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Pharmacists Challenged With Real-world Situations That May Affect ICI Outcomes


Can a patient with metastatic cancer on immune checkpoint inhibitor (ICI) therapy use acetaminophen for pain? What about medical marijuana? And does the gut microbiome play a role? With more than a decade of real-world experience with ICIs, pharmacists learned about the potential role of these and other factors during a session at the 2022 American Society of Health-System Pharmacy Midyear Clinical Meeting & Exhibition.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer care since the first FDA approval in 2011, for ipilimumab in melanoma. Since then, more ICIs have hit the market and are now cleared for more than 85 indications; the number of adjuvant/combination indications is growing.

More than 1 in 3 patients with metastatic disease and highly mutated tumors are eligible for these therapies across many different malignancies, and the more these drugs are used, the more health care professionals are learning about how they work in the real world.

A Monday session at the 2022 American Society of Health-System Pharmacy Midyear Clinical Meeting & Exhibition focused on situations that a pharmacist, whether working in internal medicine, retail, or clinical oncology, might come across, as well as updates in managing immune-related adverse events (irAEs).

The session was led by Jordan P. McPherson, PharmD, MS, BCOP, an oncology clinical pharmacist at the Huntsman Cancer Institute and adjunct assistant professor, University of Utah, College of Pharmacy Salt Lake City, Utah; and Tonya Smith, PharmD, BCPS, a clinical pharmacy specialist in internal medicine at Emory University Hospital Midtown in Atlanta, Georgia.

The clinical trials which led to the approval of ICIs enrolled patients using specific selection criteria, which is why retrospective, observational studies illustrate valuable findings that shed light on what a pharmacist might see day-to-day, he said. Case series, and other reports are illustrating some situations that may impact how ICIs performs.

“We do not have perfect data,” McPherson noted.

The presenters used the context of a case of a 63-year-old woman (“KJ”) with recently diagnosed melanoma that had spread to the bone and adrenal glands, to describe what a pharmacist might encounter, regardless of practice area, and how they can optimize care.

In this situation, KJ sought to discontinue oral opioids for acetaminophen, asks about the use of cannabis, develops a rash and severe itching, and has questions about COVID-19 and influenza vaccinations.

The presentation, which was also broadcast as a live webinar, posed various questions to the audience about non-drug factors that could impact ICI.

Infusion Time of Day

If the patient, as the one described, had the first cycle of ICI delayed due to a hospitalization, and an infusion center tried to squeeze her in as the last patient of the day, would that matter? It might, said McPherson.

Previous vaccine research has indicated that the immune response might be weaker when stimulated in the evening. A longitudinal propensity score‐matched analysis published last year examined the effect of circadian rhythms on ICI.

Using the database from the Melanoma Outcomes Following Immunotherapy (MEMOIR) trial conducted at Emory’s Winship Cancer Institute, researchers looked at patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination.

They found that having 20% or more of infusions after 4:30 PM translated into inferior overall survival, compared with those who had fewer than 20% of their infusions in that later timeframe (median overall survival 4.8 years vs not reached; HR, 2.04; 95% CI, 1.04 –4.00; P = .038).

In addition to the concerns raised by those findings, McPherson and Smith questioned whether it was considerate to infusion center staff to add a new patient at the end of the day, as well as the possibility of the patient having a reaction to the therapy later in the evening.

Pain Relief: Acetaminophen, Opioids, Cannabis

What are some of the drug-drug interactions that pharmacists need to be aware of in immunotherapy? Acetaminophen, for example, is an issue because it is widely used and available over-the-counter, but suppresses antitumor immunity via T‐cells.

Smith cited a paper published in September in Annals of Oncology that analyzed 3 sample sets using a PD‐L1 blocker or a combination of PD‐L1 and CTLA‐4 inhibitors and acetaminophen.

One sample came from the pivotal CheckMate 025 trial; 297 patients treated with nivolumab for advanced renal cell carcinoma had significantly worse overall survival (OS) if levels of acetaminophen levels were detectable compared with non‐detectable levels.

The authors then looked at 34 patients at their own institution and found a lower tumor response rate linked with detectable vs undetectable levels (0% vs. 29.4%, P = .015); however, the differences in progression-free survival (PFS) and OS were not statistically significant.

The investigators also looked at pretreatment plasma samples of 297 patients with advanced cancer in the PREMIS study. Patients had significantly worse PFS and OS if levels of acetaminophen were detectable (median PFS 2.63 vs 5.03 months; 95% CI, 0.53‐0.91; P = .009; median OS 8.43 vs 14.93 months; 95% CI, 0.32‐0.69; P < .0001).

The possibility of confounding, however, was a major limitation of this analysis. For instance, is cancer that is severe enough to cause pain the driver behind the results, or is it because the patients just had more severe disease in general? Or were the results impacted by accompaying use of opioids?

“My take home point here is just that we don't have enough information, but we need to determine if this is a clinically significant drug interaction,” said Smith.

She also cited 2 observational studies that linked opioids during immunotherapy with significantly shorter PFS and OS.

In a study of 193 patients with metastatic solid tumors, the median PFS was 3 months vs 19 months in patients taking opioids compared with no opioids; similarly, for patients taking opioids, median OS was 4 months compared with 35 months.

In a study of 300 patients with non-small cell lung cancer, median OS was 5.7 months vs 15.9 months, and median time to treatment failure was 1.8 months compared with 3.5 months.

When it comes to cannabis, some research indicates it may impact ICI efficacy. Smith noted 3 studies that looked at ICI therapy with and without the use of cannabis. Results showed a shorter time to progression, reduced tumor response rate, shorter OS and shorter median OS in patients using cannabis to manage pain.

As with the other findings, there is not enough data to make a firm recommendation about cannabis and ICI, and Smith also noted that the plant has many different forms, routes of administration, and other variables that make it a challenge to puzzle out.

Is the Gut Microbiome Connected to ICI Response?

The gut microbiome is influenced by bacteria, the use of probiotics, and fiber. With expanding knowledge about the role of the microbiome in many different aspects of health, is it possible that the microbiome impacts response to ICI therapy?

Smith shared a recent finding from a study published a year ago in Science looking at dietary fiber and probiotics. Investigators looked at a group of 293 patients with metastatic melanoma and the characterisitics of responders compared with non‐responders.

While there was no difference in overall gut microbiota composition, there was a higher abundance of Ruminococcaceae.

Using probiotics had no significant difference in median PFS. But patients who ate 20 grams of more of dietary fiber a day, and had no probiotic use, had significantly longer median PFS (NR vs 13 months).

In relaying these situations, McPherson and Smith said more work still needs to be done before any definitive conclusions and recommendations can be made, but said pharmacists should still be cognizant of the possible impact that nonprescription medications, alternative therapies, non-drug factors like infusion timing and dietary fiber can have on ICIs.

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