Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic

During the COVID-19 pandemic, it was observed that patients with cancer who were undergoing treatment had an increased risk of contracting COVID-19, and a more severe course of infection, compared with individuals who did not have a history of cancer.¹ As this increased risk was not associated with more frequent exposure to health-care systems, it was thought to reflect a weakened immune system caused by the disease itself or anticancer treatment.²

Endocrine therapy, a highly effective and well-tolerated breast cancer therapy, is the mainstay of treatment for about two-thirds of patients with breast cancer. In the metastatic setting, the addition of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors has led to substantial improvements in progression-free survival and overall survival in first-line and pre-treated settings.3, 4 The side-effects of CDK4/6 inhibitors are generally manageable, but about 60% of patients might develop grade 3 or 4 neutropenia.⁵ However, because this neutropenia is a consequence of cell cycle arrest (rather than cell death as with cytotoxic chemotherapy), it is reversible by pausing therapy for a few days. This side-effect is usually not associated with febrile neutropenia or serious infections, in contrast to what is seen with chemotherapy-induced neutropenia.⁶

Early in the COVID-19 pandemic, a guidelines manuscript suggested caution regarding the use of potentially immunosuppressive cancer therapies, including CDK4/6 inhibitors.7, 8 These guidelines might have led to reduced usage of CDK4/6 inhibitors in patients with breast cancer, potentially negatively affecting disease progression and survival.

In 2021, Erica L Mayer and colleagues,⁹ reported an interim analysis in The Lancet Oncology of the ongoing, global, phase 3 PALLAS trial, with the updated preplanned final analysis published in December, 2021.¹⁰ Between Sept 1, 2015, and Nov 30, 2018, 5761 patients with early-stage breast cancer were randomly assigned (1:1) at 406 cancer centres in 21 countries to receive either 2 years of the CDK4/6 inhibitor palbociclib in addition to standard adjuvant endocrine therapy (n=2884) or adjuvant endocrine therapy alone (n=2877).¹⁰ 2841 patients received palbociclib plus endocrine therapy and 2901 patients received endocrine therapy only; 36 individuals were excluded. The safety analysis of the PALLAS trial showed no new signals of adverse events for palbociclib, with grade 3–4 neutropenia being the most prevalent (in 1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone).⁹ Grade 3–4 upper respiratory tract infections occurred in 32 [1·1%] patients receiving palbociclib plus endocrine therapy and in three (0·1%) patients receiving endocrine treatment alone; these infections occurred at a consistent rate over the course of the trial.⁹

Given the absence of data describing the safety of CDK4/6 inhibitors during the COVID-19 pandemic, the PALLAS leadership conducted a risk–benefit assessment in March, 2020, of the safety of continuing palbociclib during the COVID-19 pandemic. It was decided by the PALLAS trial chairs and executive committee that palbociclib would not need to be paused for patients without symptoms indicative of COVID-19, with individual risk factors always being considered. This guidance was communicated in March 18, 2020, to all PALLAS site investigators via an internal study memo. In May, 2020, unique COVID-19 case report forms were introduced to the PALLAS study teams to capture information on COVID-19 testing, rates of infection, and outcomes. The testing method for COVID-19 was according to local care providers and was not mandated by the study.

As of Dec 1, 2019, of the 5761 patients who were randomly assigned and included in the intention-to-treat population,¹⁰ 5125 (89·0%) remained on study (2552 [88·5%] of 2884 allocated to palbociclib plus endocrine therapy, of whom 847 [33·2%] were still receiving palbociclib, and 2573 [89·4%] of 2877 allocated to endocrine therapy alone). From Dec 1, 2019, to Nov 20, 2020, 721 (14·1%) of 5125 patients were tested for COVID-19 (test type not mandated, 362 [14·2%] of 2552 in the palbociclib group and 359 [14·0%] of 2573 in the endocrine therapy only group). Of the 721 tested individuals, 88 (12·2%) were positive for COVID-19, with no clinically meaningful difference in infection rate by study group (41 [11·3%] of 362 patients tested were positive in the palbociclib group vs 47 [13·1%] of 359 in the endocrine therapy only group). Of the 88 patients who tested positive for COVID-19, 57 (64·8%) reported symptomatic infections (28 [68·3%] in the palbociclib group and 29 [61·7%] in the endocrine therapy only group). No patient stopped endocrine therapy due to COVID-19-related reasons, whereas 27 (1·1%) of 2552 patients ended palbociclib therapy early due to an undefined COVID-19-related reason. One patient in the palbociclib plus endocrine therapy group and two patients in the endocrine therapy only group died due to COVID-19. Only four patients overall withdrew study consent for COVID-19-related reasons. As no COVID-19 vaccination programme was active during the data collection timeframe, the impact of vaccination on the rates of infection could not be addressed in this investigation, but could be considered in a future analysis. Additionally, rates of seroconversion after infection were not measured as part of this study; therefore, the impact of ongoing palbociclib or endocrine therapy on rates of seroconversion could not be determined.

In summary, in this updated analysis of the phase 3 PALLAS trial, reported rates of COVID-19 were low, with no differences in test positivity or symptomatic infection between patients receiving palbociclib plus endocrine therapy compared with those receiving endocrine therapy alone. These data provide reassurance about the safety of using palbociclib in breast cancer treatment during the COVID-19 pandemic.

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GP reports personal fees from Novartis, Roche, AstraZeneca, Eli Lilly, and Amgen; and grants and personal fees from Pfizer, outside the submitted Comment. AD reports grants from the Alliance Foundation for Clinical Trials, during the conduct of the study; personal fees from Pfizer and Context Therapeutics; grants from Novartis, Pfizer, Genentech, Calithera, and Johnson and Johnson, outside the submitted Comment; and that their spouse is on a data safety monitoring board for a Pfizer drug not for use in oncology. CF reports grants from Pfizer, during the conduct of the study. MG reports personal fees from Amgen, Daiichi Sankyo, AstraZeneca, Eli Lilly, LifeBrain, Nanostring, Novartis, and TLC Biopharmaceuticals, all outside the submitted Comment; and that an immediate family member is employed by Sandoz. ELM reports personal fees from Eisai, Eli Lilly, and Novartis, outside the submitted work. ACD declares no competing interests. We received support from Alliance Foundation Trials, Austrian Breast and Colorectal Cancer Study Group, and the Breast International Group. The trial (including these analyses) was funded by Pfizer, who provided the study drug and financial support.