ALTTO results from ASCO 2014--addition of lapatinib to herceptin+taxane although

[Lani]

better neoadjuvantly, did not significantly improve DFS (disease free survival) in the adjuvant setting. Nevertheless, the patient stats are excellent 4 year overall survival exceeded 90% in all treatment groups. THe additional diarrhea and rashes (and cost) associated with adding lapatinib were not felt to be worth it --here is a summary below:



ALTTO: randomized, open-label, multicenter phase III trial[1]

Summary of Key Conclusions

Dual HER2 blockade with lapatinib (L) and trastuzumab (T), either sequentially or in combination, failed to significantly improve DFS vs T alone in patients with early-stage breast cancer
No significant differences seen in overall 4-year DFS
No DFS differences in subgroups stratified by hormone receptor status or timing of chemotherapy
High rates of 4-year DFS (> 80%) and OS (> 90%) in all treatment groups studied
Treatments containing L associated with increased toxicity compared with T alone
Increased pathologic CR rates with L + T in NeoALTTO trial did not translate into improved survival after 4.5-year follow-up
Study follow-up will continue to planned efficacy analysis in 2 years

Background

HER2 blockade for breast cancer
T greatly improves DFS in early-stage breast cancer
The HER2/EGFR inhibitor lapatinib has promising preclinical and clinical activity for combination treatment
NeoALTTO trial: neoadjuvant L + T significantly increased pathologic CR rate over either single agent[2]
ALTTO trial evaluated effect of dual HER2 blockade with adjuvant L + T on survival in patients with HER2-positive breast cancer

Schematic of Study Design

Eligibility

Early stage HER2-positive breast cancer
Histologically confirmed nonmetastatic operable primary invasive adenocarcinoma of the breast
Known hormone receptor status (estrogen receptor/progesterone receptor or estrogen receptor only)
ECOG performance status ≤ 1
No history of previous invasive breast carcinoma
No current or past history of melanoma

Baseline Characteristics

8381 patients from around the world randomized between June 2007 and July 2011
Efficacy results for 6281 patients were presented because the L arm was closed in August 2011 for futility and data were not presented
Treatment arms well balanced, including for trial stratification factors
Relatively high proportion of patients with node-negative disease
Relatively high proportion of patients with small tumors

Characteristic


L + T (n = 2093)


T → L (n = 2091)


T (n = 2097)

Hormone receptor positive, %


57


58


57

Chemotherapy timing, %


Sequential



55


55


55

Concurrent



45


45


45

Lymph node status, %


Negative



40


40


40

1-3 positive



29


30


29

≥ 4 positive



22


22


22

N/A (neoadjuvant chemotherapy)



8


8


9

Menopausal status, %


Premenopausal



43


44


43

Postmenopausal or male



57


56


57

Primary tumor size, %


≤ 2 cm



45


46


46

2-5 cm



49


48


48

> 5 cm



6


6


6

Missing, n



27


41


38

Histologic grade, %


x: not assessable



4


3


3

1: well differentiated



2


3


2

2: moderately differentiated



37


38


36

3: poorly/undifferentiated



57


56


59

Missing, n


10


7


9
N/A, not applicable.
Description of Current Analysis

Primary endpoint: DFS
First invasive breast cancer recurrence (any site)
Second primary cancer (first occurrence)
Death (any cause) as first event
Secondary endpoints
OS
Safety
Cardiac safety
Analysis planned after 850 DFS events or 4.5-year median follow-up in 8000 patients
Event rate lower than expected analysis completed with 555 events at 4.49-year median follow-up
Current analysis of pairwise comparisons
Lapatinib-alone arm closed after interim efficacy analysis in August 2011; patients switched to trastuzumab arm

Main Findings

High rates of 4-year DFS in all treatment groups
L + T combination reduces risk of DFS event by 16% compared with T alone in early-stage breast cancer; not significant change
No difference in DFS between sequential T → L and T alone

Result


L + T (n = 2093)


T → L (n = 2091)


T (n = 2097)

4-yr DFS


88


87


86

HR vs T (97.5% CI)


0.84 (0.70-1.02)


0.96 (0.80-1.15)


P value


.048


.61


Greatest effect of L + T seen in hormone receptor positive population and those receiving sequential chemotherapy but all differences nonsignificant

4-Yr DFS Outcome, % (n)


L + T


T → L


T

Hormone receptor positive


90 (1203)


89 (1205)


88 (1200)

Hormone receptor negative


86 (890)


84 (886)


83 (897)

Sequential chemotherapy


86 (1155)


85 (1143)


83 (1147)

Concurrent chemotherapy


90 (938)


89 (948)


90 (950)

Very high 4-year OS rates with no differences between treatment groups
L + T: 95% (HR: 0.80; 95% CI 0.62-1.03; P = .078)
T → L: 95% (HR: 0.91; 95% CI 0.71-1.16; P = .433)
T alone: 94%
4-year DFS analysis in per protocol population did not show noninferiority of T → L compared with T alone
87% in T → L arm vs 86% in T arm (HR: 0.93; 97.5% CI 0.76-1.13; P = .044)
Null hypothesis HR: 1.11
L associated with unfavorable toxicity profile compared with T
Higher rates of diarrhea, hepatobiliary events, rash/erythema
Cardiac toxicity low in all arms

Event, %


L + T (n = 2061)


T → L (n = 2076)


T (n = 2076)

Any grade


Diarrhea



75


50


20

Hepatobiliary



23


24


16

Rash or erythema



55


49


20

Grade ≥ 3


Diarrhea



15


5


1

Hepatobiliary



3


3


1

Rash or erythema



5


4


1

Any cardiac event


3.7


2.4


4.5

Primary cardiac event


0.97


0.25


0.86
Other Outcomes

Fewer patients received optimal dosing of L compared with T

≥ 85% Planned Dose Received, %


L + T


T → L


T

Sequential chemotherapy


(n = 1155)


(n = 1143)


(n = 1147)

L



72


78


--

T



92


97


94

Concurrent chemotherapy


(n = 938)


(n = 948)


(n = 950)

L



60


74


--

T



91


98


92
References

1. Piccart-Gebhart MJ, Holmes AP, Baselga J, et al. First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T → L), or their combination (T + L) in the adjuvant treatment of HER2-positive early breast cancer (EBC). Program and abstracts of the 50th Annual Meeting of the American Society of Clinical Oncology; May 30 - June 3, 2014; Chicago, Illinois. Abstract LBA4.

2. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633-640.