Immune checkpoint inhibitors and emergency medicine

Significant advancements have been made in the treatment of various cancers. In the past, patients diagnosed with non-small cell lung cancer (NSCLC) faced treatment with infamous chemotherapeutics (such as platinum-based therapies), surgical intervention, radiation or a combination of these treatments. But numerous new(er) therapeutics with immunologically based targets have shifted these therapies and could reshape the entire approach to NSCLC altogether. 

As somewhat of a newcomer to this field, my initial perception of the population that would benefit from these therapies would be small. However, upon further clarifying their position and role, I learned that more than 55% of newly diagnosed NSCLC patients have advanced disease at the time of diagnosis. So it would appear that the population able to receive these therapies is relatively large. Furthermore, because very few of the tumors in this group are surgically resectable, novel therapies such as the immune checkpoint inhibitors (ICI) PD-1/PD-L1 therapies are substantial breakthroughs.

The ICIs are one component of a much broader approach to the management of NSCLC. The ICI subclasses of PD-1 (programmed cell death-1 protein) inhibitors and PD-L1 (programmed cell death-1 ligand 1) inhibitors are options for first-line treatment of advanced NSCLC (aNSCLC). Aside from representing a shift away from cytotoxic chemotherapeutics, what’s even more exciting about these agents is their positive impact on patient-oriented outcomes. Agents like pembrolizumab can improve progression-free survival (PFS) and overall survival (OS) in patients with aNSCLC. (KEYNOTE407, KEYNOTE024, KEYNOTE042)

So what are PD-1/PD-L1 Immune Checkpoint Inhibitors?

To know what these PD-1/PD-L1 inhibitors are actually inhibiting, we first have to discuss immune checkpoints. In a nutshell, immune checkpoints allow T cells and cytotoxic T lymphocytes (CTL) to identify and differentiate healthy cells from cancerous cells and then eliminate these cancerous cells. But in many cancers, inhibitory elements to various steps in this pathway are upregulated, thus suppressing the normal immune response and creating conditions for tumor proliferation. Here’s a pretty good crash course in video format.

Of course, this is an oversimplified description of what is truly going on. T cells become primed for an immune response when T-cell receptors (TCR) identify major histocompatibility receptors (MHC) on antigen-presenting cells (APC). Under normal circumstances, this receptor/ligand interaction, along with costimulatory receptor activation, would elicit a normal T cell immune response to these APCs. But if this TCR/MHC interaction occurs in the presence of co-inhibitory receptors (you guessed it), this immune response is suppressed. 

One such inhibitory receptor/ligand combination includes the CD80 or CD86 and CTLA-4 (cytotoxic lymphocyte-associated protein 4), which causes a T cell inhibitory response. So it shouldn’t surprise you to learn that many tumor cells possess overexpression of CTLA-4, thus shutting off any host immune response.

PD-1/PD-L1 Inhibitors

PD-1 Inhibitors
PembrolizumabNivolumabCemiplimab
PD-L1 Inhibitors
AtezolizumabAvelumabDurvalumab

Considering PD-1, tumor cells with PD-L1 or PD-L2 ligand expression bind to PD-1 on the T cell to inhibit its normal immune response by way of T cell downregulation, cytokine down-regulation, and apoptosis.  Thus by blocking the PD-1/PD-L1 or PD-1/PD-L2 allows for a restoration of normal T cell function on the tumor cell (there’s also B7.1-PD-L1, fyi). This interaction can be blocked by either PD-1 inhibitors or PD-L1 inhibitors.

Minimum PD-L1 expression

In order for these agents to work successfully as monotherapy, there must be a minimum expression of PD-L1 of at least 1%. (KEYNOTE024, KEYNOTE042) While this seems at first glance to be something achievable, given that 48% of patients with metastatic NSCLC have a PD-L1 lower than 1% narrows the population able to receive this drug. Furthermore, while patients with PD-L1 expression > 50% can receive monotherapy with pembrolizumab, those with PD-L1 expression 1-49% are recommended to attempt an ICI plus chemotherapy regimen before using monotherapy ICI. But either pembrolizumab or atezolizumab plus chemotherapy regimens improved PFS and OS compared to chemotherapy alone regardless of PD-L1 biomarker testing. In this case, ICI plus chemotherapy regimens can be used.

Immune checkpoint inhibitors are not without toxicities (irAE)

Although these therapies have novel targets, they aren’t devoid of toxicities. At first glance, they appear to be equally intolerable to conventional chemotherapy. In phase 3 trials, typical adverse events of any grade were similar between ICI (63-98.5%) and chemotherapy (87-99%). Yet again, there’s more to the story. In a related post on BTK inhibitors, I described the Common Terminology Criteria for Adverse Events, which is relevant again here when further examining the safety of ICIs. 

While the overall adverse events reported were similar, adverse events that were severe or dose-limiting (Grade 3, 4, or 5) were more common with ICI PLUS chemotherapy vs chemotherapy alone.  Specifically, the immune-mediated AEs (irAE) of any grade and of grade 3 or more were significantly more common in ICI plus chemotherapy. However, a higher degree of irAEs shouldn’t be a surprise since conventional chemotherapy does not cause irAE per se. 

irAEs of any severity occur in upwards of 70% to 90% of patients receiving ICIs. While these effects include fatigue, dermatologic, GI (nausea/diarrhea), hepatitis, thyroid (either hyper/hypo), hyperglycemia, and (rarely) pneumonitis and myocarditis, conventional chemotherapy is also known to cause well-known toxicities. These conventional aNSCLC treatment-related toxicities from agents like carboplatin include bone marrow depression, anemia, leukopenia, neutropenia, and thrombocytopenia, as well as neuropathies. 

While visually comparing these irAEs may seem trivial, their impact is significant and can lead to premature drug discontinuation. Some of the most prevalent irAEs that may be relevant to ED folks include hyperglycemia (new-onset type 1 diabetes), hyponatremia, hyperthyroidism, diarrhea, and hepatitis. While recognition of these irAEs may be challenging, their management is fairly straightforward: symptomatic management/supportive care and steroids. In some cases with severe colitis, patients can potentially benefit from the use of infliximab.

The various irAEs possible with these agents is a rather large topic worthy of a post of it’s own – coming soon!

One separate consideration that must be respected is the delayed onset of these drugs. As we’ve learned today, they aren’t like chemotherapy in many respects. This includes the onset of effect. Which in the case of ICIs, onset can be delayed. Overall, compared to conventional chemotherapy, the quality of life (QOL) in the context of global health status (expressed as GHS/QOL), scores tend to favor improvements in these measures with pembrolizumab plus chemotherapy. 

Immune checkpoint inhibitors – Cost

One element that cannot be ignored is the cost of these drugs. Which is significant. The AWPs for these agents make our expensive ED drugs look like discount rack items. But with ICIs and oncologic interventions in general, there have been better descriptive tools developed to understand the cost/benefit discussions. The incremental cost-effectiveness ratio (ICER) for pembrolizumab plus chemotherapy was $104,823/quality adjusted life year (QALY). Which sounds like a lot. But in the context of the US threshold of $100,000/QALY, it is slightly above the ICER. But when considered as monotherapy pembrolizumab versus chemotherapy, it was a favorable ICER of $86,293/QALY.

ICI – Where to next?

What’s becoming clear to me, is that this is the tip of the iceberg for development into this therapeutic space. Relatively speaking, ICIs are still in their infancy of drug development, and newer more specific agents, targets, and regimens are on the horizon. Furthermore, just by checking the FDA website for new drug approval, the cost of these therapies is likely to decline due to numerous drug makers investing in this space, creating competition and driving costs down.

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