Download Herceptin - Harvard Pilgrim Health Care

Medical Policy
Herceptin® (trastuzumab)
Effective Date: October 1, 2016
Subject: Herceptin® (trastuzumab)
Overview: Herceptin is an anti-cancer drug used along with other medications or after other
drug therapy to treat a certain type of breast cancer and other types of cancer.
Policy and Coverage Criteria:
NOTE: Prior Authorization is not required
Harvard Pilgrim considers Herceptin (trastuzumab) medically necessary as a treatment for any
of the following:
 breast cancer;
 gastric, esophageal, and gastroesphogeal cancer;
 leptomeningeal metastases;
Harvard Pilgrim does not cover Herceptin (trastuzumab) for indications not listed above.
Exclusions: N/A
Supporting Information:
1. Technology Assessment: Herceptin (trastuzumab) is a recombinant humanized monoclonal
antibody directed against the human epidermal growth factor receptor 2 (HER2). After binding
to HER2 on the tumor cell surface, trastuzumab induces an antibody-dependent cell-mediated
cytotoxicity against tumor cells that overexpress HER2.
2. Literature Review:
Breast Cancer - Trastuzumab originally received approval in 1998, by the U.S. Food and
Drug Administration (FDA) for the treatment of individuals with metastatic breast cancer
whose tumors overexpressed HER2 (referred to as HER2+) and who had received one or more
chemotherapy regimens for the metastatic disease. Additionally, trastuzumab in combination
with paclitaxel as part of a first-line regimen for metastatic disease was also approved. In
2006 and 2008, trastuzumab received additional FDA approval for use in the adjuvant setting
in combination therapy for individuals with positive lymph nodes or node-negative disease with
high-risk features, or as a single agent following multi-modality anthracycline based therapy.
Although there are different FDA approved dosing recommendations, the maximum treatment
period for adjuvant therapy is 52 weeks. Treatment for metastatic breast cancer may continue
until disease progression (Product Information, 2015).
These indications were based on the results of a variety of randomized controlled trials
studying the role of trastuzumab as a treatment of metastatic breast disease, as neoadjuvant
therapy or adjuvant therapy. The trials examined the use of trastuzumab as monotherapy or
in combination with a variety of other therapies and all reported improved disease free
survival.
In 2012, the FDA approved pertuzumab (Perjeta™, Genentech, Inc., San Francisco, CA) in
combination with trastuzumab and docetaxel, for individuals with HER2+ metastatic breast
cancer who have not previously received anti-HER2 therapy or chemotherapy treatment for
the metastatic disease. The approval was based on the significantly improved progressionfree survival (PFS) results from the phase III, double-blind, placebo-controlled Clinical
Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) trial. A total of 808 participants
with HER2+ metastatic breast cancer were enrolled into the study. Participants were eligible if
they did not receive prior chemotherapy for the metastatic disease. One hormonal treatment
prior to randomization was allowed. The median PFS was 18.5 months for those randomized
to the group treated with trastuzumab, pertuzumab and docetaxel compared to a median PFS
of 12.4 months in the control group treated with placebo plus trastuzumab and docetaxel.
The control group had more frequent left ventricular systolic dysfunction (8.3%) compared to
the treatment group combining trastuzumab and pertuzumab (4.4%) (Baselga, 2012).
Gianni and colleagues (2011) reported updated results from the ongoing phase III,
randomized, open-label, multi-center international HERA (Herceptin Adjuvant) trial comparing
trastuzumab treatment for 1 year and 2 years with observation after standard neoadjuvant
and/or adjuvant therapy in women with early breast cancer. The interim analysis at a median
1-year follow-up demonstrated a significantly improved disease-free survival (DFS) with
trastuzumab compared to chemotherapy alone (hazard ratio [HR] 0.54; 95% confidence
interval [CI], 0.43-0.67). As a result, the protocol was amended in 2005, to allow individuals
from the control group who had not relapsed to cross over and receive trastuzumab. Based
on recommendations from the independent data monitoring committee, the 2-year
trastuzumab group data are not being released until the final event-driven analysis. Planned
data updates occur every 2 years for the 1-year trastuzumab treatment and the observation
group. With a median follow-up of 48.4 months, Gianni presented updated data for the 1-year
and observation cohorts. The 4-year disease-free survival rate in the 1-year trastuzumab
treatment group was 78.6% compared to 72.2% (HR 0.76; 95% CI, 0.66-0.87; p<0.0001) for
the observation group. The 4-year overall survival (OS) rate was not statistically significant
with 89.3% for the trastuzumab group and 87.7 % (p=0.11) in the observation group. Of the
1698 participants in the observation group, 885 (52%) of the individuals crossed over and
began trastuzumab treatment. In a comparison of the individuals in the selective crossover
group, the estimated HR for fewer disease free survival events was significant (p=0.0077)
compared to the observation cohort. The authors concluded that although the OS benefit was
no longer statistically significant, the benefit from 1-year treatment with trastuzumab is
maintained with longer follow-up. The data from treatment with 2-years of trastuzumab is still
pending.
It should be noted the majority of randomized studies of trastuzumab as adjuvant therapy
enrolled individuals with breast cancer and positive axillary nodes, or individuals with negative
nodes but with a primary tumor measuring greater than 1 cm in greatest dimension. The size
limitation in individuals with negative nodes was based on the assumption that small tumors
(less than 1 cm in diameter) were at low risk of recurrence such that trastuzumab would not
be beneficial, particularly considering the cardiac side effects. However, in 2008, data
presented at the San Antonio Breast Cancer Symposium challenged this assumption. GonzalezAngulo and colleagues (2009) performed a retrospective review of 1390 individuals with early
breast cancer no larger than 1 cm in any dimension and negative axillary nodes in the Breast
Cancer Management Database at the University of Texas M.D. Anderson Cancer Center
(MDACC). A total of 965 individuals were eligible for the study. A second set of 350
individuals who met identical clinical criteria at 2 other institutions in Belgium and Austria were
used to validate the MDACC results. Individuals were divided into three groups: triple negative
(i.e., negative hormone receptors and negative HER2), HER 2+ (regardless of hormone status)
and hormone receptor-positive and HER2 negative. Individuals with HER2+ breast cancer had
a significantly worse relapse free survival compared to individuals with hormone-positive
cancer or triple-negative breast cancer (p<0.0001). The authors concluded that individuals
with even small (less than 1 cm) HER2+ tumors have a significant risk of relapse and that
adjuvant systemic therapy with trastuzumab should be considered. Therefore, adjuvant
trastuzumab is considered in any individual with HER 2+ early breast cancer regardless of
nodal status or size of primary tumor.
Blackwell and colleagues (2010) reported results from a phase III randomized study
(EGF104900) of lapatinib alone or in combination with trastuzumab for women with HER2positive, trastuzumab-refractory metastatic breast cancer. A total of 296 participants were
enrolled with random assignment equally to each treatment arm. Assessments were
completed every 4 weeks through week 16, and then every 8 weeks thereafter. Participants
were allowed to cross over to combination therapy if objective disease progression was noted
after receiving a minimum of 4 weeks of monotherapy with lapatinib. In 2012, the final
planned analysis of OS included 291 participants who were available for efficacy analysis with
145 in the lapatinib monotherapy group and 146 in the combination lapatinib and trastuzumab
group. After progression of disease while on lapatinib monotherapy, 77 participants were
allowed to cross over and received combination therapy. The primary endpoint of PFS was
significantly improved in the individuals who were treated with combination trastuzumab and
lapatinib compared to lapatinib monotherapy (HR, 0.71; 95% CI, 0.58 to 0.94; p=0.011).
Median PFS was 11.1 weeks with combination therapy compared to 8.1 weeks PFS for
monotherapy with lapatinib. The median OS was 14 months for the combination therapy
versus 9.5 months for lapatinib monotherapy (HR, 0.74; 95% CI, 0.57 to 0.96; p=0.021).
Adverse events had similar incidence rates of 94% in the combination cohort compared to
90% in the single-agent group. A significantly higher rate of diarrhea was noted in
participants in the combination arm versus the monotherapy arm (62% vs. 48%). Serious
adverse events were reported by 26% in the cohort receiving combination therapy and 16% in
the cohort receiving monotherapy. The authors noted the 4.5 month survival improvement
with the trastuzumab combination supports the preclinical data that "lapatinib plus
trastuzumab combination has synergistic antiproliferative effects" (Blackwell, 2012).
In the GBG26/BIG 3-05 phase III RCT, participants were randomized to start single agent
capecitabine or continue trastuzumab and start capecitabine at the time of progressive disease
while on first-line regimens that included trastuzumab. Baselga and colleagues (2012)
reported there was no significant survival difference in the final OS analysis between treatment
arms. However, the post-hoc analysis demonstrated a better progression survival than those
who did not receive third-line anti-HER2 therapy. Post-progression survival of 18.8 months
was noted in participants who continued or restarted anti-HER2 therapy after second
progression compared to 13.3 months in those who did not receive third-line anti-HER2
therapy (p=0.02). The authors note that the results need to be confirmed in a larger metadatabase analysis to overcome potential bias related to the post-hoc review. The authors
concluded the use of anti-HER2 therapy throughout multiple lines continues to be
recommended.
The clinical practice guideline (CPG) of the National Comprehensive Cancer Network® (NCCN,
2015) recommends the use of trastuzumab to treat breast cancer. The CPG recommends
"continued trastuzumab following progression on first line-trastuzumab containing
chemotherapy for metastatic breast cancer. The optimal duration of trastuzumab in patients
with long-term control of disease is unknown." In 2014, the American Society of Clinical
Oncology (ASCO) clinical practice guideline (Ramakrishna) provided recommendations for
management of individuals with brain metastasis from HER2+ breast cancer. The guideline
includes a recommendation for individuals who developed an isolated progression in the brain
while on single-agent trastuzumab, to treat the brain metastasis and continue the single-agent
trastuzumab.
In a retrospective series of 80 individuals with brain metastases from breast cancer, the use of
lapatinib and trastuzumab-based therapy significantly improved OS compared to
chemotherapy or radiotherapy alone (Bartsch, 2012). Median OS was 13 months for those
receiving trastuzumab with or without chemotherapy and at 24 months of follow-up, the
median OS for lapatinib (with or without trastuzumab or chemotherapy) was not reached.
A phase III randomized trial (GeparQuinto, GBG 44) enrolled individuals with untreated HER2positive, operable or locally advanced breast cancer randomized to treatment with lapatinib
(ECH-TL group) versus trastuzumab (ECH-TH group) in combination with neoadjuvant
anthracycline-taxane-based chemotherapy. There were improved rates of pathologic complete
response in the ECH-TH group with 93 (30.3%) of 307 participants compared to 70 (22.7%) of
308 participants in the ECL-TL (odds ratio [OR] 0.68 [95% CI, 0.47-0.97]; p=0.04) (Untch,
2012).
Baselga and colleagues reported results from NeoALTTO, an open-label, multicenter, phase III
randomized trial of dual HER2 inhibition with lapatinib and trastuzumab versus lapatinib alone
or trastuzumab alone in the neoadjuvant setting. Individuals received 6 weeks of the assigned
biologic agent(s) followed by an additional 12 weeks of therapy in combination with paclitaxel
prior to definitive breast surgery. A significantly higher (p=0.0001) pathologic complete
response (pCR) was noted in the combination lapatinib and trastuzumab group (51.3%; 95%
CI, 43.1-59.5) compared to the group treated with trastuzumab alone (29.5%; 22.4-37.5).
Grade 3 and 4 adverse events were more frequent in the dual lapatinib and trastuzumab
cohort (21.7%) compared to 1.3% in trastuzumab alone and 18.8% in the lapatinib group.
Participants who were unable to complete the planned therapy due to side effects were higher
in the groups treated with lapatinib alone (18.8%) and combination lapatinib and trastuzumab
(39.5%) versus the trastuzumab alone group (8.1%). Additional long-term data and studies
are needed to confirm dual inhibition of HER2 in the neoadjuvant setting is safe and effective.
Event-free survival and overall survival were prespecified secondary endpoints in the phase III
NeoALTTO trial. De Azambuja (2014a) and colleagues reported at an event follow-up of 3.77
years, there was no significant difference in event-free survival between the lapatinib and
trastuzumab groups (HR 1.06, 95% CI, 0.66-1.69, p=0.81) and between the combination and
trastuzumab groups (HR 0.78, 95% CI, 0.47-1.28, p=0.33). Similarly, there was no significant
difference in the 3-year over-all survival 93% for lapatinib, 90% trastuzumab and 95% for
combination therapy. However, the authors reported for the subset of participants that
achieved pCR, the 3-year event free survival was significantly improved compared to those
that did not achieve pCR (HR 0.38, 95% CI, 0.22-0.63, p=0.0003). Those that achieved pCR
also had significantly improved overall survival when compared to those that did not achieve
pCR (HR 0.35, 95% CI, 0.15-0.70, p=0.005).
Clinical indications combining trastuzumab with lapatinib are a category 2A recommendation in
the NCCN practice guidelines (2015) for individuals with HER2 overexpressing metastatic
breast cancer that have received prior trastuzumab therapy. The CPG also notes the optimal
neoadjuvant regimen for HER2-targeting remains uncertain.
Gastric, Esophageal and Gastroesophageal Carcinoma – In October 2010, the FDA
approved trastuzumab "in combination with cisplatin and capecitabine or 5-fluorouracil, for the
treatment of individuals with HER2 overexpressing metastatic gastric or gastroesophageal
junction adenocarcinoma, who have not received prior treatment for metastatic disease."
Treatment for gastric cancer may continue until disease progression (Product Information,
2015).
Bang (2010) and colleagues reported results from ToGA (trastuzumab for gastric cancer) a
multicenter, phase III randomized trial investigating trastuzumab as first-line treatment of
locally advanced, recurrent or metastatic gastric and gastroesophageal adenocarcinoma. A
total of 3807 individuals with gastric carcinoma were tested for HER2. Eligibility for inclusion in
the study was HER2 positivity defined as IHC 3+ or FISH positive (defined as HER2: CEP17
ratio ≥2.0) (Bang, 2010). Of these, 594 individuals had HER2+ tumors and were randomized
to a control group receiving chemotherapy or to a treatment group receiving chemotherapy
plus trastuzumab. The median number of trastuzumab cycles was 8 (range 1-49). At 18.6
months of follow-up, the median OS was 13.5 months in the trastuzumab arm, compared to
11.1 months OS in the control group (p=0.0048) at a median follow-up of 17.1 months. The
overall response rate (ORR) was also significantly improved for the trastuzumab group
compared to controls, 47.3% vs. 34.5%, respectively.
The NCCN practice guideline for gastric cancer (2015) and the National Cancer Institute PDQ®
(2015) for gastric cancer list the use of trastuzumab as a part of combination therapy for
HER2-positive advanced gastric, esophageal and gastroesophageal adenocarcinoma.
In a Cochrane Review of chemotherapy for gastric cancer (Wagner, 2010), the authors
recommended HER2 overexpression testing for all gastric cancers and use of trastuzumab in
combination therapy with cisplatin and 5FU for HER2-positive gastric carcinomas.
Codes:
HCPCS:
J9355 - Injection; trastuzumab, 10 mg [Herceptin]
Medically necessary ICD-10 Diagnosis Codes
References:
1. Bang YJ, Van Cutsem E, Feyereislova A, et al.; ToGA Trial Investigators. Trastuzumab in
combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive
advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label,
randomized controlled trial. Lancet. 2010; 376(9742):687-697.
2. Bartsch R, Berghoff A, Pluschnig U, et al. Impact of anti-HER2 therapy on overall survival in
HER2-overexpressing breast cancer patients with brain metastases. Br J Cancer. 2012;
106(1):25-31.
3. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for
metastatic breast cancer. N Engl J Med. 2012; 366(2):109-119.
4. Baselga J, Perez E, Pienkowski T, Bell R. Adjuvant trastuzumab: a milestone in the
treatment of HER-2-positive early breast cancer. Oncologist. 2006; 11 Suppl 1:4-12.
5. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in
combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory
metastatic breast cancer. J Clin Oncol. 2010; 28(7):1124-1130.
6. de Azambuja E, Holmes AP, Piccart-Gebhart M, et al. Lapatinib with trastuzumab for HER2positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label,
multicentre, phase 3 trial and their association with pathological complete response. Lancet
Oncol. 2014a; 15(10):1137-1146.
7. de Azambuja E, Procter MJ, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac
events at 8 years of median follow-up in the Herceptin Adjuvant Trial (BIG 1-01). J Clin
Oncol. 2014b; 32(20):2159-2165.
8. Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to
degree of HER2 amplification for patients treated with adjuvant chemotherapy with or
without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009; 27(18):2962-2969.
9. Ebb D, Meyers P, Grier H, et al. Phase II trial of trastuzumab in combination with cytotoxic
chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth
factor receptor 2 overexpression: a report from the children's oncology group. J Clin Oncol.
2012; 30(20):2545-2551.
10. Gatzemeier U, Groth G, Butts C, et al. Randomized phase II trial of gemcitabine-cisplatin
with or without trastuzumab in HER2-positive non-small-cell lung cancer. Ann Oncol. 2004;
15(1):19-27.
11. Gianni L, Dafni U, Gelber RD, et al.; Herceptin Adjuvant (HERA) Trial Study Team.
Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2positive early breast cancer: a 4-year follow-up of a randomized controlled trial. Lancet
Oncol. 2011; 12(3):236-244.
12. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with trastuzumab
followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients
with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised
controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010;
375(9712):377-384.
13. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in
patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a
randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol.
2014; 15(6):640-647.
14. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with
breast cancer who have human epidermal growth factor receptor 2-positive, node-negative
tumors 1 cm or smaller. J Clin Oncol. 2009; 27(34):5700-5706.
15. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel
therapeutic target. Ann Oncol. 2008; 19(9):1523-1529.
16. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and
capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J
Cancer. 2012; 106(6):1033-1038.
17. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumabtreated patients with breast cancer: updated United Kingdom National Cancer Research
Institute recommendations for monitoring. Br J Cancer. 2009; 100(5):684-692.
18. Krug LM, Miller VA, Patel J, et al. Randomized phase II study of weekly docetaxel plus
trastuzumab versus weekly paclitaxel plus trastuzumab in patients with previously
untreated advanced nonsmall cell lung carcinoma. Cancer. 2005; 104(10):2149-2155.
19. Perez EA, Roche PC, Jenkins RB, et al. HER2 testing in patients with breast cancer: poor
correlation between weak positivity by immunohistochemistry and gene amplification by
fluorescence in situ hybridization. Mayo Clin Proc. 2002; 77(2):148-154.
20. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant
chemotherapy for operable human epidermal growth factor receptor 2-positive breast
cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011;
29(25):3366-3373.
21. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial
Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N
Engl J Med. 2005; 353(16):1659-1672.
22. Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac
function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide
followed by paclitaxel (ACP) With ACP plus trastuzumab as adjuvant therapy for patients
with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin
Oncol. 2012; 30(31):3792-3799.
23. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for
operable HER2-positive breast cancer. N Engl J Med. 2005; 353(16):1673-1684.
24. Semiglazov V, Eiermann W, Zambetti M, et al. Surgery following neoadjuvant therapy in
patients with HER2-positive locally advanced or inflammatory breast cancer participating in
the NeOAdjuvant Herceptin (NOAH) study. Eur J Surg Oncol. 2011; 37(10):856-863.
25. Slamon D, Eiermann W, Robert N, et al.; Breast Cancer International Research Group.
Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365(14):12731283.
26. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant
chemotherapy in HER2-positive breast cancer: a randomised controlled
trial. Lancet. 2007; 369(9555):29-36.
27. Untch M, Fasching PA, Konecny GE, et al. Pathologic complete response after neoadjuvant
chemotherapy plus trastuzumab predicts favorable survival in human epidermal growth
factor receptor 2-overexpressing breast cancer: results from the TECHNO trial of the AGO
and GBG study groups. J Clin Oncol. 2011; 29(25):3351-3357.
28. Untch M, Loibl S, Bischoff J, et al.; GBG and the Arbeitsgemeinschat Gynakologische
Onkologie-Breast (AGO-B) Study Group. Lapatinib versus trastuzumab in combination with
neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a
randomized phase 3 trial. Lancet Oncol. 2012; 13(2):135-144.
29. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human
epidermal growth factor receptor 2- positive advanced breast cancer: a German Breast
Group 26/Breast International Group 03-05 Study. J Clin Oncol. 2009; 27(12):1999-2006.
30. von Minckwitz G, Schwedler K, Schmidt M, et al.; GBG 26/BIG 03-05 Study Group and
participating investigators. Trastuzumab beyond progression: overall survival analysis of
the GBG 26/3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011;
47(15):2273-2281.
31. Yamaguchi K, Sawaki A, Doi T, et al. Efficacy and safety of capecitabine plus cisplatin in
Japanese patients with advanced or metastatic gastric cancer: subset analyses of the
AVAGAST study and the ToGA study. Gastric Cancer. 2013; 16(2):175-182.
32. Balduzzi S, Mantarro S, Guarneri V, et al. Trastuzumab-containing regimens for metastatic
breast cancer. Cochrane Database Syst Rev. 2014;(6):CD006242.
33. Giordano SH, Temin S, Kirshner JJ, et al; American Society of Clinical Oncology. Systemic
therapy for patients with advanced human epidermal growth factor recptor 2-positive
breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol.
2014; 32(19):2078-2099.
34. NCCN Clinical Practice Guidelines in Oncology © 2016 National Comprehensive Cancer
Network, Inc. For additional information visit the NCCN website: http://www.nccn.org.