The Oncologist, 2023, 28, 969–977

https://doi.org/10.1093/oncolo/oyad182
Advance access publication 26 June 2023
Original Article

Pembrolizumab Every 6 Weeks Versus Every 3 Weeks in

Advanced Non-Small Cell Lung Cancer
Maude Dubé-Pelletier*, Catherine Labbé, Jimmy Côté, Audrey-Ann Pelletier-St-Pierre
Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada
*
Corresponding author: Maude Dubé-Pelletier, MD. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, 2725 Chemin Sainte-
Foy, Québec, Canada G1V 4G5. Tel: +1 418 656 8711; Fax: +1 418 656 4762; Email: maude.dube-pelletier.1@ulaval.ca

Abstract
Background: The survival benefits and adverse effects of pembrolizumab 2 mg/kg intravenously (IV) every 3 weeks (Q3W) in advanced non-
small lung cancer (NSCLC) are well documented in the literature. Based on pharmacokinetic models, a pembrolizumab 4 mg/kg IV every 6 weeks
(Q6W) dosing regimen is also approved in some countries. To date, there is no direct comparison in the literature between these 2 regimens in
advanced NSCLC.
Methods: This retrospective study included 80 patients with advanced NSCLC who received pembrolizumab monotherapy 4 mg/kg Q6W
between March 1, 2020 and December 31, 2021 and 80 patients with advanced NSCLC who received pembrolizumab monotherapy 2 mg/
kg Q3W between January 1, 2017 and January 15, 2019 at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). The
primary outcomes of this study were to compare overall survival (OS), progression-free survival (PFS) as well as the occurrence and severity of
immune-mediated adverse events (AEs) in patients with advanced NSCLC who received pembrolizumab Q6W vs Q3W. Data cutoff date was
December 15, 2022.
Results: Median follow-up was 14.5 ± 8.6 months in the Q6W group and 18.3 ± 19.6 months in the Q3W group. Median PFS was 6.9 months
(CI 95% 5.0-10.7) in the Q6W group vs 8.9 months (CI 95% 5.6-14.1) in the Q3W group (adjusted HR 1.27 (CI 95% 0.85-1.89), P = .25). Median
OS was not reached in the Q6W group vs 20.5 months (CI 95% 13.7-29.8) in the Q3W group (adjusted HR 0.80 (CI 95% 0.50-1.29), P = .36).
Immune-mediated AEs of grade ≥ 3 occurred in 18% of patients in the Q6W group and in 19% of those in the Q3W group.
Conclusions: In this unicentric retrospective study, the pembrolizumab Q6W dosing regimen was comparable to the Q3W in terms of OS,
PFS, and toxicity.
Key words: advanced non-small cell lung cancer; pembrolizumab 4 mg/kg every 6 weeks; pembrolizumab 2 mg/kg every 3 weeks.

Implications for Practice

By demonstrating that the pembrolizumab every 6 weeks is as safe, in terms of efficacy and toxicity, as the 3-weekly dosing regimen, this
finding could significantly improve the quality of life of patients with advanced non-small cell lung cancer and reduce health system costs.

Introduction 200 mg) intravenously (IV) every 3 weeks (Q3W).2 However,

Immunotherapy is now well integrated in the treatment algo- in New Zealand and some European countries, the admin-
rithm for patients with advanced non-small cell lung cancer istration of pembrolizumab every 6 weeks (Q6W) at 4 mg/
(NSCLC). The anti-programmed cell death protein 1 (PD-1) kg (maximum 400 mg) is also authorized.3,4 This approval is
antibody pembrolizumab monotherapy is used for first-line based on pharmacokinetic models which have demonstrated
treatment of advanced NSCLC in patients with a tumor pro- that several dosages and administration schedules lead to sim-
portion score (TPS) for programmed death ligand 1 (PD-L1) ilar exposures. This supports the idea that the dose-response
of 50% or greater. This treatment is also indicated in first line relationship with immunotherapy is not as direct as with
in combination with chemotherapy for 4 cycles, regardless of chemotherapy.5 The survival benefits and adverse effects of
PD-L1 status. Thereafter, pembrolizumab is continued for main- this treatment at 2 mg/kg IV Q3W are well documented in
tenance alone or in combination with chemotherapy, depending the literature.6-9 In the 5-year analysis of KEYNOTE-024, a
on histology. This immune checkpoint inhibitor is also approved trial of pembrolizumab monotherapy for metastatic NSCLC
as second-line therapy for patients with PD-L1 TPS ≥ 1%, an with PD-L1 TPS ≥ 50%, median overall survival (OS) was
indication which is less used now that all patients have access to 26.3 months and median progression-free survival (PFS)
first-line immunotherapy as monotherapy or in combination.1 was 7.7 months. Immune-mediated adverse events (AEs)
Regardless of the indication in NSCLC, the recommended occurred in 34% of patients, including grade ≥ 3 toxicity
dosage of pembrolizumab in Canada is 2 mg/kg (maximum in 14% of patients.6 Median OS of patients who received

Received: 7 March 2023; Accepted: 1 June 2023.

© The Author(s) 2023. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
970 The Oncologist, 2023, Vol. 28, No. 11

pembrolizumab in combination with chemotherapy was 22.0 used to determine PD-L1 TPS. Information about treatment
months in metastatic nonsquamous NSCLC in the updated and outcomes were collected: line of therapy, treatment start
analysis of KEYNOTE-189 and 17.1 months in metastatic date, number of cycles received, treatment end date, date of
squamous NSCLC in the final analysis of KEYNOTE-407. disease progression, subsequent lines of therapy, and date of
Median PFS was, respectively, 9.0 and 8.0 months. Immune- last follow-up or death. Immune-related AEs were recorded
mediated AEs were reported in 26% of patients (11% of until December 15, 2022 for both groups. AEs were graded
grade ≥ 3 events) in KEYNOTE-189 and in 35% of patients using the Common Terminology Criteria for Adverse Events
(13% of grade ≥ 3 events) in KEYNOTE-407.7,8 (CTCAE) version 5.0. If AEs were not graded in real-time, we
At our center, in the context the COVID-19 pandemic, the determined it according to the clinical evaluation described in
protocol for the administration of pembrolizumab monother- the file, biological results or treatment required. Consideration
apy has been revised to a dose of 4 mg/kg IV Q6W in order to was given to the number of cycles of pembrolizumab at the
reduce visits to the oncology clinic. We conducted this mono- time of AEs, the management of immune toxicities and their
centric retrospective study to assess the toxicity and efficacy impact on pembrolizumab treatment (continuation, interrup-
of a 6 weekly dosing by comparing with data from a cohort tion or discontinuation).
of patients previously treated with a 3 weekly regimen also at The primary outcomes of this study were to compare
our center. Data from KEYNOTE-555 cohort B suggest con- OS, PFS as well as the occurrence and severity of immune-
sistent benefit-risk profile and similar overall response rate mediated AEs in patients with advanced NSCLC who received
(ORR), PFS, and AEs in a pembrolizumab 400 mg Q6W dos- pembrolizumab Q6W vs Q3W. A secondary outcome was to
ing regimen compared to a 200 mg Q3W dosing in advanced determine the impact of toxicities on continuation of immu-
melanoma.10 A recent retrospective study showed that there notherapy in each group.
was no OS difference in patients with stage IV NSCLC and
PD-L1 TPS ≥ 50% who were treated with first-line pembroli- Statistical Analysis
zumab and dosed at Q3W or Q6W intervals, based on a 2:1 Patient demographics and clinical characteristics were sum-
case-matched analysis. The median OS for Q6W dosing was marized using descriptive methods. For OS and PFS analyses,
17.1 months compared to 15.1 months for Q3W dosing, the Nelson-Aalen estimates of the cumulative hazards were
with an HR 0.83 (95% CI 0.49-1.42, P = .50).11 However, calculated. To compare patients who received pembroli-
there were only 41 patients in the Q6W cohort and the safety zumab Q6W vs Q3W, the Cox proportional hazard regres-
profile of these 2 regimens was not assessed. A study of 45 sion analysis was performed to model death-free or event-free
patients with advanced NSCLC, in whom the pembrolizumab follow-up. The adequacy of proportional hazards assumption
dosage was switched from 200 mg Q3W to 400 mg Q6W, was checked using a graphical representation of logarithm
raised concern about new or worsening immune-related AEs, cumulative hazard rates versus time. A multivariate Cox pro-
especially pneumonitis in 11 (24%) patients.12 To our knowl- portional hazard model was used to compare patients who
edge, there is no direct comparison in the literature between received pembrolizumab Q6W vs Q3W adjusted for age, gen-
these 2 regimens for toxicity and efficacy in NSCLC. der, stage, PD-L1 TPS, ECOG PS, and histology. All parame-
ters were investigated first using univariate regression models.
An artificially time-dependent covariate was added to the
Materials and Methods
model to test the proportionality assumption with covariates.
Study Design For all variables, the proportional hazards assumptions were
This retrospective study included all patients with advanced not rejected as local tests linked to the time-dependent covari-
NSCLC who received pembrolizumab monotherapy 4 mg/kg ates were not significant. Statistical significance was present
IV Q6W between March 1, 2020 and December 31, 2021 with a 2-tailed P–value < .05. Analyses were performed using
at Institut universitaire de cardiologie et de pneumologie de SAS version 9.4 (SAS Institute Inc., Cary, NC).
Québec (IUCPQ). In the pembrolizumab Q6W group, patients
who previously received pembrolizumab Q3W as monother-
apy or in combination with chemotherapy were excluded. In
Results
order to have a comparative group with an equivalent number Patients
of patients, all patients with advanced NSCLC who received One hundred and twenty-five patients with advanced NSCLC
pembrolizumab monotherapy 2 mg/kg IV Q3W between received pembrolizumab 4 mg/kg IV Q6W between March
January 1, 2017 and January 15, 2019 at our institution were 1, 2020 and December 31, 2021. Forty-five patients were
included in the Q3W group. Patients were identified from the excluded, of which 37 patients who previously received pem-
Oncology Database (SICTO). brolizumab Q3W and 2 patients who switched to pembroli-
zumab Q3W. Four patients had incomplete follow-up, one
Data Collection patient had synchronous tumors with different PD-L1 TPS
Data were collected until December 15, 2022. Demographic and the other was initially misdiagnosed because he had con-
data collected for this study included age, gender, weight, current tonsil cancer which was later found. Eighty patients
smoking status, and Eastern Cooperative Oncology Group were therefore included in the pembrolizumab Q6W group.
performance status (ECOG PS). The medical charts were also Of those, 70 patients had stage IV NSCLC and 10 patients
reviewed for histopathological diagnosis, date of diagnosis, had locally advanced NSCLC but were not candidate for sur-
sites of metastases, EGFR, ALK, BRAF, ROS1, and PD-L1 gical resection or definitive chemoradiation. Between January
status. We reported these molecular alterations since they 1, 2017 and January 15, 2019, 83 patients were treated with
were specifically tested at our institution at this time as we pembrolizumab 2 mg/kg IV Q3W. Immunotherapy was dis-
were not routinely performing next-generation sequencing continued after one cycle because an ROS1 mutation was
yet. PD-L1 immunohistochemistry (IHC) 22C3 pharmDx was discovered allowing targeted therapy in one patient, who was
The Oncologist, 2023, Vol. 28, No. 11 971

excluded. Two patients had incomplete follow-up. Finally, the that a 4 mg/kg Q6W dose corresponded to 2 cycles for calcu-
pembrolizumab Q3W group was composed of 80 patients, lation. Between March 1, 2020 and December 15, 2022, 55
including 73 patients with stage IV NSCLC and 7 patients (69%) patients had disease progression, among which 33/55
with locally advanced NSCLC not eligible for curative treat- (60%) received subsequent lines of treatment, and 36 (45%)
ment. The data cutoff date was December 15, 2022 (Fig. 1). patients died. The subsequent therapeutic strategy was che-
Median follow-up was 14.5 ± 8.6 months in the pembroli- motherapy in 32 (58%) patients, immunotherapy rechallenge
zumab Q6W group and 18.3 ± 19.6 months in the pembroli- in 1 (2%) patient and targeted therapy in 4 (7%) patients.
zumab Q3W group. Five (9%) patients received local treatment by surgery or ste-
Baseline characteristics of all patients are summarized in reotactic body radiation therapy (SBRT) in the context of oli-
Table 1. Most patients in both groups were female, former goprogression. At data cutoff, 5 (6%) patients had completed
or current smokers, had adenocarcinoma and were ECOG PS 2 years of treatment and 8 (10%) patients were still treated
0-1. Patients in the pembrolizumab Q6W group were slightly with this regimen.
older (70.0 vs 66.0 years). There was one patient with an In the pembrolizumab Q3W group, the median number
EGFR mutation in the Q3W group, while no patient carried of cycles received was 6. Six (8%) patients had completed 2
a BRAF V600E mutation nor an ALK or ROS1 rearrange- years of treatment. Between January 1, 2017 and December
ment. BRAF V600E mutation and ROS1 rearrangements 15, 2022, there were 65 (81%) disease progression, among
were often unknown because they were not tested systemat- which 35/65 (54%) received subsequent lines of treatment,
ically especially in the cohort of patients who received pem- and 69 (86%) deaths. The subsequent therapeutic strategy
brolizumab between January 1, 2017 and January 15, 2019. was chemotherapy in 33 (51%) patients and immunotherapy
Pembrolizumab was prescribed mainly as first-line mono- rechallenge in 2 (3%) patients. Four (6%) patients received
therapy in patients with PD-L1 TPS ≥ 50%, which represents local treatment by surgery or SBRT in the context of oligo-
100% of patients in the pembrolizumab Q6W group and progression (Table 2).
91% of those in the pembrolizumab Q3W group. Bone, lung Median PFS was 6.9 months (CI 95% 5.0-10.7) in the pem-
and pleura were the most common sites of metastases. brolizumab Q6W group vs 8.9 months (CI 95% 5.6-14.1) in
the pembrolizumab Q3W group (Fig. 2, adjusted HR 1.27 (CI
95% 0.85-1.89), P = .25). Median OS was not reached in the
Efficacy pembrolizumab Q6W group vs 20.5 months (CI 95% 13.7-
Patients treated with the Q6W dosing regimen received a 29.8) in the Q3W group (Fig. 3, adjusted HR 0.80 (CI 95%
median number of 8 cycles of pembrolizumab. We considered 0.50-1.29), P = .36).

Figure 1. CONSORT diagram. NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1. *Patient can be in more than one category.
**Data cutoff = December 15, 2022.
972 The Oncologist, 2023, Vol. 28, No. 11

Table 1. Patient characteristics.

Pembrolizumab Q6W Pembrolizumab Q3W P-value

N = 80 N = 80

Median age, years ± SD 70.0 ± 7.7 66.0 ± 7.9 .0008

Male sex 35 (44%) 32 (40%) .7487
Median weight, kg ± SD 65.8 ± 15.3 71.4 ± 14.5 .1637
Former or current smoker 79 (99%) 76 (95%) .3671
ECOG PS
 0-1 61 (76%) 62 (77%) .6838
 2 15 (19%) 12 (15%)
 3 0 2 (3%)
 Not reported 4 (5%) 4 (5%)
Histology
 Adenocarcinoma 61 (76%) 61 (76%) .6887
 Squamous carcinoma 12 (15%) 10 (12%)
 Adenosquamous carcinoma 1 (1%) 2 (3%)
 NSCLC NOS 6 (8%) 4 (5%)
 Large cell carcinoma 0 1 (1%)
 Sarcomatoid/pleomorphic carcinoma 0 2 (3%)
EGFR mutation
 Positive 0 1 (1%) .6530
 Negative 67 (84%) 69 (87%)
 Not tested (squamous carcinoma) 12 (15%) 10 (12%)
 Unknown 1 (1%) 0
ALK rearrangement
 Positive 0 0 .6530
 Negative 67 (84%) 70 (88%)
 Not tested (squamous carcinoma) 12 (15%) 10 (12%)
 Unknown 1 (1%) 0
BRAF V600E mutation
 Positive 0 0 <.0001
 Negative 52 (65%) 7 (9%)
 Not tested (squamous carcinoma) 12 (15%) 10 (12%)
 Unknown 16 (20%) 63 (79%)
ROS1 rearrangement
 Positive 0 0 <.0001
 Negative 66 (82%) 7 (9%)
 Not tested (squamous carcinoma) 12 (15%) 10 (12%)
 Unknown 2 (3%) 63 (79%)
PD-L1 status
 <1% 0 0 .0136
 1-49% 0 7 (9%)
 ≥50% 80 (100%) 73 (91%)
Sites of metastases at diagnosis
 CNS 12 (15%) 15 (19%) .6735
 Lung 24 (30%) 29 (36%) .5019
 Pleura 23 (29%) 24 (30%) 1.0000
 Liver 8 (10%) 10 (12%) .8032
 Bone 21 (26%) 26 (33%) .4877
 Adrenal 13 (16%) 13 (16%) 1.0000
 Pericardium 2 (3%) 3 (4%) 1.0000
 Other site* 10 (12%) 23 (29%) .0182

*
The other sites were predominantly intra-abdominal and soft-tissue metastases and extra-thoracic lymphadenopathy.
Abbreviations: ALK: anaplastic lymphoma kinase; CNS: central nervous system; ECOG PS: Eastern Cooperative Oncology Group performance status;
EGFR: epidermal growth factor receptor; NOS: not otherwise specified; NSCLC: non-small cell lung cancer; PD-L1: programmed death-ligand 1; Q3W:
every 3 weeks; Q6W: every 6 weeks; SD: standard deviation.
The Oncologist, 2023, Vol. 28, No. 11 973

Table 2. Treatment and outcomes.

Pembrolizumab Q6W Pembrolizumab Q3W

N = 80 N = 80

Median dosage of pembrolizumab, mg ± SD 263.2 ± 61.2 142.8 ± 29.0

Median number of pembrolizumab cycles† 8 6
Median follow-up, months ± SD 14.5 ± 8.6 18.3 ± 19.6
Median time to onset of adverse effects, months ± SD 4.1 ± 4.2 4.2 ± 6.0
Immune-mediated adverse events requiring to hold pembrolizumab, n (%) 8 (10%) 7 (9%)
Immune-mediated adverse events leading to discontinuation of pembrolizumab, n (%) 13 (16%) 15 (19%)
Disease progression, n (%) 55 (69%) 65 (81%)
Completed treatment, n (%) 5 (6%) 6 (8%)
Subsequent lines of treatment in patients with disease progression, n (%)
 0 22/55 (40%) 30/65 (46%)
 1 19/55 (34%) 19/65 (29%)
 2 7/55 (13%) 12/65 (19%)
 3 7/55 (13%) 4/65 (6%)
Death, n (%) 36 (45%) 69 (86%)
Ongoing treatment with pembrolizumab at data cutoff, n (%) *
8 (10%) 0

Dose of 4 mg/kg = 2 cycles.

†

Data cutoff = December 15, 2022.

*

Abbreviations: NSCLC: non-small cell lung cancer; Q3W: every 3 weeks; Q6W: every 6 weeks; SD: standard deviation.

Safety Regarding patient characteristics, the study sample in

Median time to onset of AEs was 4.1 ± 4.2 and 4.2 ± 6.0 each group still represents the usual population of patients
months in the Q6W group and the Q3W grouprespectively. with advanced NSCLC. The patients were slightly older, all
Immune-mediated AEs requiring to hold immunother- tumors had PD-L1 status ≥ 50% and there were less com-
apy occurred in 8 (10%) patients with the Q6W regimen monly metastases in other site in the pembrolizumab Q6W
and in 7 (9%) patients with the Q3W regimen. There were group compared to the Q3W group, but there were no other
slightly more immune-mediated AEs leading to discontin- statistically significant differences between the 2 groups.
uation of pembrolizumab in the Q3W dosing regimen, 15 Most patients were former or current smokers, had adeno-
(19%) patients, compared to 13 (16%) patients in Q6W carcinoma and plurimetastatic disease. The 2 cohorts had a
group (Table 2). Immune-mediated AEs occurred in 76% of lower proportion of males compared to that usually observed,
patients, including grade ≥ 3 toxicity in 18% of patients in 44% and 40% of patients in each group respectively. We do
the Q6W group. In the Q3W group, immune-mediated AEs not believe this influenced our results since we used Cox mul-
were reported in 74% of patients (19% of grade ≥ 3 events). tivariable regression model adjusting for age, gender, stage,
Immunosuppressive therapy was required for 26 AEs in the PD-L1 TPS, ECOG PS, and histology.
Q6W group compared to 23 AEs in the Q3W group. The There was no statistically significant difference for PFS and
only fatal event was myocarditis, which happened with the OS between the 2 groups. The shorter follow-up in the Q6W
Q3W dosing regimen. There were less pneumonitis with the regimen limits the interpretation of the long-term tendency.
Q6W regimen, 6 (8%) patients in the Q6W group vs 9 (11%) Median OS was not reached in the Q6W group and was 20.5
patients in the Q3W group. Serious pneumonitis (grade ≥ 3) months (CI 95% 13.7-29.8) in the Q3W group, which is con-
occurred equally in the 2 groups, in 4 (5%) vs 3 (4%) patients sistent with studies of first-line pembrolizumab in advanced
in the Q6W group and the Q3W group respectively (Table 3). NSCLC. Median PFS of 6.9 and 8.9 months, respectively, in
the Q6W group and the Q3W group were also comparable to
data in the literature.
Immune-mediated AEs of grade ≥ 3 were comparable in
Discussion both groups, 18% of patients in the Q6W group vs 19% of
This single-center retrospective study evaluated the pembroli- those in the Q3W group, which is consistent with the toxicities
zumab alternative dosing regimen of 4 mg/kg Q6W compared data available in the literature. However, our results differ from
to a 2 mg/kg Q3W dosing in advanced NSCLC. To decrease immune-mediated AEs of any grade described in the studies,
the risk of exposure of patients to COVID-19 by reducing vis- mainly related to skin reactions. In our study, all rashes of any
its to oncology clinic, this study was appropriate in this par- grade were considered immune toxicity until proven otherwise.
ticular context. Furthermore, the Q6W dosing regimen offers In KEYNOTE-024, KEYNOTE-189, and KEYNOTE-407 tri-
quality of life benefits for patients with uncurable lung can- als, only severe skin reactions were considered immune-related
cer and decreases health costs to society. The question of the AEs and they were comparable in terms of frequency to grade
study therefore remains relevant even without the pandemic ≥ 3 skin toxicities that occurred in our 2 cohorts of patients.6-8
situation and the study design seems adequate to determine The incidence of pneumonitis of any grade and grade ≥ 3 is sim-
safety and efficacy of the pembrolizumab Q6W regimen. ilar in the 2 groups of our study and consistent with the data
974 The Oncologist, 2023, Vol. 28, No. 11

Figure 2. Adjusted progression-free survival of patients who received pembrolizumab Q6W versus patients who received pembrolizumab Q3W. Q3W =
every 3 weeks; Q6W = every 6 weeks. *Pembrolizumab Q3W = reference group for HR calculation.

Figure 3. Adjusted overall survival of patients who received pembrolizumab Q6W versus patients who received pembrolizumab Q3W. Q3W = every 3
weeks; Q6W = every 6 weeks. *Pembrolizumab Q3W = reference group for HR calculation.

from KEYNOTE-024 where 8.4% of patients had pneumoni- (less frequent in the Q6W group). This might be explained by
tis of any grade and 3.2% of patients had grade ≥ 3 pneumo- better understanding and management of immune toxicities
nitis.6 Between the 2 groups, there were slight differences with acquired through the experience of clinicians with immuno-
regard to immune-mediated AEs requiring to hold (more fre- therapy in the most contemporary group, namely the patients
quent in the Q6W group) and to discontinue immunotherapy who received pembrolizumab Q6W.
Table 3. Immune-mediated adverse events.

Pembrolizumab Q6W Pembrolizumab Q3W

N = 80 N = 80

Any grade Grades 1-2 Grade 3 Grade 4 Grade 5 Grades 3-5 Any grade Grades 1-2 Grade 3 Grade 4 Grade 5 Grades 3-5

Any immune-mediated adverse event 61 (76%) 47 (59%) 13 (16%) 1 (1%) 0 14 (18%) 59 (74%) 44 (55%) 14 (18%) 0 1 (1%) 15 (19%)
Skin toxicity
 Rash 13 (16%) 11 (14%) 2 (3%) 0 0 2 (3%) 15 (19%) 10 (13%) 5 (6%) 0 0 5 (6%)
Endocrinopathies
 Hypothyroidism 11 (14%) 11 (14%) 0 0 0 0 7 (9%) 7 (9%) 0 0 0 0
 Hyperthyroidism 1 (1%) 1 (1%) 0 0 0 0 1 (1%) 1 (1%) 0 0 0 0
The Oncologist, 2023, Vol. 28, No. 11

Adrenal insufficiency 3 (4%) 3 (4%) 0 0 0 0 2 (3%) 2 (3%) 0 0 0 0

 Diabetes 1 (1%) 0 1 (1%) 0 0 1 (1%) 1 (1%) 0 1 (1%) 0 0 1 (1%)
Gastrointestinal toxicity
 Colitis 7 (9%) 5 (6%) 2 (3%) 0 0 2 (3%) 6 (8%) 5 (6%) 1 (1%) 0 0 1 (1%)
 Oral mucositis 1 (1%) 1 (1%) 0 0 0 0 0 0 0 0 0 0
 Pancreatitis 0 0 0 0 0 0 1 (1%) 0 1 (1%) 0 0 1 (1%)
Hepatotoxicity
 Hepatitis 2 (3%) 0 2 (3%) 0 0 2 (3%) 6 (8%) 5 (6%) 1 (1%) 0 0 1 (1%)
Pulmonary toxicity
 Pneumonitis 6 (8%) 2 (3%) 4 (5%) 0 0 4 (5%) 9 (11%) 6 (8%) 3 (4%) 0 0 3 (4%)
Rheumatological toxicity
 Arthritis 10 (13%) 8 (10%) 2 (3%) 0 0 2 (3%) 8 (10%) 6 (8%) 2 (3%) 0 0 2 (3%)
Nephrotoxicity
 Nephritis 3 (4%) 2 (3%) 0 1 (1%) 0 1 (1%) 1 (1%) 1 (1%) 0 0 0 0
Neurological toxicity
 Neuropathy 1 (1%) 1 (1%) 0 0 0 0 1 (1%) 1 (1%) 0 0 0 0
Other toxicity
 Conjunctivitis 1 (1%) 1 (1%) 0 0 0 0 0 0 0 0 0 0
 Xerostomia 1 (1%) 1 (1%) 0 0 0 0 0 0 0 0 0 0
 Myocarditis 0 0 0 0 0 0 1 (1%) 0 0 0 1 (1%) 1 (1%)

Abbreviations: NSCLC = non-small cell lung cancer; Q3W = every 3 weeks; Q6W = every 6 weeks.
975
976 The Oncologist, 2023, Vol. 28, No. 11

Limitations Myers Squibb, Jazz Pharmaceuticals, LEO Pharma, Lilly,

Our results are limited by the retrospective nature of the Merck, Novartis, Pfizer, Roche, and Sanofi Genzyme. The
study, by a small sample and by the fact that the study is uni- other authors indicated no financial relationships.
centric. The 2 cohorts were not simultaneous and this could
interfere with the management and impact of AEs on contin-
Author Contributions
uation of immunotherapy in each group as clinicians have
gained experience with pembrolizumab over the years. Also, Conception/design: all authors. Provision of study material
our analysis would have been more robust if the follow-up of or patients: all authors. Collection and/or assembly of data:
the pembrolizumab Q6W had been longer. We are still con- M.D.-P., C.L. Data analysis and interpretation: M.D.-P., C.L.
vinced that the 2 treatment regimens are comparable in terms Manuscript writing: M.D.-P., C.L. Final approval of manu-
of OS, PFS and toxicity. script: all authors.

Conclusion Data Availability

In this retrospective study evaluating toxicity and efficacy The data presented in this study are available on request from
of pembrolizumab every 6 weeks compared to a standard the corresponding author.
3 weekly regimen, 80 patients with advanced NSCLC were
included for analysis in each group. Median follow-up was
14.5 months in the Q6W group vs 18.3 months in the Q3W Institutional Review Board Statement
group. Median PFS was 6.9 months (CI 95% 5.0-10.7) in The study was conducted according to the guidelines of the
the pembrolizumab Q6W group vs 8.9 months (CI 95% Declaration of Helsinki, and approved by the Institutional
5.6-14.1) in the pembrolizumab Q3W group (adjusted HR Review Board (or Ethics Committee) of Institut Universitaire
1.27 (CI 95% 0.85-1.89), P = .25). Median OS was not de Cardiologie et de Pneumologie de Québec (protocol code
reached in the pembrolizumab Q6W group vs 20.5 months 2021-3593, 22029, on 2 March 2021).
(CI 95% 13.7-29.8) in the Q3W group (adjusted HR 0.80
(CI 95% 0.50-1.29), P = 36). The differences obtained are
not statistically significant, which supports the argument Informed Consent Statement
that the 2 treatment regimens are comparable. The out- Patient consent was waived due to the fact that it was a retro-
comes with the Q6W regimen were also comparable to data spective chart review with no impact on patients.
in the literature with the Q3W regimen. The occurrence and
severity of immune-mediated AEs were comparable, with
18% of grade ≥ 3 events in the Q6W group vs 19% in the References
Q3W group. 1. Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV
In summary, a dosing regimen of 4 mg/kg every 6 weeks non-small-cell lung cancer without driver alterations: ASCO and
demonstrated a risk-benefit profile which justifies the appli- OH (CCO) joint guideline update. J Clin Oncol. 2020;38(14):1608-
cation and continuation of this dosing regimen for pembroli- 1632. https://doi.org/10.1200/JCO.19.03022.
2. Merck Canada Inc. Product monograph: Keytruda (pembrolizum-
zumab monotherapy in advanced NSCLC. Based on available
ab). 2020150 pp.
pharmacokinetic data, we believe that this also applies for 3. European Medicines Agency. Annex 1: summary of product char-
countries using fixed dosing rather than weight-based dos- acteristics. 2019:166 pp.
ing. This represents a very interesting treatment alternative 4. Medsafe. New Zealand Medecines and Medical Devices Safety
for patients with palliative therapy and a considerable finan- Authority. New Zealand Datasheet: Keytruda (pembrolizumab).
cial benefit to society in decreasing patient visits. Large mul- 2020:63 pp.
ticenter studies with long-term follow-up analysis are needed 5. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for
to support our findings. pembrolizumab in patients with cancer based on evaluation using
modelling and simulation. Eur J Cancer. 2020;131(3062):68-75.
https://doi.org/10.1016/j.ejca.2020.02.016.
Acknowledgments 6. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year out-
comes with pembrolizumab versus chemotherapy for metastatic
The authors acknowledge Serge Simard, MSc stats, from the non-small-cell lung cancer with PD-L1 tumor proportion score ≥
Centre de recherche de l’Institut universitaire de cardiologie 50. J Clin Oncol. 2021;39(21):2339-2349. https://doi.org/10.1200/
et de pneumologie de Québec, Université Laval, Québec, for JCO.21.00174.
statistical analyses. 7. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis
from KEYNOTE-189: pembrolizumab or placebo plus peme-
trexed and platinum for previously untreated metastatic non-
Funding squamous non-small-cell lung cancer. J Clin Oncol. 2020 May
10;38(14):1505-1517. https://doi.org/10.1200/JCO.19.03136.
This research received no external funding.
8. Paz-Ares L, Vicente D, Tafreshi A, et al. A randomized, placebo-
controlled trial of pembrolizumab plus chemotherapy in patients
Conflict of Interest with metastatic squamous NSCLC: protocol-specified final anal-
ysis of KEYNOTE-407. J Thorac Oncol. 2020;15(10):1657-1669.
Catherine Labbé has received honoraria from Amgen,
https://doi.org/10.1016/j.jtho.2020.06.015.
AstraZeneca, Brystol-Myers Squibb, Merck, Pfizer, and 9. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus che-
Roche. She has also received payment for expert testimony motherapy for previously untreated, PD-L1-expressing, locally
from Jazz Pharmaceuticals, Pfizer, and Roche. She has also advanced or metastatic non-small-cell lung cancer (KEYNOTE-
been on advisory boards for Amgen, Astra Zeneca, Brystol- 042): a randomised, open-label, controlled, phase 3 trial. Lancet.
The Oncologist, 2023, Vol. 28, No. 11 977

2019;393(10183):1819-1830. https://doi.org/10.1016/S0140- ≥ 50%: 3 weekly compared to 6 weekly dosing. Curr Oncol.

6736(18)32409-7. 2022;29(11):8686-8692. https://doi.org/10.3390/curron-
10. Jacobs C, Rapoport B, Chan SW, et al. KEYNOTE-555 Cohort B: col29110685.
efficacy, safety, and PK of pembrolizumab (pembro) 400 mg every 6 12. Higashiyama RI, Yoshida T, Yagishita S, et al. Safety implications
weeks (Q6W) as 1L therapy for advanced melanoma. J Clin Oncol. of switching pembrolizumab dosage from 200 mg every 3 weeks
2021;39(15_suppl):9541-9541. to 400 mg every 6 weeks in patients with advanced NSCLC. J
11. Jones L, Rittberg R, Leung B, et al. Alternate pembroli- Thorac Oncol. 2022;17(10):1227-1232. https://doi.org/10.1016/j.
zumab dosing interval in advanced NSCLC with PD-L1 TPS jtho.2022.06.010.