Date of first round report: 1 September 2016 Date of second round report: 30 January 2017



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Combination of palbociclib and letrozole Study 1008 ‘Top-line summary’


All-causality adverse events were reported for 98.9% of patients in the palbociclib plus letrozole arm and for 95.5% of patients in the placebo plus letrozole arm.

Table 25: A5481008 Summary of of all-causality treatment-emergent adverse events (As-treated population) – source Table 6, Top-line summary





Comment:

  1. While the total TEAE rates were similar, there was a striking imbalance in the severity of the events between the arms. Notably, Grade 3 or 4 events occurred in 52.3% more patients, compared with the placebo and letrozole arm. Not surprisingly, these resulted in higher rates of discontinuations from the study, of either palbociclib or letrozole, as well as higher rates of treatment interruption or dose reduction in the palbociclib and letrozole arm.

  2. The table above for the Summary of all-causality treatment-related adverse events, states that 6.1% and 5.0% of patients permanently discontinued letrozole due to an AE in the experimental and comparator arms, respectively. This figure exceeds that for those permanently discontinuing the study due to an AE for those arms (2.5% and 1.8%, respectively). The sponsor is requested to provide details regarding how these patients were treated and followed up from this point of discontinuation.

  1. Was palbociclib or placebo continued as monotherapy in any patients? If so, how many in each arm?

  2. If both letrozole and the placebo or palbociclib were discontinued, what is the difference between the group permanently discontinuing the study and those labeled as permanently discontinuing letrozole?

The most common treatment-emergent, all grades, all-causality AEs (reported in >10% of patients either arm) were presented. These data were presented by individual MedDRA terms and thus the summary below is done by the evaluator, bringing together terms that capture similar or identical events. The most commonly reported treatment emergent adverse events (TEAEs) in the palbociclib and letrozole arm experienced by >20% of patients were neutropenia (85.8%; ‘neutrophil count decreased’, ‘neutropenia’), fatigue (37.4%), nausea (35.1%), and vomiting (15.5%), arthralgia (33.3%), alopecia (32.9%), diarrhoea (26.1%), cough (25%), leucopenia (23.9%), anaemia (23.2%), back pain (21.6%), headache (21.4%) and hot flushes (20.9%).

Bone marrow suppression occurred much more commonly in the palbociclib than comparator arm: neutropenia/neutrophil count decreased (85.8% versus 6.4%), white blood cell decreased (16.2% versus 1.8%), anaemia (23.2% versus 9%), leukopenia (23.9% versus 0.5%).

Other TEAEs that occurred > 5% more commonly in the palbociclib and letrozole arm than the comparator arm were: fatigue, nausea, alopecia, diarrhoea, cough, asthenia, stomatitis, decreased appetite, dry skin, abdominal pain, peripheral oedema, dysgeusia.

The most common TEAEs in the placebo and letrozole arm were arthralgia (33.8%), hot flushes (30.6%), fatigue (27.5%), nausea (26.1%), headache (26.1%) and back pain (21.6%). The only adverse events that was experienced more commonly by >5% patients in the comparator arm were hot flushes.



Comment:

  1. The addition of palbociclib to letrozole resulted in a dramatic increase in severe adverse events. The most striking increase was in the rates of bone marrow suppression, as with Study 1023. However, there were also increases in adverse events that have significant potential to affect quality of life. No data were presented in the top line summary to address the impact of these adverse events on patient reported outcomes. This is important given this is a palliative treatment and there has not been a demonstrated improvement in overall survival to date.

  2. Amongst most common reported TEAEs between the palbociclib arms in both Studies 1008 and 1023, there were 2 notable differences:

  1. The absolute rates of alopecia were more than double those receiving palbociclib in Study 1008 (32.9%) compared with Study 1023 (16.3%). The increase in alopecia in the palbociclib and letrozole arm over the comparator arm in Study 1008 (17.1%) was higher than the increase in the palbociclib and fulvestrant compared with comparator arm in Study 1023 (10.4%). More than one third of women experienced alopecia, while taking palbociclib and letrozole which is a distressing side effect for most patients.

  2. Events rates for TEAEs of thrombocytopenia were not reported as occurring below 10% in Study 1008. This is an artefact of the high cut-off threshold of ≥ 10% in either arm and use of separate MedDRA terms for TEAE reporting; the combination of treatment-related thrombocytopenia/platelet count decreased was 14.9% in the experimental arm and 1.4% in the comparator that is, a 10-fold increase in risk, with the lower cut-off of 5% reporting the treatment-related AEs. Furthermore with the lower threshold in the treatment-related events table, the adverse event of epistaxis also emerges which could be linked to the low platelets (this issue should be addressed when providing the CSR for Study 1008). Grade 3 or 4 thrombocytopenia occurred in 1.3% of the experimental arm with no cases in the comparator arm. When submitting the CSR for Study 1008, the sponsor is requested to include a table of TEAEs with a cut-off of ≥ 2% in either arm to assist identification of events that may require inclusion in the PI to inform clinicians and patients. The assessment of attribution of AEs considered treatment-related cannot be made without knowing the percentage listed as treatment-emergent. (Clinical Questions).

Events of severity Grade 3 or higher were very common and substantially higher in the palbociclib and letrozole arm than the placebo and letrozole arm (77.9% versus 26.1%). The rates of Grade 3 events, Grade 4 events and Grade 5 events were (respectively) 62.2%, 13.5% and 2.3% in the palbociclib and letrozole arm and 22.1%, 2.3% and 1.8% in the placebo and letrozole arm.

In the palbociclib and letrozole arm the majority of events of severity Grade 3 or higher were due to neutropenia or neutrophil count decreased (70.3% versus 1.4%) as well as other parameters indicating bone marrow suppression; other severe TEAEs that occurred more frequently in the palbociclib and letrozole arm than comparator were aspartate aminotransferase increased (2.3% versus 0.9%), alanine aminotransferase increased (2.3% versus 0), febrile neutropenia (1.8% versus 0%), back pain (1.4% versus 0), thrombocytopaenia (1.4% versus 0), general physical deterioration (1.1 versus 0.5%), pneumonia (1.1 versus 0.9), and urinary tract infections (1.1 versus 0%).

There were 10 deaths in the experimental arm and 4 in the comparator arm, with death from a pulmonary embolism in each arm the only TEAE recorded in this section – this is discussed further in the section on on-study deaths below.

        1. Other studies


Combination of palbociclib and letrozole Study 1003, Study 1010

Study 1027 is blinded and the data are not evaluable for the 20 patients randomised (1:1) enrolled to date.

Study 1003 was conducted as a Phase I, non-randomised safety and PK dose finding study of 12 patients and Phase II was a randomised, controlled open label comparison of palbociclib plus letrozole compared with letrozole alone; it was conducted in 2 parts, subsequently amalgamated for a single assessment of safety.

Comment: The randomised data will be the focus of the assessment and evaluation of safety with descriptive information from the 12 patients in the Phase I part evaluated for additional signals. Given the limited information about safety available and in the inability to evaluate severe events and deaths, there is reliance upon the safety information from this smaller study.

Safety Analysis sets

Phase I


Safety Analysis Set: All patients that receive at least one dose of any agent of the combination.

Phase II


All Treated as Treated Set (AT): All treated patients classified by the treatment actually received.

Phase II


165 women were randomised in this study:

    • 83/84 postmenopausal women with ER-positive, HER2-negative advanced breast cancer were randomised to palbociclib plus letrozole treatment received at least 1 treatment;

      • 76 patients (90.5%) receiving palbociclib plus letrozole were permanently discontinued from treatment, while 7 patients (8.3%) were ongoing as of 31 July 2015;

    • 77/ 81 postmenopausal women with ER-positive, HER2-negative advanced breast cancer were randomised to letrozole alone received at least 1 treatment;

      • patients (92.6%) were permanently discontinued from treatment, while 2 patients (2.5%) were ongoing as of July 31 2015

No updated treatment exposure was provided in the 90-day safety update; from the SCS the median duration of treatment in the Phase II part of the study for palbociclib was approximately 13.8 months (421.0 days [range: 7 days - 1615 days]) and for letrozole was approximately 14.1 months (428.0 days [range: 7 days - 1615 days]). In the letrozole alone arm, the median duration of treatment was approximately 7.6 months (231.0 days [range: 28 days - 1241 days]). In the Study 1003 CSR (cut-off date 29 November 2013), the median dose intensity was 90.2% (range: 77.7-100.3) for the palbociclib and letrozole compared with 100% for letrozole (range: 98.4-100) – no update is provided.

In the Study 1003 CSR (cut-off date 29 November 2013), 100% in the palbociclib and letrozole arm experienced an AE (compared with 84.4% in the letrozole alone arm), 14.5% discontinued due to AEs, 38.6% required a reduction in the palbociclib dose and 62.7% required a dose interruption.

The SCS updates the occurrence of TEAEs to 85.7% in the letrozole alone arm and there were more events also in the experimental arm, but the additional events are not specified between the reports.

Comment: The CSR dose intensity levels reflect that adding in palbociclib results in significant toxicities requiring dose interruptions or reductions compared with letrozole alone. No updated information was provided in the SCS – updated Table as per Table 68 of Study 1003 CSR requested).

Table 26: Study A5481003 Overview of treatment-emergent adverse events Phase II As treated set. Source CSR, cut-off date November 29 2013 -no updated table provided in SCS see Clinical Question)



The most frequently reported TEAEs (20% of patients) in that treatment arm were neutropenia (74.7%), leukopenia (43.4%), fatigue (41.0%), anaemia (34.9%), nausea (30.1%), arthralgia (24.1%), hot flushes (22.9%), alopecia (21.7%), as well as decreased appetite and diarrhoea (20.5% each). The most frequently reported TEAE in the letrozole alone arm was fatigue (23.4%).

As of 2 January 2015, in Phase II (Ph2P1+Ph2P2), the following AEs were reported at a ≥ 10% greater frequency in the palbociclib plus letrozole arm compared with the letrozole alone arm:

Neutropenia/granulocytopenia/neutrophil count decreased (77.1% versus 5.2%);

Leukopenia (43.4% versus 2.6%);

Fatigue (41.0% versus 23.4%);

Thrombocytopenia/platelet count decreased (19.5% versus 1.3%);

Anaemia (34.9% versus 6.5%);

Nausea (30.1% versus 14.3%);

Alopecia (21.7% versus 2.6%);

Decreased appetite (20.5% versus 6.5%)

Dyspnoea (18.1% versus 7.8%)

Vomiting (14.5% versus 3.9%);

URT infection (13.3% versus 2.6%);

as of 2 January 2015 (SCS), the following were noted on review of the source tables:

Diarrhoea (20.5% versus 11.7%);

Neuropathy peripheral/ peripheral sensory neuropathy (14.4% versus 5.2%), including 1 patient with Grade 3 event in the palbociclib and letrozole arm.

Stomatitis (12% versus 2.6%)

No AEs were reported at a ≥ 10% greater frequency in the letrozole alone arm compared with the palbociclib plus letrozole arm.

Comment:


  1. Using the cluster terms for MedDRA preferred terms to capture related events increased both the numbers and the proportion with severe AEs such as neutropenia thus the differential between the arms would be likely to increase further for many of the events if presented by SOC by MedDRA preferred terms.

  2. Grade 1, 2 and 3 peripheral neuropathy is a prominent adverse event in this study and in Study 1023, and should be a Precaution and also included in the adverse drug reactions table in the PI (currently no mention of this anywhere). Frequency and severity have both increased over time which suggests a cumulative effect based on longer exposure (PI Comments).

80.7% of patients in the palbociclib and letrozole arm experienced at least one adverse event of >3 grading compared with 23.4% in the letrozole alone arm (no Grade 4 events). Grade 4 events occurred in 15 patients (18.1%) in the experimental arm: neutropenia (5/15), pulmonary embolism (5/15), fatigue (2/15), leukopenia, anaemia and bone pain (all one patient each). Grade 3 TEAEs were experienced by 61.4% in the experimental arm compared with 23.4% of the comparator arm.

Comment: Even with the high cut-off for reporting AEs of >10% in the palbociclib and letrozole arms and without using cluster terms - both of which would capture a larger number of high grade adverse events - there is a striking difference between the 2 arms indicating the addition of palbociclib is associated with a significant increase in toxicity, some of which are life-threatening. The draft PI currently does not adequately inform clinicians of these risks.

The CSR states that palbociclib and letrozole treatment was associated with an increased risk of developing stomatitis, constipation, asthenia, influenza, upper respiratory tract infection, nasopharyngitis, decreased appetite, bone pain, musculoskeletal pain, headache, epistaxis, dyspnoea, and cough; for back pain, the relative risk was <1. (CSR cut-off 29 November, 2013 – no update provided)



Comment: The clinical evaluator considers palbociclib and letrozole treatment is also associated with an increased risk of pulmonary embolism and peripheral neuropathy.
        1. Phase I


The Phase I part of the study (12 patients) revealed no additional toxicities over and above those described in the Phase II section. An AE of cataract development was reported in the SCS. The dose-limiting toxicities were neutropenia (2 cases) and a rise in creatinine (1 case) subsequently attributed at least in part to concomitant zoledronic acid. Notably, 2 patients developed pulmonary emboli (1 Grade 4), but no patients discontinued treatment permanently and no treatment-related or SAE-related deaths were reported. The overall rate of all-causality treatment-emergent Grade 3/4 Neutropenia was 91.7% (66.7% Grade 3, 16.7% Grade 4) and dose reductions of palbociclib due to any TEAE was 25.0%, with neutropenia the most common reason for dose reduction (16.7%).
        1. Study 1010

Phase I Part 1

Dose limiting toxicities were consistent with those observed in other trials (neutropenia and thrombocytopenia).
Phase I Part 2

All 6 patients experienced a TEAE: 4 patients had Grade 3 events (neutropenia, white blood cell decreased, pyrexia, urinary tract infection) and 2 patients had Grade 4 events (neutropenia (2) and gastrointestinal perforation (1)).

A small postmarketing study, Study 1034 provides limited safety information from the 90-day safety update and the narratives provided. No CSR is provided.


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