Immunotherapy Drugs and Related Side Effects

Immunotherapy Drugs and Related Side Effects: Comparison

Please note this is a comparison between Version 2 by Conner Chen and Version 3 by Gavin Hui.

Numerous immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), have been approved for the treatment of genitourinary (GU) malignancies. While ICIs have improved treatment outcomes and expanded treatment options, they can cause immune-related adverse events (irAEs).

immune-related adverse event

1. Introduction

Genitourinary (GU) malignancies include primarily the cancers of the prostate, bladder, and kidney. Ts, and testicular and penile cancers are included and occur less frequently. In 2021, the US had an estimated 83,730 new cases and 17,200 deaths from bladder cancer ^[1]. In addition, the US had an estimated 76,080 new cases and an estimated 13,780 deaths from kidney cancer in 2021 ^[2].

While GU malignancies are prevalent, recent discoveries in cancer biology and therapeutics, particularly the addition of immunotherapeutic agents, suggest that the tide may be turning for the treatment of these diseases. The most established application of cancer immunotherapy is immune checkpoint inhibitors (ICIs). A class of monoclonal antibodies, ICIs, act to enhance T-cell antitumor immune surveillance through action on three key targets: programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Numerous drugs within the ICI class have been approved for the treatment of kidney, bladder cancer, and other non-GU cancers. These include the PD-1 inhibitors nivolumab and pembrolizumab, the PD-L1 inhibitor avelumab, and combination therapies have shown benefits in overall and progression-free survival ^[3][4][5]. These important benefits of ICI therapy are balanced by a significant risk of “off-target” adverse effects, formally known as immune-related adverse events (irAEs), which occur as a result of unregulated immune activity against non-cancer tissue. One recent study estimates that irAEs will affect nearly 60% of patients treated with combination ipilimumab and nivolumab ^[6]. The scope of irAEs is also quite broad, with dozens of distinct irAEs affecting nearly every organ system described in the literature ^[7]. While significant attention has been directed towards characterizing and quantifying the scope of irAEs, comparatively little is known of the rheumatologic side effects of ICIs and the effects of ICIs on patients with pre-existing autoimmune or rheumatologic disease.

Autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and multiple sclerosis (MS), among many others, are highly prevalent, affecting somewhere between 24 and 50 million people in North America alone. RA prevalence has been estimated to be around 0.5–1% in the US and northern European countries, and RA incidence is estimated to be 40 per 100,000 persons annually ^[8]. In addition, the prevalence of IBD in North America was above 0.3% ^[9]. There is evidence of an association between autoimmune disease and increased risk of cancer, including bladder and kidney cancer ^[10][11]. Despite this association, patients with pre-existing autoimmune disease have often been excluded from clinical trials of ICIs based on concern for exacerbating or triggering further autoimmunity.

2. Immunotherapy Drugs in Bladder Cancer

Several ICI drugs have been approved for advanced bladder cancer (Table 1). In particular, anti-PD-1 and PD-L1 therapies have been used in the second line for patients who have progressed during or after platinum-based chemotherapy. Avelumab, nivolumab, and pembrolizumab have been approved as second-line therapy ^[3][4][12]. Durvalumab and atezolizumab were given accelerated approval for similar indications, but they were recently withdrawn given new study results showing no OS benefit over chemotherapy ^[5][13].

Table 1. Immunotherapy approved for metastatic urothelial carcinoma (mUC).

Drug	Mechanism	Trial	Indications
Pembrolizumab	Anti PD-1	KEYNOTE-045 (second-line) KEYNOTE-052 (first-line)	Second-line: progression during or following platinum-based chemotherapy First-line: not eligible for platinum-based chemotherapy
Nivolumab	Anti PD-1	CheckMate-275	Second-line: progression during or following platinum-based chemotherapy
Avelumab	Anti PD-L1	JAVELIN	Second-line: progression during or following platinum-based chemotherapy Maintenance therapy after first line platinum-based chemotherapy
Atezolizumab	Anti PD-L1	IMvigor210	First-line: not eligible for cisplatin-based chemotherapy and tumors express PD-L1 ≥5% OR not eligible for any platinum-based therapy

While the preferred treatment option for treatment-naïve patients with advanced bladder cancer is platinum-based chemotherapy, pembrolizumab and atezolizumab can also be offered in the first-line setting for patients who are cisplatin-ineligible and have PD-L1 positive expressing tumors or who are platinum ineligible ^[4][14].

3. Immunotherapy Drugs in RCC

Pembrolizumab, nivolumab, avelumab, and ipilimumab are all approved for the treatment of mRCC in the first and second-line settings. Treatment selection depends on the evaluation of the patients’ risk profile and stratification. Risk is determined based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria ^[15][16]. In addition, Motzer et al. have developed a five-factor prognostic model that stratifies patients into low, intermediate, and high-risk groups ^[17]. It is worth noting, however, that IMDC and Motzer risk stratification algorithms were developed and reported before the use of immunotherapy in frontline mRCC treatment. Many of the regimens used to treat mRCC combine ICI agents with vascular endothelial growth factor (VEGF) inhibitors, which have been the standard-of-care treatments for mRCC since their marketing approvals in the mid-2000s. The VEGF inhibitors approved for the treatment of mRCC are sunitinib, pazopanib, cabozantinib, axitinib, sorafenib, lenvatinib, and tivozanib ^{[18][19][20][21]}. For patients that have been determined to have favorable-risk disease, combinations of pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, nivolumab plus cabozantanib, nivolumab plus ipilimumab, and avelumab plus axitinib are approved as first-line treatment options ^{[22][23][24][25][26][27][28][29]}. Patients with intermediate or high-risk diseases have similar treatment options when it comes to immunotherapy. Combinations of pembrolizumab plus lenvatinib or pembrolizumab plus axitinib or nivolumab plus cabozantinib or nivolumab plus ipilimumab are all approved treatment strategies in this risk class. Avelumab plus axitinib combination therapy has also recently been approved. Among these options, clinical trials with pembrolizumab plus axitinib and nivolumab plus cabozantinib have demonstrated the most significant treatment benefit for patients with non-favorable risk ^[22][25][29].

4. Treatment-Related Immune-Mediated Side Effects

IrAEs are categorized clinically via the common terminology criteria for adverse events (CTCAE) ^[30]. CTCAE grading ranges from 1 to 5, and lower grades indicate more mild adverse events that can be managed usually with supportive measures alone, are reversible, and patients can remain on treatment. At the other end of the spectrum, grade 5 is usually fatal toxicity. Commonly reported immune-mediated events across the ICIs discussed above can be categorized into systemic effects, dermatitis, enterocolitis, endocrinopathies, and arthritis ^[31]. Each side effect presents at varying frequency and severity depending on the specific ICI, combination with other anti-tumor agents, length of treatment, and treatment population. The common symptoms are fatigue, pruritus, rash, diarrhea, and joint pain. In patients with locally advanced or metastatic urothelial carcinoma on ICI monotherapies, Grade 1 or 2 diarrhea per CTCAE is seen in 7% on nivolumab, 8.4% on durvalumab, 9.0% on pembrolizumab, 16.6% on avelumab, and 12% on atezolizumab ^{[3][4][13][14]}. In the same patient population, these rates significantly increased in combination therapies where Grade 1 or 2 diarrhea was seen in 23.1% and 32.6% on nivolumab and ipilimumab. However, these therapies provided superior efficacy ^[3]. The frequency of Grade 1 or 2 events differs significantly in metastatic renal cell carcinoma (mRCC) patients on monotherapy with 18% seen on nivolumab, 13.9% on pembrolizumab, 12.9% on avelumab, and 11% on atezolizumab ^{[32][33][34][35]}. Conversely, rates are nearly equal for those on ICI combination regimens with 27% on nivolumab and ipilimumab ^[26]. Some serious but rare irAEs, such as pneumonitis, occur with both anti-CTLA-4 and anti-PD-1 agents in a small minority of patients but can quickly become life-threatening. The combination of these therapies increases the likelihood, demonstrated by the 2% incidence on nivolumab and ipilimumab compared with <1% on nivolumab, 1% on ipilimumab, and 1% on pembrolizumab ^[3][36][37]. Pulmonary co-morbidities are significant indicators of this event.