patients in clinical trial overwhelmingly prefer subcutaneous herceptin administratn

[Lani]

CancerNetwork
RESEARCH REPORT
HER2-Positive Breast Cancer Patients Prefer Subcutaneous Trastuzumab
By Leah Lawrence | September 3, 2013

Results of the PrefHer study indicated that when given the option between subcutaneous trastuzumab(Drug information on trastuzumab) and intravenous trastuzumab, significantly more patients with HER2-positive breast cancer preferred the subcutaneous administration.

This preference combined with previously published noninferiority results indicates that a fixed dose of 600 mg subcutaneous trastuzumab every 3 weeks is a “validated, well tolerated and preferred option of patients for the treatment of HER2-positive breast cancer.”


Intravenous trastuzumab is currently the standard of care for patients with HER2 disease. However, a subcutaneous version of the drug has been developed that would allow patients to self-administer with a single-use injection device. Prior research showed that the subcutaneous formulation of the drug was noninferior to the intravenous formulation.

In this study, researchers led by Xavier Pivot, MD, of CHU Jean Minjoz in Besancon, France, randomly assigned 124 patients to receive subcutaneous trastuzumab followed by intravenous trastuzumab, and 124 patients to receive the opposite sequence. All patients were aged 18 years or older and had HER2-positive primary breast adenocarcinoma with no residual, recurrent or metastatic disease. The results of the study were published in Lancet Oncology.

Of the 124 patients in each arm, 117 from the subcutaneous first group and 119 in the intravenous first group were included in the intent-to-treat population. In order to determine patient preference for subcutaneous vs intravenous administration, the researchers interviewed patients at baseline and after both treatments.

At study end, 91.5% of patients interviewed stated that they preferred the subcutaneous administration of trastuzumab compared with intravenous (95% CI, 87.2–94.7; P < .0001). In contrast, 6.8% of patients preferred intravenous administration (95% CI, 3.9–10.8). Four patients reported no preference.

The increased preference for subcutaneous administration occurred despite an increased occurrence of adverse events. Fifty-eight percent of patients reported adverse events during subcutaneous treatment compared with 44% during intravenous administration.

In an editorial accompanying the study, Bohuslav Melichar, MD, of Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic, pointed out that patients with HER2-positive disease may be on treatment with trastuzumab for several years and that the use of the regimen in the metastatic or adjuvant setting “imposes an important burden on resources and, most importantly, on patients.”

Melichar congratulated the researchers on conducting this study for providing evidence in support of the use of subcutaneous trastuzumab, which could be self-administered in situations where patients live far from cancer centers, and for examining the question of patient preference at all.

[karen z]

Interesting- thanks for posting.

[KsGal]

Thank you for posting that. I wasn't even aware that Herceptin could be injected subcutaneous. It's definitely an interesting prospect.

[Lani]

I have posted about this before. Subcutaneous herceptin is now approved in the EU but Genentech reps at various meetings have told me Genentech has NO plans to even apply for approval of subcutaneous herceptin in the US with the FDA.

[michka]

Lani, do you know why Genentech has no plan to apply for approval in the US?
A question of quality of the product that would not pass the FDA vs EU? A question of health systems? Could it be because the Drs in the US earn more money with infusions?
It is such good news that the product should be available for all.
Michka

['lizbeth]

I was Googling for more information on the increased adverse events with the subcutaneous Herceptin and discovered that two (2) adverse events were treatment-related deaths in the HannaH study, out of four deaths in this smaller study of 600. Three for the subcutaneous arm and one for the IV arm.

The subcutaneous arm had more infections and infestations. Ummmm . . . I can understand infections, but infestations? I hope that is someone's way of saying increased influenza.

I don't see any information on the treatment related deaths, so do not know the specifics.

Lancet Oncol. 2012 Sep;13(9):869-78. doi: 10.1016/S1470-2045(12)70329-7. Epub 2012 Aug 9.
Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial.

Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C.
Source

Hospital Amaral Carvalho, Jaú, Brazil. gismael@uol.com.br

Abstract

BACKGROUND:

A subcutaneous formulation of trastuzumab has been developed, offering potential improvements in patient convenience and resource use compared with the standard intravenous infusion of the drug. We compared the pharmacokinetic profile, efficacy, and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer.
METHODS:

The HannaH study was a phase 3, randomised, international, open-label, trial in the (neo)adjuvant setting. Patients with HER2-positive, operable, locally advanced or inflammatory breast cancer were randomly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) or subcutaneously (fixed dose of 600 mg); 1:1 ratio. Chemotherapy consisted of four cycles of docetaxel (75 mg/m(2)) followed by four cycles of fluorouracil (500 mg/m(2)), epirubicin (75 mg/m(2)), and cyclophosphamide (500 mg/m(2)), every 3 weeks. After surgery, patients continued trastuzumab to complete 1 year of treatment. Coprimary endpoints were serum trough concentration (C(trough)) at pre-dose cycle 8 before surgery (non-inferiority margin for the ratio between groups of 0·80) and pathological complete response (pCR; non-inferiority margin for the difference between groups of -12·5%), analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT00950300.
FINDINGS:

299 patients were randomly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab. The geometric mean presurgery C(trough) was 51·8 μg/mL (coefficient of variation 52·5%) in the intravenous group and 69·0 μg/mL (55·8%) in the subcutaneous group. The geometric mean ratio of C(trough) subcutaneous to C(trough) intravenous was 1·33 (90% CI 1·24-1·44). 107 (40·7%) of 263 patients in the intravenous group and 118 (45·4%) of 260 in the subcutaneous group achieved a pCR. The difference between groups in pCR was 4·7% (95% CI -4·0 to 13·4). Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints. The incidence of grade 3-5 adverse events was similar between groups. The most common of these adverse events were neutropenia (99 [33·2%] of 298 patients in the intravenous group vs 86 [29·0%] of 297 in the subcutaneous group), leucopenia (17 [5·7%] vs 12 [4·0%]), and febrile neutropenia (10 [3·4%] vs 17 [5·7%]). However, more patients had serious adverse events in the subcutaneous group (62 [21%] of 297 patients) than in the intravenous group (37 [12%] of 298); the difference was mainly attributable to infections and infestations (24 [8·1%] in the subcutaneous group vs 13 [4·4%] in the intravenous group). Four adverse events led to death (one in the intravenous group and three in the subcutaneous group), all of which occurred during the neoadjuvant phase. Of these, two--both in the subcutaneous group--were deemed to be treatment related.
INTERPRETATION:

Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non-inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.
FUNDING:

F Hoffmann-La Roche.
Copyright © 2012 Elsevier Ltd. All rights reserved.


http://www.ncbi.nlm.nih.gov/pubmed/22884505

[Lani]

The most common adverse events of any grade (>25% in either group) were alopecia (62·8% [187 of 298] in the intravenous group vs 62·6% [186 of 297] in the subcutaneous group), nausea (48·7% [145 of 298] vs 48·5% [144 of 297]), neutropenia (46·3% [138 of 298] vs 44·1% [131 of 297]), diarrhoea (36·6% [109 of 298] vs 33·7% [100 of 297]), asthenia (25·2% [75 of 298] vs 24·6% [73 of 297]), and fatigue (26·5% [79 of 298] vs 22·6% [67 of 297]). The same proportion of patients (52%) in each group had a severe adverse event ( [Table 4] , [Table 5] ). There were numerically more grade 3 and grade 4 adverse events in the intravenous group than in the subcutaneous group (table 5). The pattern of severe adverse events was comparable between study groups (table 6). Most grade 3 or worse adverse events were haematological toxic effects, followed by gastrointestinal disorders (table 6). The most common severe adverse events were neutropenia, leucopenia, and febrile neutropenia (table 6).
...

No infection was associated with a subcutaneous trastuzumab injection site. Overall, the type of serious adverse event reported was in line with what would be expected of the investigated trial population and study treatment. Four adverse events led to death (one [<1%] of 298 in the intravenous group vs three [1%] of 297 in the subcutaneous group), all of which occurred during the neoadjuvant phase of the study. In the intravenous group, a 66-year-old obese patient with a history of pulmonary fibrosis experienced fatal acute pneumonia. In the subcutaneous group, one 59-year-old obese patient with a history of hypertension and hyperuricaemia died of a myocardial infarction 8 days after the first study drug; one 71-year-old overweight patient with hypertension and diabetes experienced sudden death; and one 77-year-old patient with prior grade 2 and 3 anaemia developed grade 4 febrile neutropenia and thrombocytopenia, leading to fatal septic shock. Two of the deaths in the subcutaneous group—those from septic shock and myocardial infarction—were judged to be treatment related by the investigator.



F Hoffmann-La Roche.
Copyright © 2012 Elsevier Ltd. All rights reserved.


http://www.ncbi.nlm.nih.gov/pubmed/22884505

[AlaskaAngel]

I appreciate those who are taking a cautious approach in our behalf.

However, I also believe there are those whose life situations make it next to impossible for them to take on the difficulties involved with IV treatments (and risks involved with IV treaments); risks due to aging and/or other concomitant health conditions that would not be significant risks if administration was by sub-Q injection; and the major time commitment away from work and family obligations some people have in order to just survive.

How can these be "counted", to measure in balance with being cautious in our behalf while watching Europe come up with better answers for us? And why don't we have an equivalent trial investigation to look to for results "in our behalf", or is there one even allowed to happen?

['lizbeth]

Home > September 25, 2012 - Volume 34 - Issue 18 > HER2-Positive Breast Cancer: Subcutaneous Trastuzumab as Eff...

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Oncology Times:
25 September 2012 - Volume 34 - Issue 18 - p 8–10
doi: 10.1097/01.COT.0000421351.11905.a0
News

HER2-Positive Breast Cancer: Subcutaneous Trastuzumab as Effective as Intravenous

Carlson, Robert H.






A subcutaneous formulation of trastuzumab appears to be equivalent to the standard intravenous formulation in terms of producing pathologic complete response (pCR) as well as in safety and pharmacokinetics in the treatment of women with HER2-positive breast cancer, according to the results of a Phase III, multicenter, neoadjuvant trial published in Lancet Oncology (2012;13:869–878).

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The shortened duration of subcutaneous administration has the potential to save time for patients, physicians, and nursing staff, the first author and co-principal investigator, Gustavo Ismael, MD, a medical oncologist and Medical Coordinator of Clinical Research at Hospital Amaral Carvalho, Miraglia in Jaú, Brazil, noted in a telephone interview. “The injection takes no more than five minutes, instead of 30 to 60 minutes for an infusion.”
The subcutaneous formulation of trastuzumab is possible with the development of recombinant human hyaluronidase PH-20 (rHuPH-20), an enzyme that temporarily degrades interstitial hyaluronic acid in the subcutaneous space, allowing injection of larger volumes—in this case, 5 ml of the drug injected into the thigh with a hand-held syringe.
The study's neoadjuvant setting made it possible to determine pCR, but Ismael said the potential convenience of a subcutaneous formulation could be in the adjuvant setting, when patients would typically return to the clinic every three weeks for IV treatment.
The researchers also point to other potential benefits including improved patient convenience, better compliance, reduced pharmacy preparation times, and optimization of medical resources.

GUSTAVO ISMAEL, MD, ...
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The randomized, open-label “HannaH” study (enHANced treatment with NeoAdjuvant Herceptin) enrolled women with newly diagnosed HER2-positive, operable, locally advanced, or inflammatory invasive adenocarcinoma of the breast, clinical stage I to IIIC, with primary tumors 1 cm or larger by ultrasound or 2 cm or larger by palpation. The patients' mean age was 50.
Patients were randomly assigned to receive eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every three weeks: 299 were assigned to be treated intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose) and 297 to be treated subcutaneously (fixed dose of 600 mg, with no loading dose).

CHRISTIAN JACKISCH, ...
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Chemotherapy consisted of four cycles of docetaxel (75 mg/m2) followed by four cycles of the FEC regimen—fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2)—every three weeks. After surgery, patients continued trastuzumab for one year, continuing with SC or IV administration as assigned in the neoadjuvant portion of the trial.

Back to Top | Article Outline
Non-Inferiority in Co-Primary Endpoints

The co-primary endpoint of pCR was achieved in 107 of 263 patients in the intravenous group (40.7%) and 118 of 260 (45.4%) in the subcutaneous group. Similarly, the “co-primary endpoint of geometric mean presurgery serum trough of trastuzumab concentration” was 51.8 μg/mL (coefficient of variation 52.5%) in the intravenous group and 69.0 μg/mL (55.8%) in the subcutaneous group.
“Thus, subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both coprimary endpoints,” the authors reported.
The safety profiles were also similar for the two routes of administration. The most common grade 3–5 adverse events were neutropenia, with an incidence of 33.2% among 298 patients in the intravenous group and 29.0% of 297 in the subcutaneous group; leucopenia in 5.7% vs. 4.0%; and febrile neutropenia, 3.4% vs. 5.7%.
However, more patients had serious adverse events in the subcutaneous group (21%) than in the intravenous group (12%). Ismael attributed the difference to more infections at the injection site in the SC group—8.1% vs. 4.4% in the intravenous group. The cardiac safety profile was comparable between both groups, with no severe symptomatic congestive heart failure reported. Two patients in the subcutaneous trastuzumab group developed congestive heart failure NYHA class II, but both had preexisting risk factors of obesity and hypertension.
Four adverse events led to death, one in the intravenous group and three in the subcutaneous group, all occurring in the neoadjuvant phase. Two of the deaths, both in the subcutaneous group, were considered treatment related. But Ismael noted that treatment included anthracycline chemotherapy and that one of those patients had a history of heart disease.

Back to Top | Article Outline
Survival Not Addressed

Survival data will take years to accumulate, but in a telephone interview, the study's other co-principal investigator, Christian Jackisch, MD, Professor and Director of the Department of OB/GYN at Klinikum Offenbach in Germany, stressed that survival was not a study endpoint: “Everyone is asking about survival data, but that was not the question of this trial, which was simply whether the C-trough concentration was the same, and secondarily, was efficacy the same in terms of pCR.”
He said previous studies have correlated pCR rates with survival times and reduced mortality. “And since it is the same drug and the same disease, what should be the difference—that is my opinion.”
Study sites were located around the world including Europe, Canada, South America, South Africa and Korea, but none were in the U.S.
The drug's manufacturer, Roche, which funded the study and was involved in the design and the interpretation of the data, is now testing subcutaneous trastuzumab in two other studies, a news release notes:
* SafeHer is a Phase III prospective, non-randomized, open-label study currently recruiting patients to assess the safety of assisted- and self-administered SC trastuzumab as adjuvant therapy in patients with operable HER2-positive early breast cancer. The study allows the use of both vial administration and administration via the ready-to-use device with the option of self-administration.

EDITH A. PEREZ, MD: ...
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CHARLES L. SHAPIRO, ...
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* And PrefHer (Preferences for Herceptin SC or IV administration) will use pre- and post-treatment questionnaires to determine patients' and health care professionals' satisfaction with the two methods.

And, the company noted, as a result of the HannaH data, a Line Extension Application for Herceptin SC has been submitted to the European Medicines Agency for the treatment of HER2-positive breast cancer.

Back to Top | Article Outline
Faster Delivery, Accelerated Approval?

In an accompanying editorial (Lancet Oncology 2012;13:850–861), Jose Perez-Garcia, MD, and Javier Cortes, MD, both of Vall d'Hebron Institute of Oncology in Barcelona, listed the obvious advantages of rapid, subcutaneous delivery including convenience for staff and patients and a psychological benefit for patients.
This might be moot, however, if a treatment regimen includes IV agents as well as trastuzumab, they noted.
In the larger picture, though, Perez-Garcia and Cortes said HannahH may be the first example of a neoadjuvant trial leading to accelerated approval of a drug for breast cancer, if pCR is indeed predictive of overall and disease-free survival.
Using neoadjuvant outcomes for drug approval has some major limitations, they continued:
* First, it is unknown what improvement in pCR would be necessary to translate into a benefit for disease-free or overall survival;
* Second, it is also unknown what proportion of patients achieving a pCR would be needed to establish noninferiority between two drugs or between two methods of administering the same drug; and
* Third, the method of categorizing long-term adverse effects “might be insufficient, because many adverse events might appear after pCR, so if pCR is enough for regulatory purposes, the consequences of these long-term events might not be taken into account.”

The editorial also advised trialists to take into account the higher immunogenicity of subcutaneous administration of a monoclonal antibody.

Back to Top | Article Outline
Ease Clinic Congestion

Also asked to comment on the study for this article, Edith A. Perez, MD, Professor of Medicine and Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, FL, said the subcutaneous formulation could be a very important improvement for the quality of life of breast cancer patients.
The time savings could also potentially relieve the congestion that sometimes exists in oncology practices, she noted. In practice, she explained, patients are usually not managed with trastuzumab (Herceptin) alone, and it would typically be given in the adjuvant setting.
“But in the setting in which we traditionally use intravenous Herceptin, this seems to be a good alternative to consider,” Perez said.
Also asked for his opinion, Charles L. Shapiro, MD, Professor of Medicine at the Wexner Medical Center and Section Chief of Breast Cancer at Ohio State University Comprehensive Cancer Center, noted that a subcutaneous version of trastuzumab could be important to women in less developed areas of the world with limited access to a cancer clinic. On the other hand, compliance might be an issue in home administration.
In terms of efficacy, Shapiro said it is still not certain whether complete response is an adequate surrogate for long-term survival, and that he would want to see larger trials confirm the efficacy outcomes.

© 2012 Lippincott Williams & Wilkins, Inc.


http://journals.lww.com/oncology-tim...taneous.2.aspx

['lizbeth]

However, more patients had serious adverse events in the subcutaneous group (21%) than in the intravenous group (12%). Ismael attributed the difference to more infections at the injection site in the SC group—8.1% vs. 4.4% in the intravenous group.

This is what I had been chewing on, the 21 vs 12 seemed large, but when they show the numbers it came from 8.1% vs. 4.4%.

Hmmm . . . I wonder why the increase in febrile neutropenia with the subcutaneous. But as studies go this number could be skewed by the smaller study number. In a large study it could calculate differently.

@Lani,

Okay dead is dead. Treatment related deaths are not acceptable. I don't care how the medical community or pharmaceutical industry or doctors try and spin it. As a patient I'm following a treatment plan because I want to live. So the deaths many be in line percentage wise with all the studies out there. I see the justification and it just doesn't fly with me.

That is a tremendous amount of chemo, 8 treatments.
Clearly the subH is more convenient, ah, but not for everyone. Dying is very inconvenient.

[AlaskaAngel]

Such debates in their intricate and lengthy considerations always cause me to wonder just how many bc patients don't make it due to drug administration problems and/or because we aren't permitted to find out whether there are patients who get equal benefit from administration of

trastuzumab w/o chemo

trastuzumab w/o chemo plus ovarian ablation

trastuzumab w/o chemo plus tamoxifen (+/- ovarian ablation)

trastuzumab w/o chemo plus an AI (+/- ovarian ablation)

['lizbeth]

Alaska,

NCT00999804 - I think this trial does not have neoadjuvant chemo.
Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy (HELEX)



Primary Outcome Measures: To evaluate the rate of pathologic complete response, defined as no residual invasive cancer in the breast, after 12 or 24 weeks of lapatinib/trastuzumab with or without endocrine therapy. [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]We propose a randomized multicenter neoadjuvant clinical trial in HER-2 overexpressing breast cancer patients with 12 vs. 24 weeks of lapatinib plus trastuzumab, with or without endocrine therapy, during which serial cancer tissue samples will be obtained for molecular studies in relation to tumor response. The patients will receive either 12 or 24 weeks of therapy to determine the pathologic complete response rate to this combined targeted therapy regimen, without the addition of any cytotoxic chemotherapy.

['lizbeth]

ClinicalTrials.gov Identifier:
NCT01042379

This is the current I-SPY trial which will be completed in a little over a year. Should be amazing information coming out of this study. Looking forward to becoming a breast cancer treatment dinosaur with the upcoming changes to standard of care.

I thought there were treatment arms without chemo, but the I-SPY website said chemo is given.

[AlaskaAngel]

Hi 'lizbeth,


I pulled up the study on clinicaltrials.gov and the actual table description of the arms is poorly done (it shows one arm noted to be HER2 positive patients receiving lapatinib and trastuzumab only, with the other arm being ER/PR positive and receiving letrozole only, and does not show any patients in the trial who happen to be both HR positive and HER2 positive) while the initial description indicates the trial is designed

1. To establish the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy

It is also described as being an "extension" study, in which the patients chosen are from an earlier study (I'm not sure what the treatment in the arms were for that earlier study, but it sounds like these were patients who have already completed some lapatinib and trastuzumab but I don't know if that earlier study required any administration of chemotherapy?)

A.A.

['lizbeth]

A.A. Good observations.



This is from a different page, the last paragraphs explain that they will also receive Herceptin and Tykerb.
The extension I believe is of the trial, and not the patient's treatment.

Breast cancer cells have certain characteristics or traits--these traits are called biomarkers. There are three biomarkers that help doctors decide which treatment to give any given patient. These biomarkers are the estrogen receptor (ER), progesterone receptor (PgR), and HER2 protein. Breast cancer cells that have a large number of estrogen or progesterone receptors are called ER and/or PgR positive. Cancers that are ER and/or PgR positive use the hormones estrogen and progesterone to help them grow. Not all breast cancers are ER or PgR positive. Patients are being asked to take part in this study that have a special type of breast cancer called HER2 positive breast cancer. HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor-2 (HER2). HER2 is located on the outer surface of a cancer cell. The HER2 protein sends a signal to the inside of the cancer cells telling it to grow and divide.
Two medications that directly target this HER2 protein. One is called trastuzumab(Herceptin), and the other is called lapatinib (Tykerb). Both medications are FDA-approved for the treatment of women with HER2+ breast cancer. Each medication attaches to the protein so that it can no longer function. Once the protein stops working, the cancer cells can no longer make copies of themselves. This makes cancer shrink. Both drugs target HER2; however each drug works a little bit differently.
Some patients respond better to Herceptin, and some patients respond better to Tykerb. Right now, we are not sure why some patients respond to one drug but do not respond to the other drug. One possibility is that in some patients, the HER2 protein finds another way to send its message to the inside of the cell (similar to a road detour). For example, when one path is "closed" because the drug is blocking it, the HER2 protein finds a different way to send its signal. We think that we can completely block the HER2 protein by giving patients both Tykerb and Herceptin.
Some patients with HER positive breast cancer are also ER and/or PgR positive. Even after HER2 is completely blocked, these types of cancer cells can still grow by using the estrogen or progesterone receptor. If a patient is told they are ER and/or PgR positive, they will also take an anti-estrogen pill along with Tykerb and Herceptin. We think that we can stop cancer growth more completely by blocking both the HER2 protein and the ER/PR receptors.

['lizbeth]

http://clinicaltrials.gov/ct2/show/N...rceptin&rank=9

If this trial enrolls it could be the start of only targeted therapies prior to surgery.