Phase IIIb study on the efficacy and safety of Palbociclib used in combination with letrozole versus placebo used with letrozole.

1. Ilkin Bakirli Palbociclib and Letrozole Slovak Medical University
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Palbociclib and Letrozole in Advanced Breast Cancer
Introduction
The largest therapeutic subtype of breast cancer is the hormone-receptor-positive type, which
makes up 60-65% of all the disease. Treatment for the past 50 years was focused on targeting
the estrogen receptor signalling pathway, but resistance to hormonal blockade calls for new
approaches. Cyclin-dependent kinases (CDKs) regulate the cell cycle. Cyclin-D interacts with
CDK4 and CDK6 inducing hyperphosphorylation of the retinoblastoma (Rb) gene product,
which allows progression of the cell through the G1 checkpoint of the S phase of the cell
cycle. Any disturbance in the Cyclin-D-CDK4/6-Rb pathway results in loss of the critical
regulation point and leads to malignancies with endocrine resistance in breast cancer.
Disturbances could be amplification, loss, mutation of cyclin-D or Rb itself. Palbociclib
(Pfizer) is an inhibitor of CDK4 and CDK6. Studies have proved that it inhibits the
proliferation of estrogen-receptor(ER)- positive breast cancer cells, synergises with
antiestrogens and reverses endocrine resistance. This led to the idea of PALOMA-1, which is
a randomized, open-label, proof of concept study that compared palbociclib plus letrozole
versus letrozole alone as a first line therapy in postmenopausal women with ER-positive,
human epidermal growth factor receptor (HER2) negative advanced breast cancer. Results
showed that it prolonged progression-free survival of the patients and was approved by FDA
in the United States. PALOMA-2 is a larger study than PALOMA-1 and it was conducted to
confirm and further asses the findings of safety and efficacy.
Methods of research– study design, patients’ eligibility, procedures, imaging, end-points
and statistics.
It was a double-blind, Phase 3 study, all patients were given 2.5mg letrozole orally and 2:1 of
patients received palbociclib and placebo 125mg orally in 4week cycles (3 weeks treatment
and 1 week off). Randomization was divided to site of disease, status prior to adjuvant or
neoadjuvant anticancer therapy and disease-free interval from the end of adjuvant or
neoadjuvant treatment to disease reoccurrence. Treatment period according to Response
Evaluation Criteria in Solid Tumours (RECIST) 1.1, was from administration of first dose to
observation of disease progression, development of toxic effects or withdrawal of consent.
Treatment could be continued if it was in the best intention for the patient. Reduction of
palbociclib or placebo dose were permitted because of side effects, but letrozole dose changes
were not permitted.

2. Ilkin Bakirli Palbociclib and Letrozole Slovak Medical University
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Eligible patients were women with ER-positive, HER2 negative advanced breast cancer who
had not received prior systemic therapy for advanced diseases. Fresh metastatic or recurrent
tumour biopsies were obtained or latest archival tumour tissues were eligible and ER status
was tested. HER2 status was assessed using the FDA-approved assay. Postmenopausal status
was deducted if the women had no menses for 12 months of longer, had bilateral
oophorectomy or FSH and estradiol levels were in postmenopausal range. Prior treatment
with nonsteroidal aromatase inhibitors was allowed unless the disease had recurred. Organ
function had to be at least 0-2 (0 being no symptoms and increasing in severity up to 5) and
measurable disease severity in RECIST 1.1. Patients with short-term life threatening
situations were excluded. Patients were screened with CT or MRI 4 weeks before
randomization and repeated every 11-13 weeks. Bone scans were done 12 weeks before
randomization and every 23-25 weeks. Imaging continues till disease progresses, new
anticancer therapy is initiated or due to withdrawal from the study. Vital signs are assessed at
every day 1 of the cycles. Laboratory tests are performed at day 1 and day 14 of the first 2
cycles and day 1 of the further cycles. Adverse effects were observed and graded.
Relationship to the medication or placebo was also recorded by the investigator.
The primary end point of the research was the progression free survival, defined as the
starting time of the study to a radiologically confirmed disease progression according to
RECIST 1.1, or death. Secondary end points include overall survival, objective response and
duration of response, clinical benefit of response, patient-reported outcomes, safety and tissue
biomarker analyses. Statistics were analysed using a prespecified log-rank test divided to
presence or absence of visceral disease. 347 events were required to estimate a 90% power to
hazard ratio of 0.69 at a one sided alpha level of 0.025. The target number of patients was
650. An interim analysis was planned after 65% of total number of disease progressions or
deaths occurred in patients. It would allow the study to stop earlier due to either compelling
evidence of efficacy or lack of evidence. Kaplan-Meier method was used to estimate median
progression free survival. Cox proportional-hazard models were used to evaluate hazard ratio.
Results- Patients, study treatment, adverse events and efficacy
A total of 666 women at 186 sites in 17 countries were assigned in a 2:1 ratio, 444 patients to
palbociclib-letrozole (Palb) and 222 to placebo-letrozole (Pla). Median age was 62 in the
former and 61 in the later. 48.6% had visceral disease, 62.8% had prior systemic therapy for
breast cancer, 37.2% had newly diagnosed cancer, 40.7% were disease free for more than one

3. Ilkin Bakirli Palbociclib and Letrozole Slovak Medical University
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year and 22.1% had a disease free interval for less than one year. Less than half of patients
had received chemotherapy and 53.6% had prior endocrine therapy, 22.7% had bone-only
disease.
The final data analysis on February 26, 2016, 331 events of disease progression or death
occurred 194 patients with Palb and 137 with the Pla. 199 were still receiving Palb and 61
were receiving Pla. Dose of Palbociclib was reduced inn 160 of 444 according to protocol.
Main reason for discontinuation of study was disease progression in 172 in the Palb group
and 125 in Pla group. Discontinuation due to side effects happened In 43 patients of Palb
group and 13 ptients in Pla group.
Adverse events were neutropenia, leukopenia, fatigue, nausea, arthralgia and alopecia. 57%
had grade 1 or 2 symptoms and 39.2% had grade 3 or higher. Neutropenia was found in
79.5% in the Palb group as opposed to 6.3% in the Pla group. Leukopenia (39.0% vs 2.3%),
anemia (24.1% vs 9.0%), thrombocytopenia (15.5% vs 1.4%). Fatigue was observed in
37.4% in the Palb vs 27.5% in the Pla group, nausea 35.1% vs 26.1% and arthralgia in 33.3%
vs 33.8%. A higher ratio of alopecia was observed in the Palb group. Diarrhoea, cough and
stomatitis were also observed more in the Palb group. Incidences of hot flushes and
headaches were lower in the Palb group. The serious adverse events of any etiology occurred
in 19.6% of the Palb group and 12.6% of the Pla group. Pulmonary embolism was observed
in 0.9% in the Palb group. During the treatment, 10 deaths occurred in the Palb group and 4
deaths in the Pla group.
Progression-free survival of 24.8 months was noted as the end point in PALOMA-2 in the
Palb group, compared to 14.5 months of the Pla group. Hazard ratio of disease progression or
death was 0.65. The benefit of palbociclib-letrozole therapy was proved in all subgroup
analyses. Patients with or without visceral disease, patients who had or had not received prior
hormonal therapy and patients with more than 12 months or less than 12 months of disease
interval benefited from the therapy. In the subgroup of metastatic disease, patients also had a
lower risk of disease progression or death than in those taking placebo-letrozole. The rate of
benefit in all patients who were given palbociclib-letrzole was 84.9% as opposed to 70.3% in
placebo-letrozole. Overall survival data are not yet concluded but will be performed when
390 deaths occur as per protocol.

4. Ilkin Bakirli Palbociclib and Letrozole Slovak Medical University
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Panel A shows progression-free survival in the intention-to-treat population, as assessed by the
investigators (primary analysis); the median progression-free survival was 24.8 months (95% CI,
22.1 to not estimable) among the 444 patients in the palbociclib–letrozole group and 14.5 months
(95% CI, 12.9 to 17.1) among the 222 patients in the placebo–letrozole group.
Panel B shows progression-free survival in the intention-to-treat population, as assessed by means of
blinded, independent central review; the median progression-free survival was 30.5 months (95% CI,
24.7 to not estimable) among the 444 patients in the palbociclib–letrozole group and 19.3 months
(95% CI, 16.4 to 30.6) among the 222 patients in the placebo–letrozole group.

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Discussion and conclusion
PALOMA-2 was a phase 3 study that proved the addition of a CDK inhibitor to standard
endocrine therapy highly improved the outcome as a first-line treatment of ER-positive,
HER2-negative advanced breast cancer. The idea of developing CDK4 and CDK6 inhibitors
is that the hormone receptor-positive breast cancer is dependent on CDK4 and CDK6
pathways. This study confirmed the efficacy and safety of palbociclib-letrozole combination
therapy as a first line treatment of postmenopausal women with ER-positive advanced breast
cancer. It proved beneficial irrespective of the disease site, age, prior chemotherapy, prior
endocrine treatment or histologic subtype. Even though a high incidence of hematologic
adverse events such as neutropenia was observed in 79.5% of patients, only 2% of the
incidences were febrile neutropenia. The median progression-free survival of 14.5 months in
the placebo-letrozole group was improved to 24.8 months with the palbociclib-letrozole
combination. Longer progression-free survival prolonging overall survival is still uncertain
until follow-up is completed.
In conclusion, PALOMA-2 asserted the prolongation of progression-free survival in
postmenopausal women with ER-positive, HER2 negative advanced breast cancer and gave
evidence about the efficacy of inhibiting of CDK4 and CDK6. The therapy resulted in a
higher incidence of myelotoxic effects than the placebo-letrozole, but it could be managed
with dose reductions and appropriate supportive care.
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