenic and when dual immunotherapies, namely ipilimumab plus nivolumab, have been trialled in other cancers, the results haven’t been as impressive, says medical oncologist Professor Michael Boyer.
Though not for lack of trying. Over a hundred clinical trials in various stages are testing immunotherapy combinations, in advanced lung, head and neck cancers through to urothelial, breast, prostate and pancreatic tumours.
“Like most things, the data isn’t ever straightforward,” says Professor Boyer, who is in the thick of it as the chief clinical officer at Chris O’Brien Lifehouse in Sydney.
Professor Boyer, who is also no stranger to negative trials, recently presented results from the first trial in advanced non-small cell lung cancer (NSCLC) comparing two checkpoint inhibitors, pembrolizumab and ipilimumab, to pembrolizumab alone, and not to chemotherapy as others had done before.
This is just one example of how oncologists are trying to outmanoeuvre cancer on two fronts at once. But in Professor Boyer’s trial, dual immunotherapy delivered the same outcomes for patients with high PD-L1 tumour proportion scores as single-agent therapy, with added toxicity.
Other trials are adding immunotherapies and anti-angiogenic drugs to chemotherapy in a bid to help a wider range of patients with advanced NSCLC, for example, not just those with high levels of PD-L1 expression, a predictive marker of immune activity.
At the same time, oncologists are waiting to see the results from trials adding newer forms of checkpoint inhibitors and drugs blocking alternative immune pathways to standard immunotherapies to treat immunotherapy-resistant tumours.
“It looks promising in some patients and eventually we’ll know the answer to that,” Professor Boyer says. “The truth of the matter is, at the moment, there are no completed randomised trials to tell us that any of those combination approaches work beyond anti-CTLA-4 and anti-PD-L1 combinations.”
Some leaders in the field have suggested that research needs to go beyond lumping two well-established therapies together to considering the interplay of precise mechanisms to inform future combinations.
Professor Boyer also suspects the biggest advances in immunotherapies may have already happened, and that progress will be more incremental from here.
“Of all the immunotherapy trials, there are as many negative ones as there are positive ones, which just tells us that, that we don’t know before we do the trial what the outcome will be,” he says.
Dr Arutha Kulasinghe
BIOMARKERS IN THE MAKING
It’s a similar story with biomarkers. A host of new markers are in development, and they can’t come quickly enough with the increasing number of indications for immunotherapy set to place significant strain on healthcare systems.
“These drugs are expensive,” says Dr Arutha Kulasinghe, a researcher at Queensland University of Technology in Brisbane who is investigating new biomarkers of immunotherapy response. “They cost about $150,000 per patient, per year so it can’t be given broadly. It needs to be informed.”
The main markers currently used across multiple tumour types to predict response to immune checkpoint inhibitors are PD-L1 expression levels and tumour mutational burden. But both markers centre around tumour cells (not immune cells) and can give mixed results, with patient outcomes sometimes defying expectations – and not in a good way.
In particular, tumour mutational burden hasn’t quite lived up to its early promise. Various cut-offs for eligible patients are used and debated, and studies have reported less than ideal concordance between commercial assays.
Even so, in June 2020 the US FDA approved pembrolizumab for patients with high tumour mutational burden scores across a number of solid tumour types.
However, like PD-L1 expression, tumour mutational burden is just one biomarker, says Dr Kulasinghe. “It doesn’t give the full story.”
To look for new candidate markers of immunogenicity that predict favourable outcomes, Dr Kulasinghe is following a promising avenue of pre-clinical research profiling the tumour microenvironment, where immune cells meet tumour cells, the extracellular matrix and everything in between.
In this realm of research, taking a spatial approach means identifying not only which immune cells are active, but where they are in the tumour and the degree of immune recognition – which is simply not possible to see with other methods, such as inflammatory signatures generated from bulk expression data.
Specifically, Dr Kulasinghe is using a method of profiling large sections of intact tumours with digital colour-coded barcodes detecting up to hundreds of proteins and RNA targets per slide, each of which can be compared to clinical outcomes.
“It’s giving us insights into the tissue biology that we weren’t able to look at before,” he says.
Integrating imaging and expression data will be the way of the future, Dr Kulasinghe says, so that any biomarker that predicts response will be coupled with the markers already used in clinical practice to improve patient selection for immunotherapies.
“We believe combining these methodologies and layering these datasets together will be really powerful to predict how well immunotherapies may work in individual patients,” he says.
NEW ROLE FOR RADIOTHERAPY
Meanwhile, radiation oncologists are stepping up to the plate, using radiation therapy to activate, amplify or reinvigorate a patient’s immune response and improve outcomes.
Again, it’s just one way of modulating the tumour microenvironment that clinicians are exploring to maximise benefit from immunotherapies.
“When used in combination with immunotherapy, radiation can influence the tumour microenvironment, and it has the potential to really complement the effect of the immunotherapy,” says Dr Chua, who is involved in a number of clinical trials in skin cancer.
No longer a simple cytotoxic treatment, radiation is capable of turning so-called cold tumours, which exclude immune cells or keep them sidelined at the periphery, into hot or “inflamed” tumours where immune cells penetrate deep within, making these tumours more responsive to immunotherapy, Dr Chua explains.
It does so by triggering tumours to release antigens that T cells target, and the effect is not restricted to the primary treatment site. Radiation therapy can occasionally unleash a T-cell mediated immune response that hits secondary tumours outside the irradiated area as well, especially when used alongside immune checkpoint inhibitors.
Expectations are building with a growing number of case reports and studies showing better response rates and extended survival times with radiation plus immunotherapy, in metastatic melanoma for example, than immunotherapy alone.
“This is very promising, especially when patients become resistant of immunotherapy,” says Dr Chua.
“At that point we can use radiation therapy to salvage, to reinvigorate their immune response so they continue to benefit.”
She says about between 20% to 30% of advanced melanoma patients start to respond to immunotherapy again after adding radiation therapy. Research also shows radiation therapy can improve outcomes for a number of other metastatic cancers, such as lung cancer, when combined with immune checkpoint inhibitors.
Metastatic Merkel cell carcinoma (MCC) is another target. In one trial currently recruiting at Peter MacCallum Cancer Centre, radiotherapy is added to first-line immunotherapy (avelumab, an anti-PD-L1 drug) in treatment-naïve patients with advanced MCC, while in another trial avelumab is added to standard of care radiotherapy in early stage disease.
“Given that Merkel cell carcinoma is so radiosensitive, we are hoping to see if we can further improve response rate to immunotherapy with the addition of radiotherapy to improve survival,” Dr Chua says.
The biggest unknown is still how best to combine the two treatment modalities, considering there are also situations where radiation can dampen the immune response in some cases.
Early data from advanced melanoma suggests a short course of radiotherapy with less than five moderate doses delivered early or sequentially with immunotherapy could potentially be more beneficial than a prolonged course or a single high dose of radiotherapy – although the jury is still out, Dr Chua says.
“It’s not new but if we can add radiation therapy which has a long history of treating cancer successfully and add it on to immunotherapy, and it’s well tolerated, there’s great potential there,” she says.
SUPPORTIVE CARE
The landscape of supportive care is shifting too. Balancing the hype of immunotherapies with reality, and managing patient expectations about their treatment is one part well known to all clinicians involved in cancer care.
“But it’s also managing the completely different toxicity profile that we’re seeing with immunotherapies,” says Associate Professor Judith Lacey, head of supportive care and integrative oncology at Chris O’Brien Lifehouse.
While immunotherapies are generally much better tolerated than toxic chemotherapies, research shows up to 30% of patients on immune therapies experience severe side effects that health professionals are just beginning to understand, recognise and treat.
“The fatigue from immunotherapy can be quite profound, and a big gap I think is still how we are addressing that fatigue in a proactive manner,” says Associate Professor Lacey.
Chronic joint pain, sleep problems, ongoing bowel disturbances are other mild to moderate toxicities from immunotherapies, which Associate Professor Lacey says people are often content to live with, however troublesome, if it means their disease is going to be controlled.
At the other end of the spectrum are patients who are responding well to immunotherapy with few or manageable side effects.
“It’s a whole new population that we are seeing who are living really well with a diagnosis of advanced cancer,” which means supportive care has to adapt both ways, Associate Professor Lacey says.
At Chris O’Brien Lifehouse, Associate Professor Lacey and her team have trialled a proactive supportive care program designed to help patients improve their overall health from the outset to put them in the best position possible should their treatment cause toxicities or should they stop responding and need to switch therapies.
Getting people exercising, eating well, off unnecessary drugs, and developing a mind-body practice hopefully helps people cope with uncertainty and stay on treatment so they are living well for longer, she says.
Finding alternative therapies to long-term steroids, the mainstay treatment for acute and chronic treatment-related toxicities, will also be important if patients are living for years, not months, she says.
However, even the most dramatic responses don’t always last.
Breathlessness, nausea and diarrhoea could be the first signs that patients on immunotherapies are developing more serious side effects, says Dr Wong, so doctors need to be attentive to these very common complaints.
To increase awareness about immune-related adverse events, guidelines have been developed in recent years but there is still a way to go, says Dr Wong.
He says supportive care practices can vary between treatment centres based on experience or local health service policy, but strategies should really be standardised to ensure the best care and to ensure that new therapies are available to all patients.
In another decade’s time, hopefully more people will be able to access and benefit from immunotherapies.
