Palbociclib

IBRANCE is a kinase inhibitor indicated:

• for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with: o an aromatase inhibitor as initial endocrine-based therapy ( 1.1 ); or o fulvestrant in patients with disease progression following endocrine therapy. ( 1.1 )
• in combination with inavolisib and fulvestrant for the treatment of adult patients with endocrine-resistant, PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA‑authorized test, following recurrence on or after completing adjuvant endocrine therapy. ( 1.1 )
• in combination with trastuzumab, with or without pertuzumab, and endocrine therapy for the maintenance treatment of adult patients with HR-positive, HER2‑positive locally advanced or metastatic breast cancer following induction treatment. ( 1.2 ) 1.1 HER2-Negative Metastatic Breast Cancer IBRANCE is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:
• an aromatase inhibitor as initial endocrine-based therapy; or
• fulvestrant in patients with disease progression following endocrine therapy. IBRANCE is indicated in combination with inavolisib and fulvestrant for the treatment of adult patients with endocrine-resistant, PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA- authorized test, following recurrence on or after completing adjuvant endocrine therapy. 1.2 HER2-Positive Metastatic Breast Cancer IBRANCE is indicated in combination with trastuzumab, with or without pertuzumab, and endocrine therapy for the maintenance treatment of adult patients with HR-positive, HER2-positive locally advanced or metastatic breast cancer following induction treatment.

125 mg tablets: Oval, light purple, film-coated tablets debossed with "Pfizer" on one side and "PBC 125" on the other side. 100 mg tablets: Oval, green, film-coated tablets debossed with "Pfizer" on one side and "PBC 100" on the other side. 75 mg tablets: Round, light purple, film-coated tablets debossed with "Pfizer" on one side and "PBC 75" on the other side. Tablets: 125 mg, 100 mg, and 75 mg. ( 3 )

None. None. ( 4 )

• Neutropenia: Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. ( 2.2 , 5.1 )
• Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for pulmonary symptoms of ILD/pneumonitis. Interrupt IBRANCE immediately in patients with suspected ILD/pneumonitis. Permanently discontinue IBRANCE if severe ILD/pneumonitis occurs. ( 5.2 )
• Embryo-Fetal Toxicity: IBRANCE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 )

5.1 Neutropenia Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80% and PALOMA-3 with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% of patients receiving IBRANCE plus letrozole in PALOMA-2 and 66% of patients receiving IBRANCE plus fulvestrant in PALOMA-3. In PALOMA-2 and PALOMA-3, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1) ] . Neutropenia was the most frequently reported adverse reaction in PATINA with an incidence of 78%. Grade ≥3 neutropenia was reported in 61% of patients receiving IBRANCE in combination with trastuzumab, with or without pertuzumab, and endocrine therapy. Based on laboratory findings, 93% had a decrease in neutrophil counts including 47% with Grade 3 and 3.1% with Grade 4. The median time to first episode of any grade neutropenia was 22 days and the median duration of Grade ≥3 neutropenia events was 9 days [see Adverse Reactions (6.1) ] . Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration (2.2) ] . Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Febrile neutropenia has been reported in 0.8% of patients exposed to IBRANCE in the PATINA study. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17) ] .

5.2 Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 and no fatal cases were reported. In PATINA, 1% of IBRANCE-treated patients had ILD/pneumonitis of any grade. No Grade 3, 4, or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported [see Adverse Reactions (6.2) ] . Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis [see Dosage and Administration (2.2) ] .

5.3 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1) ] .

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Neutropenia [see Warnings and Precautions (5.1) ]
• ILD/Pneumonitis [see Warnings and Precautions (5.2) ] Most common adverse reactions (incidence ≥20%) in combination with either letrozole or fulvestrant, including laboratory abnormalities, were white blood cell count decreased, neutrophils decreased, blood creatinine increased, hemoglobin decreased, platelets decreased, infections, aspartate aminotransferase increased, alanine aminotransferase increased, fatigue, nausea, stomatitis, diarrhea, and alopecia. ( 6.1 ) The most common adverse reactions (incidence ≥20%) in combination with inavolisib and fulvestrant, including laboratory abnormalities, were neutrophils decreased, hemoglobin decreased, fasting glucose increased, platelets decreased, lymphocytes decreased, stomatitis, diarrhea, calcium decreased, fatigue, potassium decreased, creatinine increased, alanine aminotransferase (ALT) increased, nausea, sodium decreased, magnesium decreased, rash, decreased appetite, COVID-19 infection, and headache. ( 6.1 ) The most common adverse reactions (incidence ≥20%) in combination with trastuzumab, with or without pertuzumab, and endocrine therapy, including laboratory abnormalities, were white blood cell decreased, neutrophil count decreased, creatinine increased, hemoglobin decreased, diarrhea, infections, platelet count decreased, stomatitis, aspartate aminotransferase increased, decreased calcium, alanine aminotransferase increased, decreased potassium, fatigue, alkaline phosphatase increased, nausea, asthenia, headache, rash, pruritus, and muscle spasms. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. PALOMA-2: IBRANCE plus Letrozole Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy The safety of IBRANCE plus letrozole was evaluated in a randomized, double-blind trial (PALOMA-2) in 666 patients with ER-positive, HER2-negative advanced breast cancer [see Clinical Studies (14.1) ] . The median duration of treatment for IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months. Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in PALOMA-2. Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (10%) patients receiving IBRANCE plus letrozole and in 13 of 222 (6%) patients receiving placebo plus letrozole. Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%). The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia. The most frequently reported Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia. Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 4. Table 4. Adverse Reactions (≥10%) in PALOMA-2 Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable; IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222) Adverse Reaction All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Infections and infestations Infections Infections includes all reported preferred terms (PTs) that are part of the System Organ Class Infections and infestations. 60 Most common infections (≥1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis. 6 1 42 3 0 Blood and lymphatic system disorders Neutropenia Leukopenia Anemia Thrombocytopenia 80 39 24 16 56 24 5 1 10 1 <1 <1 6 2 9 1 1 0 2 0 1 0 0 0 Metabolism and nutrition disorders Decreased appetite 15 1 0 9 0 0 Nervous system disorders Dysgeusia 10 0 0 5 0 0 Gastrointestinal disorders Stomatitis Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. Nausea Diarrhea Vomiting 30 35 26 16 1 <1 1 1 0 0 0 0 14 26 19 17 0 2 1 1 0 0 0 0 Skin and subcutaneous tissue disorders Alopecia Rash Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption. Dry skin 33 Grade 1 events – 30%; Grade 2 events – 3%. 18 12 N/A 1 0 N/A 0 0 16 Grade 1 events – 15%; Grade 2 events – 1%. 12 6 N/A 1 0 N/A 0 0 General disorders and administration site conditions Fatigue Asthenia Pyrexia 37 17 12 2 2 0 0 0 0 28 12 9 1 0 0 0 0 0 Clinically relevant adverse reactions in <10% of patients who received IBRANCE plus letrozole in PALOMA-2 included epistaxis (9%), lacrimation increased (6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%). Table 5. Laboratory Abnormalities in PALOMA-2 N=number of patients; WBC=white blood cells. IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222) Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % WBC decreased 97 35 1 25 1 0 Blood creatinine increased 96 2 <1 91 0 0 Neutrophils decreased 95 56 12 20 1 1 Hemoglobin decreased 78 6 0 42 2 0 Platelets decreased 63 1 1 14 0 0 Aspartate aminotransferase increased 52 3 0 34 1 0 Alanine aminotransferase increased 43 2 <1 30 0 0 PALOMA-3: IBRANCE plus Fulvestrant Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of IBRANCE plus fulvestrant was evaluated in a randomized, double-blind trial (PALOMA-3) in 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer [see Clinical Studies (14.1) ] . The median duration of treatment for IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months. Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in PALOMA-3. Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). […]

Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A.

• CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the strong inhibitor cannot be avoided, reduce the IBRANCE dose. ( 2.2 , 7.1 )
• CYP3A Inducers: Avoid concurrent use of IBRANCE with strong CYP3A inducers. ( 7.2 )
• CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices may need to be reduced when given concurrently with IBRANCE. ( 7.3 )

7.1 Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) ] .

7.2 Agents That May Decrease Palbociclib Plasma Concentrations Effect of CYP3A Inducers Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine, enzalutamide, and St John's Wort) [see Clinical Pharmacology (12.3) ] .

7.3 Drugs That May Have Their Plasma Concentrations Altered by Palbociclib Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared to administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced, as IBRANCE may increase its exposure [see Clinical Pharmacology (12.3) ] .

• Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on AUC (see Data ) . Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Data Animal Data In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose. In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of palbociclib up to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis. The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights. At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the recommended dose, respectively. CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.

8.2 Lactation Risk Summary There is no information regarding the presence of palbociclib in human milk, its effects on milk production, or the breastfed infant. Because of the potential for serious adverse reactions in breastfed infants from IBRANCE, advise a lactating woman not to breastfeed during treatment with IBRANCE and for 3 weeks after the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Females of reproductive potential should have a pregnancy test prior to starting treatment with IBRANCE. Contraception Females IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose. Males Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with IBRANCE and for 3 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Males Based on animal studies, IBRANCE may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of IBRANCE in pediatric patients have not been established. The safety and effectiveness of IBRANCE were assessed but not established in three trials: one open-label trial [A5481092, (NCT03709680)] that included 98 pediatric patients 2 to <17 years of age who received IBRANCE in combination with chemotherapy for recurrent or refractory solid tumors and two open-label trials that included 42 pediatric patients 4 to <17 years of age who received IBRANCE as a single agent for recurrent or refractory solid tumors [APEC1621I, (NCT03526250)] or primary central nervous system (CNS) tumors [PBTC-042, (NCT02255461)]. No new safety signals were observed in these trials. Palbociclib exposures in pediatric patients who received IBRANCE as a single agent or in combination were within range of those observed in adults given a similar dose based on body surface area. Juvenile Animal Toxicity Data Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology study in rats that were immature at the beginning of the studies and were most prevalent in males at oral palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with lower incidence and severity in a 15 week repeat-dose toxicology study in immature rats. Altered glucose metabolism or associated changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-week repeat-dose toxicology study in rats that were mature at the beginning of the study and in dogs in repeat-dose toxicology studies up to 39 weeks duration. Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast degeneration/necrosis, mononuclear cell infiltrate). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

8.5 Geriatric Use Of 444 patients who received IBRANCE in PALOMA-2, 181 patients (41%) were ≥65 years of age and 48 patients (11%) were ≥75 years of age. Of 347 patients who received IBRANCE in PALOMA-3, 86 patients (25%) were ≥65 years of age and 27 patients (8%) were ≥75 years of age. Of the 260 patients who received IBRANCE in PATINA, 41 patients (16%) were ≥65 years of age and 13 patients (5%) were ≥75 years of age. No clinically significant differences in safety or effectiveness of IBRANCE were observed between patients 65 years of age and older and younger adult patients. Of the 162 patients who received IBRANCE in combination with inavolisib and fulvestrant in INAVO120, 15% were ≥ 65 years of age and 3% were ≥ 75 years of age. Dosage modifications or interruptions due to adverse reactions occurred at a higher incidence in patients ≥ 65 years of age compared with younger patients (79% versus 68%, respectively). Clinical studies of IBRANCE in combination with inavolisib and fulvestrant did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days [see Dosage and Administration (2.2) ] . […]

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following palbociclib removal and was greater if antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug alone. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.