CDK4/6 inhibitors in metastatic breast cancer,a comparison of toxicity and efficacy across agents in a real-world dataset

Abstract

Introduction

CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy.

Methods

A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy.

Results

Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32–95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23–32.5), ribociclib 29 months (95% CI 21.5–37.0) and abemaciclib 20.6 months (95% CI 15.0–26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5–42.5), ribociclib 33.9 months (95% CI 26.7–41.1) and abemaciclib 27.3 months (95% CI 22.5–32.1).

Conclusions

Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible.

Keywords

Metastatic breast cancer CDK4/6 inhibitor toxicity

Introduction

Cyclin and cyclin-dependent kinases (CDK) regulate transition of the cell cycle through its phases. CDKs 1–4 and CDKs 6–7 regulate transition and division and CDKs 7–11 mediate cell cycle gene transcription. Oestrogens promote cell cycle transition in oestrogen positive breast cancer cells and mediate cyclin D1 via oestrogen receptor directed transcription. The potential synergy between CDK4/6 inhibitors and oestrogen blockade has been clinically exploited in the treatment of breast cancer.

CDK 4/6 inhibitors have been utilized as a standard of care therapy for metastatic breast cancer since their approval in 2017. The licensed agents comprise palbociclib, ribociclib and abemaciclib. All three agents demonstrated improvement in progression-free survival (PFS) in oestrogen positive, her-2 negative metastatic breast cancer when combined with endocrine therapy, versus endocrine therapy alone in first- and second-line settings across a number of phase II- III trial series of PALOMA,^1–3 MONALEESA^4–6 and MONARCH^7–9, respectively. Overall survival (OS) was not a primary endpoint of these trials and ribociclib is the only agent to date to have demonstrated statistically superior OS to endocrine therapy alone in the first line setting.^10,11 None of these agents have been directly compared in any setting and all remain acceptable first line therapy options in metastatic disease. Additional consideration as to the choice of agent to use in which patient may be based on the pharmacology, the different toxicity profiles of each agent,¹² the clinical efficacy data from individual trials and pooled trial data analyses on sites of metastases and response or survival benefit.^13,14

Palbociclib is given at a dose of 125 mg once daily for 21 days followed by 7 days off. The drug has a half-life of 29 h (+/−5 h) and acts in the G1 phase of the cell cycle targeting CDK4/6 only. Ribociclib is dosed at 600 mg once daily continuously. It has a half-life of 32 h and similar mechanism of action as palbociclib. Abemaciclib is given at a dose of 150 mg twice a day continuously. The drug has a half-life of 18 h and is the only agent of the three that inhibits multiple CDKs and other kinases, acting in G1 and G2 phases of the cell cycle. Abemaciclib is the only CDK4/6 inhibitor to have shown single agent activity of tumour size regression rather than growth inhibition although the exact mechanism is unknown.^15,16 All three CDK4/6 inhibitors are primarily metabolized in the liver.

Regarding toxicity all three agents have individual and common toxicities, the frequency of which differs according to the individual agent. Common toxicities include fatigue, nausea, vomiting, stomatitis, rash, diarrhoea, decreased appetite, and cytopenia although febrile neutropenia or sepsis is rare. Palbociclib is associated with myelosuppression, diarrhoea and fatigue but not hepatitis.^11,17,18 Ribociclib toxicity includes myelosuppression, hepatitis, increased creatinine, hyponatraemia and QTC prolongation.^12,19–21 The median time in pivotal trials, to onset of severe hepatotoxicity (Grade ≥ 3) with ribociclib was 85 days and the median time to resolution to Grade ≤ 2 was 22 days. Abemaciclib toxicity includes fatigue, hepatitis, thrombotic events, diarrhoea and myelosuppression (less than with ribociclib or palbociclib).^22,23 The median time to onset of severe hepatotoxicity (Grade ≥ 3) with abemaciclib in MONARCH 3 was approximately 60 days and median time to resolution to < Grade 3 was approximately 14 days. The FDA mandates that in patients starting any CDK4/6 inhibitor the neutrophil counts are checked at baseline, every two weeks for the first two months, then monthly for two months and as clinically indicated thereafter. Liver function tests require monitoring when ribociclib or abemaciclib are started in a similar manner. ECG and electrolytes additionally need to be checked at baseline and on treatment with ribociclib.

We aimed to investigate CDK4/6 inhibitor therapy in a real-world data set of metastatic breast cancer patients with particular regard to toxicity profiles seen with each of the three licensed agents over the whole treatment period and additionally analysing the variability in the first three months of therapy in full blood counts and liver tests, with a view to reviewing blood test monitoring requirements on treatment. We also sought to explore the survival outcomes of PFS and OS in the first line setting.

Methods

We performed a retrospective study of patients with metastatic breast cancer treated with a CDK4/6 inhibitor at our tertiary referral centre between July 2017 and December 2021 (audit approval number CARMS-17860). Patients were identified from pharmacy prescription records and screened to produce a final list of patients after excluding those with early disease and incomplete data records (Figure 1). Data was extracted on gender, age, ethnicity, ECOG/performance status and distribution of disease.

Toxicity using Common Terminology Criteria for Adverse Events (CTCAE) version 5 was collected over the treatment period. Full blood counts and liver function tests were analysed over the first three months of treatment to examine the risk of anaemia, neutropenia and neutropenic sepsis and hepatitis. Blood test data was collected from clinical records (day 0 (assigned to within two days of the CDK4-6 inhibitor being prescribed) and weekly counts thereafter). The mean and median values for each data point were than calculated from all data available. This method allowed us to map haemoglobin, neutrophil count and alanine transferase in a time-accurate way and allow for objective blood-test data comparison between the CDK4-6 inhibitor agents.

Given the heterogeneity of the patient population and the real-world nature of the dataset, the dataset was filtered for analysis; patients who were switched within one month of therapy with one CDK inhibitor to another CDK4/6 inhibitor due to toxicity, are described separately and excluded from all group analysis. The filtered dataset of patients treated with only one CDK4/6 inhibitor was used to describe toxicity of each agent but was further filtered to exclude patients treated with a CDK4/6 inhibitor in the 2nd or higher treatment setting (see Figure 1). Survival analysis using Kaplan-Meier curves was then performed on these patients (treated with a CDK4/6 inhibitor in the first line setting only. This definition allowed for previous endocrine only therapy in the metastatic setting but not chemotherapy or everolimus).

Results

A total of 217 patients were included in this study; of these the majority were treated with palbociclib (59% (N = 128/217)) followed by abemaciclib (25% (N = 55/217)) and ribociclib (16% (N = 34/217)) and 86% of patients received the agent as first line therapy (Figure 1). The majority of patients were women, white British with a median age of 61 years (range 32–95 years) and 72% had an ECOG 0 or 1. Concomitant gonadorelin analogues were used in 35 patients; goserelin in 30 patients (14%) and leuprorelin in 5 (2%). Denosumab was used in 125 (58%) patients, Table 1 summarises patient characteristics.

Table 1.

Patient characteristics.

Characteristic		Overall N (%)	Palbociclib N (%)	Ribociclib N (%)	Abemaciclib N (%)
Characteristic		217	128	34	55
Age	Mean Median ± (IQR)	60.6, 61.0 (52.0–71.0)	62.0, 63.0 (53.5–73)	56.0, 55.0 (46.3–64)	59.5, 59 (52.5–68)
Gender
	Female	216	127	34	55
	Male	1	1	0	0
Ethnicity
	White/White British	137 (63)	81 (63)	23 (68)	33 (60)
	Mixed/Multiple ethnic groups	3 (1)	2 (2)	0	1 (2)
	Asian/Asian British	28 (13)	19 (15)	4 (12)	5 (9)
	Black/African/Caribbean/Black British	11 (5)	7 (5)	1 (3)	3 (5)
	Other ethnic group	1 (1)	1 (1)	0	0
	Unknown	37 (17)	18 (14)	6 (17)	13 (24)
ECOG
	0	74 (34)	38 (30)	17 (50)	19 (35)
	1	81 (38)	54 (42)	9 (27)	18 (33)
	2	24 (11)	19 (15)	1 (3)	4 (7)
	3	4 (2)	2 (2)	1 (3)	1 (2)
	Unknown	33 (15)	14 (11)	6 (17)	13 (23)
Distribution of disease
	Bone only disease	66 (31)	43 (34)	11 (32)	12 (22)
	Advanced local disease	3 (1)	1 (1)	0	2 (4)
	Brain	13 (6)	7 (5)	1 (3)	5 (9)
	Visceral disease^a	104 (48)	55 (44)	21 (62)	28 (51)
Number of metastatic sites (by organ)
	0	3 (1)	1 (1)	0	2 (4)
	1	89 (41)	58 (45)	14 (41)	17 (31)
	2	68 (31)	39 (31)	7 (21)	22 (40)
	3	43 (20)	23 (18)	9 (26)	11 (20)
	≥ 4	14 (7)	7 (5)	4 (12)	3 (5)
Concomitant endocrine therapy backbone
	Letrozole	137 (63)	102 (80)	24 (71)	11 (20)
	Fulvestrant	70 (32)	16 (12)	10 (29)	44 (80)
	Exemestane	6 (3)	6 (5)	0	0
	Anastrozole	4 (2)	4 (3)	0	0

Visceral disease is defined as metastases present in lung, pleural tissue, liver or other intrabdominal tissue.

Toxicity and disease course of patients treated with more than one CDK4/6 inhibitor sequentially

Twelve patients of the N = 217 patients were switched from one CDK4/6 inhibitor to another due to toxicity on the first agent. The duration of treatment on the first CDK4/6 inhibitor ranged from 7 to 125 days with a median of 39 days (not accounting for any treatment breaks during these periods to manage toxicity). The second agent was started once toxicity had resolved and this varied between no documented interval to 42 days apart from in three outlier patients who started their 2nd agent 170, 322 and 348 days, respectively, after discontinuation of the first CDK4/6 inhibitor regimen. Two of these patients had intervening chemotherapy and the remainder had endocrine therapy alone.

The toxicity prompting the switch from the first agent varied. In the N = 8 who started palbociclib and switched to abemaciclib neutropenia in seven patients occurred with either additional mucositis or bleeding gums and diarrhoea and vomiting, or hepatitis alone or with hair thinning. One patient had a suspected allergic rash prompting the switch. Two patients started ribociclib and switched to abemaciclib due to deranged liver function in one patient (no documented reason was given for the other patient). Lastly two patients commenced abemaciclib but switched to palbociclib due to Grade 3 fatigue, grade 2 nausea, diarrhoea, loss of appetite, light-headedness and dehydration with acute kidney injury in one patient and severe diarrhoea with cramps in the other. The tolerability and disease course varied once the patients had started the alternative agent; of the eight patients switching from palbociclib to abemaciclib two patients had to stop abemaciclib due to toxicity (one after 14 days due to haematological adverse events and the other after 21 days due to hepatic toxicity), whilst the other six patients continued therapy, three of whom remain on treatment at the time of data analysis. In patients switching from abemaciclib to palbociclib or ribociclib to abemaciclib, all four patients tolerated the subsequent agent (one remains on treatment). The duration of therapy with the subsequent agent if not stopped for toxicity, ranged from 21 to 922 days, with four patients still on treatment). OS ranged from 1.5 to 31.9 months with a median of 15 months (five patients had died at the time of analysis).

Toxicity during treatment

Toxicity was assessed in N = 205 patients. The greatest incidence of neutropenia was observed with palbociclib followed by ribociclib and then abemaciclib. The incidence of fatigue was greatest with ribociclib followed by that seen with palbociclib then abemaciclib. Gastrointestinal symptoms of diarrhoea were more common with abemaciclib followed by ribociclib then palbociclib, however, nausea occurred in more patients on ribociclib followed by abemaciclib then palbociclib. Hepatic transaminitis occurred with both palbociclib and abemaciclib. Pneumonitis only occurred with abemaciclib. There was one incidence of neuropathy which occurred with palbociclib. Toxicity (described as all grade toxicity and grade 3 and above) over the treatment period is summarised in Table 2.

Table 2.

Treatment-related toxicity with CDK4/6 agents over the whole treatment period.

	Overall N (%)	Palbociclib N (%)	Ribociclib N (%)	Abemaciclib N (%)
	205	120	32	53
All grade toxicity
Neutropenia	69 (33.7)	53 (44)	10 (31)	6 (11.3)
Mucositis	30 (14.6)	21 (17.5)	3 (9.4)	6 (11.3)
Fatigue	61 (29.8)	35 (29.2)	13 (40.6)	13 (24.5)
Nausea	51 (24.9)	24 (20.0)	9 (28.1)	18 (24.5)
Thrush	3 (1.5)	2 (1.7)	1 (3.1)	0 (0.0)
Hot flushes	14 (6.8)	11 (9.2)	2 (6.3)	1 (1.9)
Diarrhoea	53 (25.9)	14 (11.7)	8 (25.0)	31 (58.5)
Vomiting	16 (7.8)	8 (6.7)	2 (6.3)	6 (11.3)
Hair thinning	7 (3.4)	5 (4.2)	1 (3.1)	1 (1.9)
Headache	8 (3.9)	7 (5.8)	1 (3.1)	0 (0.0)
Watery eyes	4 (2.0)	2 (1.7)	0 (0.0)	2 (3.8)
Dry eyes	3 (1.5)	1 (0.8)	1 (3.1)	1 (1.9)
Abdominal pain	5 (2.4)	3 (2.5)	0 (0.0)	2 (3.8)
Pruritis	9 (4.4)	5 (4.2)	0 (0.0)	4 (7.5)
Dry skin	7 (3.4)	6 (5.0)	0 (0.0)	1 (1.9)
Pneumonitis	4 (2.0)	0 (0.0)	0 (0.0)	4 (7.5)
Hepatic transaminitis	4 (2.0)	2 (1.7)	0 (0.0)	2 (3.8)
Epistaxis	4 (2.0)	3 (2.5)	0 (0.0)	1 (1.9)
Neuropathy	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
Grade 3 or above toxicity
Neutropenia	44 (21)	37 (31)	6 (19)	1 (1.9)
Thrombocytopenia	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
Myelosuppression ^a	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
Nausea	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
General deterioration	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
Nausea, vomiting, acute kidney injury	1 (0.5)	1 (0.8)	0 (0.0)	0 (0.0)
Diarrhoea	1 (0.5)	0 (0.0)	0 (0.0)	1 (1.9)
Hepatic transaminitis	1 (0.5)	0 (0.0)	0 (0.0)	1 (1.9)

Myelosuppression indicates both neutropenia and thrombocytopenia.

In patients on palbociclib 62/120 patients remained on treatment at the time of analysis, 58 had stopped and been treated for a mean period of 311 and median of 244 days (range 15–923 days). Dose reductions or cessation for toxicity for any grade occurred in 65/120 patients, with one reduction necessary in 32 patients (due to neutropenia (N = 27), fatigue (N = 2), nausea/vomiting and acute kidney injury (N = 1), raised ALT (N = 1) and general myelosuppression (N = 1)). Two dose reductions were needed in 30 patients (due to neutropenia (N = 26), fatigue and diarrhoea (N = 1), diarrhoea and nausea (N = 1) and general myelosuppression (N = 2)). Two patients discontinued therapy without attempts to rechallenge at a reduced dose.

In the ribociclib group 15 remained on treatment, 17 had stopped after a mean period on therapy of 308 and median 212 days (range 29–966). Dose reduction or cessation for any grade toxicity occurred in 21 patients. One dose reduction occurred in 15 patients (due to fatigue (N = 5), neutropenia (N = 7), rash (N = 1) and gastrointestinal symptoms (nausea/vomiting/diarrhoea) in N = 2). Two dose reductions were needed in four patients (due to neutropenia (N = 3) and general myelosuppression and nausea (N = 1)). Two patients discontinued treatment without rechallenge (due to myelosuppression and gastrointestinal symptoms (N = 1) or gastrointestinal toxicity alone (N = 1)).

For abemaciclib patients 21 patients remained on treatment and 32 had stopped therapy with a mean of 268 and median of 263 days of therapy (range 10–804). Dose reductions were required in 23 patients; one reduction in 18 patients (due to general deterioration (N = 2), myelosuppression (N = 4), gastrointestinal symptoms (N = 11), fatigue, diarrhoea, transaminitis and pneumonitis (N = 1)). Two dose reductions occurred in five patients (due to gastrointestinal symptoms and myelosuppression (N = 1), gastrointestinal toxicity and fatigue (N = 1), gastrointestinal toxicity (N = 1) and myelosuppression (N = 2)).

The dose reductions for all three agents occurred at various timepoints on treatment and for a variety of grades of toxicity, the majority of which were not grade 3 (Table 2).

The incidence of neutropenic sepsis and infections were evaluated separately. Ribociclib had the greatest incidence of febrile neutropenia/neutropenic sepsis. Palbociclib treatment resulted in the greatest number of infective episodes overall and abemaciclib had the lowest incidence of neutropenic sepsis or non-neutropenic infection (Table 3).

Table 3.

Episodes of infection and neutropenic sepsis over the whole treatment period.

Infection	Overall N (%)	Palbociclib N (%)	Ribociclib N (%)	Abemaciclib N (%)
Infection	205	120	32	53
Episode of neutropenic sepsis/febrile neutropenia	11 (5.4)	7 (5.8)	3 (9.4)	1 (1.9)
Episodes of non-neutropenic infections
Infective episode with hospitalisation	26 (12.7)	16 (13.3)	5 (15.6)	5 (9.4)
Infective episode managed in community	34 (16.6)	25 (20.8)	5 (15.6)	4 (7.5)
Infective episode requiring no management	7 (3.4)	6 (5.0)	0 (0.0)	1 (1.9)

Serial blood count variability over the first three months of therapy

Haematological and liver blood parameters were examined over the first three months of treatment or three cycles. Anaemia was seen with all three agents but Grade 3 or higher neutropenia was more common with palbociclib followed by ribociclib and then abemaciclib. Grade 2 neutropenia was similar across all agents. Low grade hepatitis was seen with all agents but grade 2 hepatitis was seen with palbociclib then abemaciclib but not ribociclib (Table 4). Examining the trends in the median values of haemoglobin and neutrophil counts, the greatest variability was seen with ribociclib treatment. In terms of variability of alanine transferase levels over the first three months, the greatest variability was with abemaciclib. Overall, the variability with any agent in any of the parameters was greatest in the first four weeks of treatment (Figure 2). We additionally evaluated the time from start of therapy to the first recorded grade 1 neutropenia; for palbociclib this was 23 days, for ribociclib it was 21 days and for abemaciclib it was 25 days.

Table 4.

Treatment-related myelosuppression and hepatitis toxicity in the first 3 cycles of CDK4/6 inhibitor therapy.

Toxicity in the first 3 cycles of treatment	Overall N (%)	Palbociclib N (%)	Ribociclib N (%)	Abemaciclib N (%)
Toxicity in the first 3 cycles of treatment	205	120	32	53
Haematological toxicity
Episode of anaemia (Hb < 120 g/L)	130 (63.4)	71 (59.2)	20 (62.5)	39 (73.6)
Episode of neutropenia
Grade 2 neutropenia (1.5 × 10⁹/L ≥ NEUT > 1.0 × 10⁹/L)	47 (22.9)	30 (25.0)	6 (18.8)	11 (20.8)
Grade 3 neutropenia (1.0 × 10⁹/L ≥ NEUT ≥ 0.5 × 10⁹/L)	73 (35.6)	51 (42.5)	15 (46.9)	7 (13.2)
Grade 4 neutropenia (NEUT < 0.5 × 10⁹/L)	2 (1.0)	2 (1.7)	0 (0.0)	0 (0.0)
Episode of hepatic transaminitis
Episode of Grade 1 transaminitis (ALT) (> 165 U/L (3×Upper limit of normal)	6 (2.9)	1 (0.8)	3 (9.4)	2 (3.8)
Episode of Grade 2 transaminitis (ALT) (> 275 U/L (5×Upper limit of normal)	3 (1.5)	2 (1.7)	0 (0.0)	1 (1.9)

Subsequent therapy after first line CDK4/6 inhibitor and survival outcomes

A total of N = 187 received a CDK4/6 inhibitor in the metastatic first line setting. The subsequent treatment received by these patients (where this information was available) is shown in Table 5. The number of patients receiving subsequent therapy was greatest immediately after stopping the CDK4/6 inhibitor and decreased for each sequential line of therapy thereafter (a maximum of three subsequent lines of therapy were recorded). Even immediately after the CDK4/6 agent, only 40% of patients were noted to have had at least one more line of subsequent therapy. The percentages of patients receiving subsequent therapy immediately after a first line CDK 4/6 inhibitor were: after 1st line palbociclib: 47% received further therapy, of whom 21% received a hormonal agent, 3% a targeted therapy and 23% chemotherapy. Of patients treated with 1st line ribociclib 32% were treated; 3% with a hormonal agent, 4% with targeted therapy and 25% with chemotherapy. After 1st line abemaciclib 43% of patients received a subsequent therapy of which 9% had hormonal therapy, 0% had targeted therapy and 34% received chemotherapy.

Table 5.

Subsequent therapies after progression on a first line CDK4/6 inhibitor (where this data was recorded).

	Overall N (%)	Palbociclib N (%)			Ribociclib N (%)			Abemaciclib N (%)
	187	115			28			44
Subsequent therapy (to first line CDK4/6inhibitor)		1st therapy N = 54	2nd therapy N = 22	3rd therapy N = 8	1st therapy N = 9	2nd therapy N = 1	3rd therapy N = 1	1st therapy N = 19	2nd therapy N = 10	3rd therapy N = 3
Hormonal agent	Letrozole	14			1
	Anastrozole	1
	Exemestane	1	8
	Fulvestrant	8	1	1			1	3
	Tamoxifen		2
	Megesterol acetate							1
Targeted therapy	Everolimus + exemestane	3	2		1
Chemotherapy	Paclitaxel/abraxane	10	7	2	1	1		2	6	1
	Capecitabine	17	1	4	6			11	1	1
	Erubilin								1
	Epirubicin + cyclophosphamide +/- 5FU		1	1				2		1
	Vinorelbine								1
	Carboplatin								1

The PFS for each agent was palbociclib 27.9 months (95% CI 23–32.5), ribociclib 29 months (95% CI 21.5–37.0) and abemaciclib 20.6 months (95% CI 15.0–26.0). The OS for each agent was palbociclib 38.0 months (95% CI 33.5–42.5), ribociclib 33.9 months (95% CI 26.7–41.1) and abemaciclib 27.3 months (95% CI 22.5–32.1) (Figures 3 and 4).

Discussion

The development of CDK4/6 inhibitor combinations with hormonal agents has been a major advance in the treatment of oestrogen positive metastatic breast cancer. The added synergistic activity has been shown to be superior to hormonal agents alone in registration phase III studies, and with the convenience of oral dosing these regimens have become standard first line regimens of choice. However, the toxicity of any of the three licensed agents is not insignificant and requires careful monitoring and management.

Our data confirms that the first two to three months of therapy require careful management with treatment breaks to manage neutropenia and hepatitis in particular. However, a trial of an alternative CDK4/6 inhibitor can be successful in terms of tolerability and subsequent benefit from therapy. We attempted to evaluate serial blood tests over the first three months of therapy to help guide how intensive monitoring including blood tests should be in the first months of treatment. The results indicate that neutropenia of any grade is common with all three agents but treatment is generally required for at least four weeks before the full blood count values start to decrease Our results also suggest that up to a grade 2 neutropenia is common and asymptomatic. Whilst our toxicity data per agent generally agreed with published data, neutropenia occurred with all agents and hepatitis occurred with palbociclib, whilst fatigue was more commonly reported with ribociclib. The number of patients in each treatment group was not large enough to statistically evaluate if individual toxicities were associated with particular agents. We were also unable to examine look at if baseline characteristics including distribution of disease affected toxicity on treatment or indeed survival. The trials conducted with palbociclib, ribociclib and abemaciclib have suggested that visceral disease may be best treated with ribociclib^4–6 or abemaciclib,^7–9 whilst palbociclib may be best to treat bone only disease.^1–3 Abemaciclib is the only agent to have shown central nervous system activity in a clinical trial.²⁴ Forty percent of our patients were treated with further lines of therapy post-progression on a CDK4/6 inhibitor. The number of patients treated with each CDK4/6 inhibitor agent was too small to enable an analysis as to the effect of the choice of CDK4/6 inhibitor and subsequent treatment. Many patients required a dose reduction whilst on treatment and the majority of reductions were made for grade 2 or below toxicity often occurring across organ systems. We could not accurately assess dose intensity across the treatment period but it was clear from the clinical noting that treatment suspension to manage toxicity (especially neutropenia) did occur for longer periods than the licensed schedule for the agent or original trial protocols allowed. All three CDK4/6 inhibitors are licensed for use with endocrine therapy. Some of our patients had an initial trial of endocrine therapy alone for metastatic disease prior to starting the CDK4/6 inhibitor. As the first line survival data for all of these inhibitors has strengthened and physicians are better informed about toxicity and its management, there has been increased use and in a wider population (more reflective of real-world practise than the clinical trial population) of combined endocrine and CDK4/6 inhibitor first line therapy as per their licensed use. Further study is needed on the optimal sequencing of therapies post-progression on CDK4/6 inhibitor agents or if sequencing of CDK4/6 inhibitor agents could be efficacious. The longer-term effect of CDK4/6 inhibitor therapy on reserve organ function, particularly considering the chronic nature of the toxicity and the management required of this, and how this affects outcome with subsequent anti-cancer therapy is an area of continued research.

Our study is limited by its retrospective nature as well as the difficulties in using real-world data considering the gaps in data caused by incomplete documentation or analysis of specified blood tests. Nevertheless, the data presented here allows us to initiate a more measured approach to serial monitoring of patients starting these agents, anticipating the toxicities seen with each agent to tailor the choice of agent to a patient and the opportunity to rechallenge a patient with an alternative CDK4/6 inhibitor should the initial agent cause intolerable toxicity.

Footnotes

Author contributions

W.B. formulated the concept and design of the work, acquisition, analysis and interpretation of data, drafted and approved the final version. L.P. formulated the concept and design of the work, drafted and approved the final version. T.C. formulated the concept and design of the work, approved final version. L.K. formulated the concept and design of the work, acquisition, analysis and interpretation of data, drafted and approved the final version.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Leila Khoja

References

Finn

Crown

Lang

, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015; 16: 25–35.

Finn

Martin

Rugo

, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med 2016; 375: 1925–1936.

Turner

Andre

, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373: 209–219.

Hortobagyi

Stemmer

Burris

, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016; 375: 1738–1748.

Slamon

Neven

Chia

, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 2018; 36: 2465–2472.

Tripathy

Colleoni

, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018; 19: 904–915.

Dickler

Tolaney

Rugo

, et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast cancer. Clin Cancer Res 2017; 23: 5218–5224.

Goetz

Toi

Campone

, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017; 35: 3638–3646.

Sledge

Toi

Neven

, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017; 35: 2875–2884.

10.

Hortobagyi

Stemmer

Burris

, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med 2022; 386: 942–950.

11.

Cristofanilli

Turner

Bondarenko

, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17: 425–439.

12.

Onesti

Jerusalem

. CDK4/6 Inhibitors in breast cancer: differences in toxicity profiles and impact on agent choice. A systematic review and meta-analysis. Expert Rev Anticancer Ther 2021; 21: 283–298.

13.

George

Qureshi

Omene

, et al. Clinical and pharmacologic differences of CDK4/6 inhibitors in breast cancer. Front Oncol 2021; 11: 693104.

14.

Yardley

Nusch

Yap

, et al. Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) −3 and −7 trials. J Clin Oncol 2020; 38: 1054.

15.

Hafner

Mills

Subramanian

, et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem Biol 2019; 26: 1067–1080.e8.

16.

Patnaik

Rosen

Tolaney

, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016; 6: 740–753.

17.

Finn

Rugo

Gelmon

, et al. Long-Term pooled safety analysis of palbociclib in combination with endocrine therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: updated analysis with up to 5 years of follow-up. Oncologist 2021; 26: e749–ee55.

18.

Verma

Bartlett

Schnell

, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). Oncologist 2016; 21: 1165–1175.

19.

Costa

Talamantes

, et al. Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: palbociclib and ribociclib. Breast 2017; 35: 1–7.

20.

Tripathy

Hortobagyi

Chan

, et al. Pooled efficacy analysis of first-line ribociclib (RIB) plus endocrine therapy (ET) in HR+/HER2: advanced breast cancer (ABC). Ann Oncol 2019; 30: iii49–iii50.

21.

Hortobagyi

Stemmer

Burris

, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2019; 30: 1842.

22.

Rugo

Huober

Garcia-Saenz

, et al. Management of abemaciclib-associated adverse events in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: safety analysis of MONARCH 2 and MONARCH 3. Oncologist 2021; 26: e522.

23.

Johnston

Martin

Di Leo

, et al. MONARCH 3 Final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019; 5: 5.

24.

Tolaney

Sahebjam

Le Rhun

, et al. A phase II study of abemaciclib in patients with brain metastases secondary to hormone receptor-positive breast cancer. Clin Cancer Res 2020; 26: 5310–5319.