The Great Irony of Modern Oncology: Immunotherapy's Imprecision

Bishal Gyawali, MD, PhD


August 30, 2022

The oncology community loves to talk about precision medicine.

We don't get tired of praising ourselves for being able to "select" patients for our newer drugs based on biomarkers. We congratulate ourselves for being able to find those biomarkers not only in the tissue but also in blood. We even have journals and conferences dedicated to precision medicine.

Another recent glory for the oncology community is immunotherapy. Immunotherapy has been transformational in the treatment of certain cancers such as melanoma and lung cancers. And we can reasonably congratulate ourselves for the transformation we've seen in patients' lives. These are drugs that are improving the longevity and quality of patients' lives.

However, I think that the paradigms of immunotherapy and precision medicine have become antithetical to each other. We have let our precision medicine principle of "right dose for the right patient at the right time" fly out the window when it comes to immunotherapy.

Let me explain why. To put it simply, immunotherapy feels anything but precise.

With immunotherapy, we are treating too many patients too long too often, and at too high a dose.

Too Many Patients

Contrary to the premise of precision medicine, we don't have good biomarkers to predict a patient's response to immunotherapy nor do we have good biomarkers to predict toxicities. Some patients derive long-term benefit from immunotherapy, whereas others don't benefit at all.

The immune-oncology biomarker space is crowded and messy. Take programmed death-ligand 1 (PDL1). From variations in positivity rates to measurement strategies, our PDL1 biomarkers are, to put it politely, imperfect. Using PDL1 in clinical decision making is almost worse than having no biomarker because it gives us the illusion of precision.

Adding to this issue, we see shrewd nested subgroup analyses performed to increase the potential pool of patients who will use a drug. But the results can be misleading. For example, if there is substantial benefit among patients with PDL1 above 50%, studies will also typically show results for patients with PDL1 above 10% and 1%. And these results often also look positive given the substantial benefit seen in the 50% subgroup.

Adjuvant trials are even more problematic. Some patients receiving adjuvant immunotherapy won't relapse and thus do not need treatment, whereas others will relapse despite treatment. Yet, our approach is to treat 100% of the patients with immunotherapy in the hope of helping a small percentage delay their relapse.

In other words, I believe that we are treating too many patients with immunotherapy.

Too Long

Most chemotherapy regimens are prescribed for a short period in the adjuvant setting. Even in advanced or metastatic cancers, chemotherapy usually doesn't go on for too long. In advanced cholangiocarcinoma, for instance, we stop chemotherapy after eight cycles, which lasts 24 weeks.

Even with chemotherapy options, such as FOLFOX or FOLFIRI in metastatic colorectal cancer, there is a tendency to stop treatment after several months to allow breaks.

With immunotherapy, however, the adjuvant trials can run for 1-3 years, often with no overall survival data to show for it. That's an enormous therapeutic burden on too many patients for an unproven benefit.

In fact, my colleagues and I did a systematic study to find the basis for this extended duration for immunotherapy in the adjuvant setting. No surprise, we found none.

In the metastatic setting, treatment duration is even worse. Patients may receive these agents for an indeterminate period — as long as the patient tolerates the drug or does not develop severe side effects.

I find this baffling, especially given how immunotherapy works. Unlike chemotherapy, immunotherapy activates the immune system which likely continues to remain active for a long time. We've seen evidence of this long-acting effect from patients who have had to stop their immunotherapy treatment owing to side effects but end up continuing to respond long after.

Too Much

I am convinced that we are giving our patients unnecessarily high doses of immunotherapy.

Several studies have shown that there is no dose-response relationship with immunotherapy. For instance, peripheral receptors may become saturated at a dose of 0.3mg/kg of nivolumab.

However, giving a lower dose is not in the financial interest of the healthcare business ecosystem. Instead of reducing the dose, we moved from a "personalized" weight-based dosing to a flat dose, irrespective of weight. This approach alone costs the United States over $800 million a year for pembrolizumab in non–small cell lung cancer alone.

In fact, a recent study in head and neck cancer from India, presented at this year's American Society of Clinical Oncology meeting as a poster, found that adding low dose nivolumab 20 mg to metronomic chemotherapy improved survival.

I am confident that if we conducted more trials of lower-dose immunotherapy, we will find more of these pleasant surprises.

Too Often

The pandemic was a good opportunity to study treatment deescalation.

Oncologists developed regimens to allow patients to get the care they needed but at fewer intervals, limiting their contact with the healthcare system. Immunotherapy treatments, for instance, shifted from every 3 weeks to every 6 weeks.

Unfortunately, as a result, the manufacturer decided to double the doses, despite knowing there is no dose-response relationship with immunotherapy.

I think this represents a missed opportunity.

Immunotherapy has been transformative for many patients. But there is no denying that major issues remain with how we wield this incredible tool.

We need to focus more on understanding when we can do the best for our patients. It is time we address the irony that in the era of precision medicine: The most promising treatments we have are also the most imprecise.

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