alternative trial - journal club

1. Phase III, Randomized Study of Dual Human
Epidermal Growth Factor Receptor 2 (HER2)
Blockade With Lapatinib Plus Trastuzumab in
Combination With an Aromatase Inhibitor in
Postmenopausal Women With HER2-Positive,
Hormone Receptor–Positive Metastatic Breast Cancer:
Updated Results of ALTERNATIVE

2. Metastatic Breast Cancer (MBC)
Landscape
HER2+
Triple negative
~15%
• Dawood S, et al. Survival differences among women with de novo stage IV and relapsed breast cancer. Ann Oncol. 2010
Nov;21(11):2169-74.
• Howlader N, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst.
2014 Apr 28;106(5). pii: dju055.
Women
living with MBC
HR+
HR+/HER
2-
~61%
HR+/HER
2+
~15%
HR-
/HER2+
~9%
Roughly 30% of women who
have had early disease will
develop advanced or
metastatic disease
6% to 10% of all women with
breast cancer present with
metastatic disease at the
time of initial diagnosis3
(20-25%)

3.  Endocrine therapy alone or in combination with HER2- targeted
therapy is a less toxic approach compared with HER2-targeted
therapy combined .
 But due to aggressive nature of this subgroup --patients with HER2-
positive metastatic breast cancer (MBC) are usually treated with
chemotherapy-based regimens irrespective of HR status.
 However, not all patients with HER2-positive/HR-positive MBC
may need or tolerate chemotherapy, and these patients could be
candidates for anti-HER2 therapies plus ET.
Her2-targeted therapy plus chemotherapy
Endocrine therapy alone +/- with her2-targeted therapy

5. HER 2 targeted therapies

6. HR+ Her2 + Breast Cancer

7. Resistance:
• Preclinical evidence suggests that cross talk between HER2- and HR-
signaling pathways contributes to endocrine resistance.

8. • Furthermore, in HER2-positive and estrogen receptor (ER)–positive BC
cells, either HER2 or ER can function as the major promoter of survival.
• With effective HER2 inhibition in these cells, ER can become the primary
driver of proliferation, resulting in relative resistance to anti-HER2
therapy.
• Therefore, co-targeting HER2 and ER simultaneously may be essential
for obtaining optimal benefit in patients with HER2-positive/HR-positive
MBC.

9. Trastuzumab
Pertuzumab
Lapatinib
T-DM 1
Anastrozole
Letrozole
Exemestane

10. TAnDEM (Trastuzumab and Anastrozole Directed Against
ER-Positive HER2-Positive Mammary Carcinoma )
 Improved PFS from 4.8m to 2.4m(hazard ratio = 0.63; 95% CI, 0.47 to 0.84; log-
rank P = .0016).
 In patients with centrally confirmed hormone receptor positivity (n = 150), median
PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole
alone arms, respectively (log-rank P = .006).
 Overall survival showed no statistically significant difference.

12.  Median PFS in the HER2+ population was significantly increased
from 3.0 months in the letrozole group to 8.2 months in the
lapatinibletrozole group [Hazard Ratio (95% CI)=0.71(0.53,0.96),
stratified log rank p=0.019].
 Overall response rate (ORR) in the HER2+ population was
significantly increased from 14.8% to 37.9% in the combination group
[Odds Ratio = 0.4 (0.2, 0.9), p=0.021], with a clinical benefit rate
(CBR) improvement from 28.7% to 48.7% [Odds Ratio = 0.4
(0.2,0.8), p=0.003].
 There was no difference in ORR or CBR in the HER2 negative
population

13. Dual Her2 Blockade
 The use of dual anti-HER2 blockade represents a potential strategy
to further improve the outcome for these patients.
 preclinical models of her2-positive BC have shown that a
combination of TRAS and lap results in a more optimal anticancer
effect.
 Dual targeting of HER2-positive tumors with TRAS and LAP is
beneficial because of differing mechanisms of action and because of
the well-characterized synergistic interaction between them in
HER2 BC models.
 In the clinic ,dual Her2 blockade has shown to improve outcomes in
both the neoadjuvant and the metastatic setting compared with
single HER2 blockade

15. EGF104900 Study
Combination resulted in :
 An improvement in PFS (median, 11 versus 8 weeks; HR 0.74, 95% CI
0.58-0.94)
 An improvement in OS (median, 14 versus 10 months; HR 0.74, 95%
CI 0.57-0.97)

16.  Therefore, the current study (EGF114299) was designed to evaluate
whether dual HER2 blockade with LAP and TRAS plus aromatase
inhibitor (AI), without chemotherapy, improves outcomes compared
with TRAS plus AI in patients with HER2-positive/HR-positive
MBC who experienced disease progression after prior
neo(adjuvant)/first-line TRAS plus chemotherapy.
 The study also included a third arm of LAP plus AI to explore
whether this combination results in different outcomes compared
with the other 2 arms.

18. On July 30, 2018, during Food and Drug Administration (FDA) review of the primary
analysis study report, the FDA identified :
 Programming error in the calculation of the hazard ratio and P value estimates of
the secondary end points of PFS and OS for LAP plus aromatase inhibitor (AI)
versus TRAS plus AIs. This error did not affect the hazard ratios for PFS and OS
for the primary end point of comparison and therefore, the interpretation of the
main objective of the study remained unchanged.
 Summary of the best overall response (BOR) categories. The sum of the individual
patients in each response category (complete response [CR], partial response [PR],
stable disease [SD], progressive disease [PD], and not evaluable [NE]) did not add
up to the number of patients in the intent to-treat population because some NE
patients (ie, those with no baseline and/or postbaseline tumor assessments) were
missed as being NE.
 The response assessment date was mapped incorrectly using the visit date instead
of the tumor scan date, which led to incorrect derivation of time-to-event efficacy
end points.

20. MATERIALS & METHODS
Study Design :
 Phase III
 Open-label study
 Eligible patients were randomly assigned (1:1:1) to
receive either LAP plus TRAS or TRAS or LAP, plus an
AI, hereafter referred to as the LAP plus TRAS plus AI,
TRAS plus AI, and LAP plus AI treatment arms,
respectively

21.  LAP + TRAS + AI arm ----- LAP dose –1000mg/day
 LAP + AI arm ------ LAP dose – 1500mg/day
 TRAS was administered intravenously at a loading dose of 8 mg/kg,
followed by the maintenance dose of 6 mg/kg intravenously every 3
weeks in both TRAS arms.
 Investigator’s choice of oral AIs was given among letrozole ,
anastrozole, exemestane.
 It was highly recommended that patients receiving LAP initiate a
prescription of loperamide treatment at the onset of diarrhea.

22. Inclusion Criteria :
 Postmenopausal women >18 years of age
 Histologically or cytologically confirmed HR-positive, HER2- positive
MBC as determined in a local laboratory.
 Prior treatment with ET and disease progression during or after a prior
regimen containing TRAS plus chemotherapy in the neo(adjuvant)
setting and/or in the first-line metastatic setting was required (maximum
of 1 prior regimen in the metastatic setting).
 ECOG performance status 0 or 1.
 Good baseline organ function-hematologic, hepatic, and renal
 No active or history of cardiac disease were included.

23. Objectives :
Primary:
 To evaluate the superiority of progression-free survival
(PFS; radiologic progression only as per investigator
assessment or death) with LAP plus TRAS plus AI
versus TRAS plus AI using RECIST version 1.1.
 Non radiologic response was based on clinical signs and
symptoms.
 PFS and response rate were based on radiologic
assessment only.

24. Secondary objectives
 PFS in defined subgroups
 Overall response rate (ORR)
 Clinical benefit rate (CBR; either complete response or
partial response or stable disease for at least 6 months)
 Duration of response
 Overall survival (OS)
 Safety
 Change in QOL status from baseline

26. Procedure
 Tumor samples were collected and retrospectively analyzed for
confirmation of HR and Her 2 status according to ASCO–College of
American Pathologists clinical practice guidelines.
 Tumor assessments were performed at baseline, within 28 days of
random assignment, and every 12 weeks thereafter until disease
progression or discontinuation of the study treatment, and at the end
of the study.
 Efficacy assessments were performed locally using radiologic
scans, including computed tomography or magnetic resonance
imaging. Safety was monitored throughout the study

27.  The severity of adverse events (AEs) was graded according to the
National Cancer Institute Common Terminology Criteria for
Adverse Events version 4.0.
 Left ventricular ejection fraction (LVEF) was evaluated every 12
weeks using echocardiogram and/or multigated acquisition scan.
 Patient-reported health-related QoL outcomes were evaluated using
the Functional Assessment of Cancer Therapy- Breast questionnaire

28. Statistical Analyses :
 A minimum of 121 PFS events in the LAP plus TRAS plus AI and
TRAS plus AI treatment arms was required to achieve 80% power
(2-sided a 5 0.05) to detect a 67% increase (hazard ratio, 0.60) in
mPFS (from an estimated 7 months in the TRAS plus AI arm to
11.7 months in the LAP plus TRAS plus AI arm).
 The intent-to-treat population, comprising all randomly assigned
patients, was used for efficacy analyses.
 PFS and OS across treatment arms were estimated using the
Kaplan-Meier method .
 Comparison of PFS for the primary end point was per- formed using
a 2-sided stratified log-rank test (using baseline stratification
factors).

29.  The Pike estimator was used to estimate the hazard ratio, together
with the 95% CI.
 Two sensitivity analyses for PFS were performed, in which
nonradiologic progressions and receipt of a subsequent anticancer
therapy were treated as events.
 The effect of prespecified baseline prognostic factors (including
measurable disease, type of AI, and prior TRAS usage) on PFS was
determined using a predefined stepwise Cox regression model.
 A stratified Fisher’s exact test was used for ORR comparison
between treatment arms.

30. RESULTS

31.  Study enrolment till March 11, 2016
 355 patients were enrolled across 112 sites in 29 countries.
 Two thirds of the patients had received a prior TRAS
chemotherapy–containing regimen in the neo(adjuvant)
setting only, and one third in the metastatic setting (with or
without prior TRAS in the neo[adjuvant] setting.
 Prior ET included tamoxifen (55%), ANA(29%), LET (28%),
and EXE (8%).

32.  In the LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI
arms, 68%, 57%, and 65% of patients, respectively, received study
treatment in the first-line metastatic setting, and 32%, 41%, and
35% of patients, respectively, in the second-line setting (or later).
 EXE (47%) was the most common AI received by patients in the
study, followed by LET (42%) and ANA (11%).
 Prior therapy in the metastatic setting included fulvestrant (n=2),
PTZ (n=17), and T-DM1 (n=1).

36.  The overall median duration of treatment across all
treatment arms was 53.6 weeks.
 The median duration of LAP treatment was 35.8 weeks
in the LAP plus TRAS plus AI arm and 24.7 weeks in
the LAP plus AI arm.
 The median duration of TRAS treatment was 36 weeks
in the LAP plus TRAS plus AI arm and 18 weeks in the
TRAS plus AI arm.

37. PROGRESSION FREE SURVIVAL

38.  A similar magnitude of benefit favoring the LAP plus TRAS plus AI
arm was observed in the following 2 sensitivity analyses of PFS:
(1) Not censoring patients receiving alternative anticancer therapies
before a PFS event (hazard ratio, 0.65 [95% ci, 0.47 to 0.91])
(2) Inclusion of nonradiologic progressions (1 and 2 additional events,
respectively) as events (hazard ratio, 0.64 [95% CI, 0.46 to 0.89] .
 A consistent PFS benefit with LAP plus TRAS plus AI was observed in
predefined subgroups: patients with measurable disease, patients treated
with AIs (steroidal/nonsteroidal), and patients who had already received
TRAS in a neo(adjuvant) or metastatic setting

40.  Cox regression analysis including all factors that had a significant
effect on PFS in addition to treatment showed that the PFS benefit
with LAP plus TRAS plus AI was consistent with the primary
analysis (hazard ratio, 0.56 [95% CI, 0.396 to 0.796]).
 A consistent PFS benefit with LAP plus TRAS plus AI was
observed in the centrally confirmed HER2-positive subpopulation
(by FISH or IHC: hazard ratio, 0.63 [95% CI, 0.40 to 1.01], and by
FISH only: hazard ratio, 0.57 [95% CI, 0.35 to 0.94]).
 Similarly, in the centrally confirmed HER2-positive/HR-positive
subpopulation, the benefit of LAP plus TRAS plus AI was
confirmed (hazard ratio, 0.72 [95% CI, 0.43 to 1.23]).

41. Overall Response Rate
 The ORR with LAP plus TRAS plus AI, TRAS plus AI, and LAP
plus AI was 31.7%, 13.7%, and 18.6%, respectively

42. Duration of Response
 The median duration of response was 14.0
months, 8.4 months, and 11.1 months,
respectively.
 The Clinical Benefit Rate was 40%, 30%, and
34%, respectively.

43. Overall Survival :
 OS data for LAP plus TRAS plus AI versus TRAS plus AI were
immature at the time of the current analysis (median OS, 46.0 v 40.0
months; hazard ratio, 0.60 [95% CI, 0.35 to 1.04] but trended in favor
of the LAP plus TRAS plus AI versus the TRAS plus AI arm, in line
with the primary PFS analysis.

44. Safety

45.  The incidence of serious adverse events (SAEs) irrespective of
causality the LAP plus TRAS plus AI, TRAS plus AI, and LAP plus
AI arms was 14%, 10%, and 17%, respectively, and treatment-
related SAEs were 5%, 2%, and 4%, respectively.
 On-treatment deaths were reported in 3 (3%), 5 (4%), and 6 patients
(5%), respectively.
 All deaths were a result of disease progression, with the exception
of 1 death as a result of cardiogenic shock and 1 death as a result of
organ failure in the LAP plus AI arm and 1 death as a result of
cardiopulmonary arrest in the TRAS plus AI arm.

46. Cardiac events :
 One, 3, and 2 patients in the LAP plus TRAS plus AI,
TRAS plus AI, and LAP plus AI arms, respectively,
discontinued treatment as the result of LVEF
decrease/cardiogenic shock.
LAP+ T + AI T + AI LAP + AI
Cardiac safety events 7% 3% 2%
Any decrease in LVEF 59% 65% 65%
>20% decrease in LVEF 3% 2% 0%
Less than lower limit of
normal
5% 1% 4%

47. Treatment discontinuation
 Overall, the incidence of AEs leading to discontinuation of study
treatment was low (3% for LAP plus TRAS plus AI [n=4];
6%forTRAS plus AI [n=7]; and 9% for LAP plus AI [n=11]).
 The most frequent AE leading to discontinuation was transaminases
increase (n=8), which occurred in the LAP plus AI arm in which the
dose of LAP was the highest.
 LAP dose reduction was observed in 20% of patients in the LAP
plus TRAS plus AI arm and in 17% of patients in the LAP plus AI
arm; the primary reasons for reduction were AEs (71% and 37%,
respectively) and patient noncompliance (25% and 63%,
respectively).

48.  Dose interruptions of LAP in the LAP plus TRAS plus AI and the
LAP plus AI arms were required in 38% and 35% of patients,
respectively, mainly because of AEs (51% and 50%, respectively).
 In the LAP plus TRAS plus AI and TRAS plus AI arms, dose delays
of TRAS were recorded in 19% and 9%, respectively; the main
reasons for the delays were AEs (38% and 15%, respectively) and
noncompliance (28% and 15%, respectively).

49.  Treatment discontinuation was reported in 75%, 82%, and 84% of
patients in the LAP plus TRAS plus AI, TRAS plus AI, and LAP
plus AI arms, respectively.
 The most common reasons for discontinuation in the LAP plus
TRAS plus AI, TRAS plus AI, and LAP plus AI arms were disease
progression (64%, 72%, and 70%, respectively) and AEs (4%, 6%,
and 9%, respectively).

50. DISCUSSION

51.  This is the first large, randomized clinical trial
exclusively evaluating this chemotherapy-sparing
regimen in a HER2-positive/HR-positive MBC
population of patients who had already received prior
ET and prior TRAS plus chemotherapy in the
neo(adjuvant) and/or first- line metastatic setting

52.  It demonstrated that the combination of LAP plus TRAS plus AI
provided a clinically meaningful prolongation of PFS compared with
TRAS plus AI (mPFS, 11.0 v 5.6 months, respectively), representing a
statistically significant 38% reduction in the risk of disease
progression (hazard ratio, 0.62).
 The PFS benefit was observed consistently in various subgroups of
patients. Furthermore, the ORR (31.7% v 13.7%) and CBR (40% v
30%) favored the LAP plus TRAS plus AI combination.
 Although survival data were immature, there was also a trend in favor
of the dual-blockade treatment (median, 46.0 versus 40.0 months).

53.  The PFS outcome observed with LAP plus TRAS plus AI in
ALTERNATIVE is in line with the results of various chemotherapy
plus single HER2 blockade regimens in patients with HER2-
positive MBC (including both HR-positive and HR-negative
patients) treated previously with TRAS and ET.
 Trials specifically designed for patients with HER2-positive/HR-
positive MBC evaluating chemotherapy plus single blockade are
limited.

54. PERTAIN- Dual Her2 blockade in metastatic setting

55. PERTAIN
However, this trial was conducted only in the first-line metastatic setting,
and approximately 77% of patients were TRAS naıve and 55% of patients
had received induction chemotherapy.

56. Dual Her2 blockade in adjuvant
setting :

57. APHINITY

58.  Invasive disease–free survival rates were 90.6% for pertuzumab vs
87.8% for placebo in the intent-to-treat population.
 Node-positive patients had clear benefit from the addition of
pertuzumab, with an absolute 4.5% improvement in 6-year invasive
disease–free survival: 87.9% with pertuzumab vs 83.4% with
placebo.
 No treatment effect was observed in the node-negative population in
the two arms: 95% and 94.9%, respectively.

59.  This discrepancy may be the result, at least in part, of
the excellent outcome with adjuvant single HER2
blockade with TRAS, making the demonstration of
additional benefit with dual blockade challenging.
 Dual HER2 blockade may benefit only a small subset of
high-risk patients.

60.  ALTERNATIVE included a third arm investigating LAP plus AI,
which was a mandated study design after the EGF30008 study and
the approval of LAP plus LET.
 The median PFS in the LAP plus AI arm was 8.3 months, which
was not statistically different compared with 5.6 months with TRAS
plus AI in patients with HER2-positive/HR- positive MBC
previously treated with TRAS plus ET.
 This finding is consistent with the findings of other randomized
trials in BC that compared LAP- and TRAS-containing regimens.

61.  The safety profile of the 3 treatment arms was consistent with the
known safety profile of LAP and TRAS.
 The frequency of AEs, mostly grade 1 or 2, was higher in the 2 LAP
arms (92% each) than in the TRAS arm (74%).
 Diarrhea, rash, paronychia, and nausea were among the most
frequent AEs.
 However, the frequency of grade 3 or 4 AEs and SAEs was similar
in the 3 arms, with the exception of grade 3 diarrhea, which was
higher in the LAP plus TRAS plus AI arm (13%).

62. CONCLUSION
 The PFS benefit obtained with LAP plus TRAS plus AI in patients with
HER2-positive, HR-positive MBC who had been treated previously with
TRAS and ET is clinically meaningful and robust.
 The ALTERNATIVE trial showed relevant clinical benefit with a relatively
good tolerability, supporting the finding that patients with HER2-
positive/HR-positive MBC who are not candidates for chemotherapy can be
adequately treated with dual HER2 blockade (LAP plus TRAS) plus an AI.
 This combination can potentially offer an effective and well-tolerated,
chemotherapy-sparing alternative treatment regimen for patients for whom
chemotherapy is not intended.