Immune-related adverse events among COVID-19 vaccinated cancer patients on immune checkpoint blockade

STRUCTURED ABSTRACT

Background:

Whether COVID-19 vaccination and the associated immune response increases susceptibility to immune related adverse events (IRAEs) among patients treated with immune checkpoint inhibition (ICI) remains unknown. Short-term follow-up can assess the safety of concurrent administration of the vaccine and ICI treatment.

Methods:

Electronic health record analysis of a cohort of 408 patients with cancer on ICI therapy who received COVID-19 vaccination from January to March, 27, 2021. Patients were followed from 90 days from day of first dose in this single-institution tertiary care center. We evaluated incidence of IRAE as well as frequency of each event type and grade among patients who experienced an IRAE. We also evaluated the incidence of IRAE in patients who began a new immunotherapy agent following vaccination.

Results:

Among 408 patients with cancer on ICI therapy (Median age 71, 217 (53%) male), administration of a COVID-19 mRNA vaccine within 90 days of ICI treatment was not associated with an increased incidence of IRAEs, including among those with previous IRAEs from ICI. No excess risk of COVID-19 diagnosis was seen in this subset of patients on ICI therapy, and no breakthrough COVID-19 cases were seen following full COVID-19 vaccination.

Conclusions:

These findings should reassure providers that COVID-19 vaccination during ICI therapy is safe and efficacious.

INTRODUCTION

Recently introduced COVID-19 vaccines are a critical advance against the COVID-19 pandemic ^{1, 2}. The post-vaccine reduction in COVID-19-related hospitalization heralds the immense promise of these tools to reduce the impact of the COVID-19 pandemic among those at most significant risk, including cancer patients³.

Active cancer treatment predisposes to severe COVID-19 disease, and subdued vaccine immune responses are expected with certain cancer treatments. Among cancer therapies, immune checkpoint inhibitors (ICI) have a negligible effect on vaccine-elicited immune responses. For example, influenza vaccine studies demonstrate comparable immunogenicity in ICI-treated patients and healthy individuals and the overall safety of immunization⁴. Still, with higher rates of immediate post-vaccine adverse reactions with mRNA vaccines⁵, concerns have emerged about the risk for immune-related adverse events (IRAEs) following COVID-19 immunization. In addition, patients on active cancer treatment were excluded from key COVID-19 vaccine trials^{1, 2}. Therefore, establishing the safety and efficacy of mRNA vaccines in patients on ICI therapy by extended monitoring for post-vaccine IRAE is critical.

This study characterizes IRAE and COVID-19 incidence in patients who received an mRNA vaccine within 90 days of ICI treatment.

METHODS

Memorial Sloan Kettering Cancer Center (MSKCC) is a 574-bed tertiary care cancer center in New York City. The study institution began vaccinating patients with the two SARS CoV-2 mRNA vaccines on January 16, 2021 following a priority scheme developed by New York State. Electronic pharmacy records were used to identify all patients vaccinated with a first dose between January 16 and March 27, 2021 who received FDA-approved ipilimumab, pembrolizumab, or nivolumab within 90 days before or after first vaccination dose. Clinicopathologic parameters related to any grade new onset IRAE occurring after first vaccine dose and ICI initiation, as defined by the Common Terminology Criteria for Adverse Events, version 4.0, were collected along with data on vaccine manufacturer, age at vaccination, sex, tumor type, dates and type(s) of ICI administration, and death during the follow-up period

We determined the incidence of IRAE in patients who received immunotherapy within 90 days before or after the first dose of an mRNA SARS-CoV-2 vaccine, following patients for 90 days from day of vaccination. For patients who experienced an IRAE during the follow-up period, we summarized the frequency of each event type and grade. In bivariate analyses (chi-square test, Fisher’s exact test, Wilcoxon rank sum test) we compared patients who did versus did not experience an IRAE during the follow-up period with respect to age, sex, tumor type, previous IRAE, previous SARS-CoV-2 infection, vaccine type, immunotherapy type, proximity of immunotherapy administration to vaccine, initiation of new immunotherapy following vaccination, death during follow-up, and total days of follow-up observed. We also calculated the incidence rate of IRAE in patients who began a new immunotherapy agent following vaccination.

The MSKCC institutional review board granted a HIPAA waiver of authorization to conduct this study.

Results

Four hundred and eight patients received a first dose of SARS-CoV-2 mRNA vaccine within 90 days before or after treatment with an ICI agent. Patients ranged in age from 55 to 93 years (median=71) and the cohort was 53% male (n=217). Patients were in treatment for thoracic (n=122, 30%), genitourinary (n=84, 21%), upper gastrointestinal (n=50, 12%), melanoma (n=47, 12%), gynecologic (n=41, 10%), sarcoma (n=20, 5%), head and neck (n=19, 5%), lower gastrointestinal (n=13, 3%), glioblastoma (n=5, 1%), lymphoma (n=4, 1%), and breast (n=3, 1%) cancers. Within the 90 day windows before and after first vaccine dose, patients were treated with pembrolizumab only (n=264, 65%), nivolumab only (n=99, 24%), ipilimumab and nivolumab (n=41, 10%), ipilimumab (n=3, 0.7%), or all three agents (n=1, 0.3%). The majority of patients (95%, n=389) received the Pfizer-BioNTech vaccine.

Twenty-seven patients (7%) experienced a new IRAE during the follow-up period. Among patients with a history of IRAE prior to vaccination (n=54), 3 (6%) experienced an IRAE during the post-vaccination follow-up period. The majority of new IRAE were mild (n=21 Grade 1, 78%; Table 1). All four patients who experienced a severe (Grade 3) IRAE had gastrointestinal events (colitis or diarrhea). Table 2 compares characteristics of patients who did versus did not experience an IRAE. There were no significant differences in baseline characteristics or treatment between these groups, except that patients beginning a new immunotherapy agent during the follow-up period were more likely to experience an IRAE. Of 28 patients who received the first vaccine dose and ICI therapy on the same day, none developed an IRAE during the follow-up period. Among patients who began a new immunotherapy agent following vaccination (n=52), 17% developed an IRAE (n=9; incidence rate=2.7 per 1,000 patient days observed). The median follow-up after initiation of the new immunotherapy agent in these patients was 78.5 days (range: 33, 88). Figure 1 presents the swimmer’s plot describing the treatment history and trajectory of patients who experienced an IRAE during the follow-up period.

Table 1.

Type and grade of immune-related adverse events experienced by patients who received SARS-CoV-2 mRNA vaccine and immune checkpoint inhibitor therapy within 90 days

	Grade 1	Grade 2	Grade 3
Arthralgias	3	-	-
Arthritis plus rash	1	1	-
Colitis	-	-	1
Dermatitis	10	-	-
Diarrhea	2	-	3
Pneumonitis	2	1	-
Thyroiditis	1	-	-
Transaminitis	2	-	-
Total	21	2	4

Table 2.

Characteristics of patients who did and did not experience immune-related adverse events following receipt of SARS-CoV-2 mRNA vaccine and immune checkpoint inhibitor therapy within 90 days

	Patients who experienced IRAE	Patients who did not experience IRAE	p-value
N	27	381
Male sex	12 (44)	205 (54)	0.35
Age (median, interquartile range)	75 (66, 78)	71 (66, 78)	0.76
Tumor type			*
Breast	2 (7)	1 (1)
Gastrointestinal, lower	0	13 (3)
Gastrointestinal, upper	4 (15)	46 (12)
Genitourinary	6 (22)	78 (20)
Glioblastoma	0	5 (1)
Gynecologic	4 (15)	37 (10)
Head and neck	2 (7)	17 (4)
Lymphoma	1 (4)	3 (1)
Melanoma	3 (11)	44 (12)
Sarcoma	1 (4)	19 (5)
Thoracic	4 (15)	118 (31)
Previous infection with SARS CoV-2	0	11 (3)	0.99
Previous immune-related adverse event	3 (11)	51 (13)	0.99
Received Pfizer-BioNTech vaccine	27 (100)	362 (89)	0.24
Received nivolumab	11 (41)	130 (34)	0.48
Received pembrolizumab	16 (59)	249 (65)	0.52
Received ipilimumab	5 (19)	40 (10)	0.20
Died during follow-up	0	18 (5)	0.62
Receipt of vaccine first dose and immunotherapy within same week	8 (30)	189 (50)	0.04
Receipt of vaccine second dose and immunotherapy within same week (date imputed)	1 (4)	22 (6)	0.99
Started new immunotherapy agent during follow-up period	9 (33%)	43 (11%)	<0.001
Days observed (median, interquartile range)	90 (71, 90)	90 (90, 90)	0.01

Data are no. (%) unless otherwise indicated.

^*P-value not reported due to cell sizes <5.

Figure 1.

Swimmer’s plot depicting days from first dose of mRNA SARS-CoV-2 vaccine to immune-related adverse events (IRAE) among patients who received an immune checkpoint inhibitor within 90 days before or after vaccination and experienced an IRAE following receipt of immunotherapy and vaccine (N=27).

Two patients in our cohort developed COVID-19 infection following vaccination (through August, 31, 2021)

Discussion

The overall incidence of IRAE was 7 % in our cohort of 408 ICI-treated patients who received the COVID-19 vaccine. In 52 patients who began a first ICI therapy after vaccination, the incidence of IRAE (17%) is similar to published reports^{6, 7}. For example, a recent study of pembrolizumab as adjuvant therapy in 509 patients with resected stage III melanoma found an IRAE incidence of 19% within 3 months of treatment initiation⁶. The vast majority of the IRAE were mild. No differences were observed in the risk of IRAE in those with and without preexisting immune toxicities. Furthermore, there were 11 individuals with prior COVID-19 infection in our cohort, and severe immediate reactogenicity from the vaccine or IRAE was not observed in any of them.

ICI is a standard treatment option for many cancers. In contrast to conventional chemotherapy, vaccine responses are not significantly impaired in those treated with ICI. Studies with influenza vaccine report a high serological response rate among ICI recipients without an exaggerated risk of IRAE^{4, 7}. Similarly, emerging studies in mRNA vaccinated cancer patients show high antibody levels among ICI treated individuals that are comparable to healthy controls and superior to humoral responses in chemotherapy recipients^{8, 9}.

Despite proven efficacy in larger populations, there are substantial lingering concerns on the long-term safety of vaccines with ICI. Early experience from Israel in patients on ICI treatment found that 19% were vaccine reluctant due to toxicity concerns. This report examined the short-term safety of ICI with the vaccine in 134 patients and over a brief median follow-up period of 19 days after vaccination⁵. They did not observe higher immediate side-effects, risk of new IRAE, or exacerbation of preexisting IRAE. Similarly, in a study of 81 ICI-treated patients where vaccine and immunotherapy were administered within 30 days¹⁰, no patients experienced new adverse events. Our findings add a sizable number of newly treated patients and a longer follow-up period to capture IRAE. We note that any conclusions about comparative incidence must be interpreted with caution given biases implicit within cross trial comparisons. An important limitation of our study is the absence of a temporally aligned comparison group of patients at our center on ICI therapy who did not receive the Covid-19 vaccine. We further note that the sample size of our study is not appropriately powered to capture the risk of post-vaccine rare events such as Guillain-Barré syndrome and others.

In summary, our data do not show a higher risk of immune toxicity among ICI-treated patients who received the COVID-19 vaccine, including those newly started on therapy. The findings should encourage new and third dose vaccine uptake among ICI-treated cancer patients without interruption of cancer therapy.