summary of lapatinib and associated major trials

1. Lapatinib
DR POOJA GUPTA
RESIDENT MEDICAL ONCOLOGY

2. • Tyrosine kinase inhibitor
• Reversible binding to cytoplasmic domain of EGFR (ErbB1)
and HER2
• Blocking phosphorylation and activation of downstream
second messengers

3. • Combination therapy with lapatinib and endocrine therapy may
overcome endocrine resistance in HER2 and HR positive disease.
• Lapatinib as a small molecule can penetrate the blood-brain
barrier and, therefore, was claimed for therapy and prevention of
brain metastases
• Non cross resistant with trastuzumab

4. Pharmacodynamics
• ABSORPTION:
• Oral absorption is incomplete and variable and is increased when
administered with food.
• DISTRIBUTION
• Extensive binding (99%) to plasma proteins, including albumin and α1-
acid glycoprotein, and extensive tissue distribution.
• Peak plasma levels are achieved 4 hours after ingestion.
• Steady-state drug concentrations are reached in 6 to 7 days

5. • METABOLISM
• Metabolism in the liver primarily by the CYP3A4 and CYP3A5
microsomal enzymes and by CYP2C19 and CYP2C8 to a lesser extent.
• Elimination is mainly hepatic, with excretion in the feces, and renal
elimination of parent drug and its metabolites accounts for less than 2%
of an administered dose.
• The terminal half-life of the parent drug is 14 hours, and with repeat
dosing, the effective half-life is 24 hours

6. Drug interaction

7. INDICATIONS
• FDA-approved in combination with capecitabine for patients with
advanced or metastatic breast cancer whose tumors overexpress HER2
and who have received prior therapy, including an anthracycline, a
taxane, and trastuzumab.
• Metastatic breast cancer in postmenopausal women where hormone
therapy is indicated in combination with letrozole.
OFF-LABEL INDICATION:
• Neoadjuvant dual HER2 blockade with trastuzumab
• Metastatic gastric, GEJ adenocarcinoma in combination with
capecitabine and oxaliplatin

8. • DOSAGE RANGE
• oral formulation Tykerb 250 mg
• Recommended dose is 1,250 mg PO daily on days 1–21 continuously in
combination with capecitabine 1,000 mg/m2 PO bid on days 1–14, with
each cycle repeated every 21 days.
• 1500mg once daily in combination with letrozole
• 1000mg once daily in combination with trastuzumab
• Lapatinib should be taken 1 hour before or after a meal, and the daily
dose should not be divided. When capecitabine is co-administered,
capecitabine should be taken with a glass of water within 30 minutes
after a meal.

9. Adverse reaction
A (>10%)
• Diarrhea is the most common dose-limiting toxicity and occurs in 65% of
patients.
• Mild nausea/vomiting may also occur. (31 to 44%)
• Myelosuppression, with anemia more common than thrombocytopenia or
neutropenia. (56%, grade 3: <1%)
• Fatigue and anorexia (20%)
• Hand-foot syndrome (palmar-plantar erythrodysesthesia) and skin rash.
(53%)
• Pulmonary toxicity- dyspnoea (12%), epistaxis (11%)

10. • Hepatic toxicity:
• Mild-to-moderate elevation of serum transaminases and serum bilirubin.
(30 to 40%)
• Onset occur with in days to several months
• Monitor transaminases level , bilirubin and alkaline phosphatase at
baseline and every 4 to 6 wks

11. B (1 TO 10%)
• Insomnia 10%
• Cardiac toxicity with reduction in LVEF.
• With capecitabine (grade2-2%, grade 3-<1%)
• With letrozole (5%)
• QT prolongation (rare <1%)

12. • Dose adjustment:
• Renal impairment- no adjustment , minimal renal elimination
• Hepatic impairment-
• Mild to moderate preexisting impairment- no adjustment
• Severe preexisting impairment- reduce dose from 1250 to 750 once
daily in combination with capecitabine, From 1500 mg to 1000mg
once daily in combination with letrozole.
• Severe hepatic toxicity during treatment- discontinue , do not
rechallenge

13. • Diarrhea- interrupt the treatment in grade 3, may restart with reduced
dose (from 1500 mg od to 1250mg od or from 1250mg od to 1000mg od)
when resolve to grade 1 or normal.
Grade4 diarrhea permanently discontinue
• Cardiac toxicity- discontinue for at least 2 wks in grade 2 or higher
LVEF decline, if recovers to normal may be restarted at 1000mg OD (in
combination with capecitabine) or 1250mg once daily (in combination
with letrozole).
• Pulmonary toxicity- discontinue treatment for grade 3 or higher
pulmonary symptoms (ILD, pneumonitis)

14. Trials: breast
• Neoadjuvant :
• NEOALTTO
• NSABP-41
• GEPARQUINTO
• Adjuvant-
• ALTTO
• TEACH
• Metastatic
• LANDSCAPE
• EGF104900
• CEREBEL
• EGF 100151
• EGF 30008
• EMILIA
• ALTERNATE

15. NEOALTTO
• 2012 included 455 HER2-positive patients who had tumours at least 2 cm in
diameter .
• Combination of lapatinib and Trastuzumab led to a significantly higher pCR
rate (51.3%) than that of the monotherapy arms.
• The response to lapatinib was numerically lower than to Trastuzumab,
although the difference did not reach statistical significance.
• The dual combination was associated with higher toxicity, especially
diarrhoea and hepatotoxicity, and more patients discontinued therapy because
of adverse events.

17. Neo ALTTO: Survival Follow-up Analysis
Piccart M et al, SABCS 2013 abstract #S1-01
Lapatanib +
Trastuzumab
Trastuzumab Lapatinib
3 yr EFS (all) 84% 78% 78%
HR+ 83% 80% 86%
HR- 86% 72% 70%
3 yr OS (all) 95% 90% 93%
HR+ 97% 94% 93%
HR- 93% 87% 93%
None statistically significant

19. • Combination of lapatinib and Trastuzumab led to a
significantly higher pCR rate (51.3%) than that of the
monotherapy arms.
• The response to lapatinib was numerically lower than to
Trastuzumab, although the difference did not reach statistical
significance.
• Patients who achieved pCR had significantly better EFS and
OS compared with no pCR
• HER2+/ER- disease different from HER2/ER+ disease

22. GeparQuinto trial, 2012
• This randomized phase III study included 620 patients with
operable or locally advanced HER2-positive breast cancer.
• The results have confirmed a higher pCR rate for the
Trastuzumab arm (30.3%) compared with that of lapatinib
(22.7%).

24. CONCLUSIONS (I)

25. CONCLUSIONS (II)

26. HER2-positive early-breast cancer who had previously received adjuvant
chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily
lapatinib (1500 mg) or daily placebo for 12 months
210 (13%) disease-free survival events had occurred in the lapatinib group versus
264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70–1·00;
p=0·053).
marginal benefit with lapatinib in terms of disease-free survival.
TEACH STUDY

28. Retrospective analysis demonstrated that lapatinib and capecitabine combination
may reduce incidence of brain mets as first site of recurrence.

33. 2015 May 10;33(14):1564-73.

44. Common adverse events (AEs) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were
diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea
(22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively)