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CaelyxTM (Pegylated Liposomal Doxorubicin Hydrochloride) ­ A Novel Anthracycline

a report by

Dr Stephen R D Johnston

Royal Marsden Hospital, for Schering-Plough Pharmaceuticals

Introduction

disease would greatly improve utility and flexibility of anthracyclines. CaelyxTM (pegylated liposomal doxorubicin HCL) was designed to address the challenges posed by conventional anthracyclines. CaelyxTM liposomes are 80nm in diameter, a size that allows preferential extravasation through the highly permeable tumour vasculature.2 By its unique pegylated, hydrophilic outer surface, CaelyxTM avoids recognition by the mononuclear phagocyte system (otherwise known as the reticuloendothelial system).2 This allows for extended plasma circulation time. The increased circulation time increases the number of passes through the vascular bed of the tumour, increasing the opportunity for extravasation and theoretically accounting for the high intratumoral levels of CaelyxTM. However, while in the plasma, virtually all doxorubicin remains encapsulated, preventing high, cardiotoxic levels of free doxorubicin.3 These features enable CaelyxTM to deliver the same high level of efficacy as conventional anthracyclines, while reducing the risk of cardiotoxicity and avoiding or minimising many adverse events. CaelyxTM is indicated as monotherapy for patients with metastatic breast cancer, where there is an increased cardiac risk; for treatment of advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen; and for treatment of AIDS-related Kaposi's sarcoma.

CaelyxTM Design

Conventional anthracyclines are among the most active and widely used cytotoxic agents for the treatment of metastatic breast cancer. However, significant adverse events such as alopecia, myelosuppression, cardiotoxicity, nausea and vomiting can limit the usefulness and effectiveness of this class of chemotherapeutic agents. Due to an increasing risk of developing cardiotoxicity as cumulative lifetime anthracycline dose increases, the use of conventional anthracyclines, such as doxorubicin or epirubicin, is limited to 550mg/m2 and 900mg/m2, respectively. This corresponds to a lifetime duration of approximately six months of sequential cycles of chemotherapy when using a 60mg/m2 21-day (q21d) regimen of doxorubicin or 100mg/m2 q21d regimen of epirubicin. The use of conventional anthracyclines in the metastatic setting is further complicated if the patient received an anthracycline-containing regimen in the adjuvant setting, where typical exposure is approximately 300mg/m2 of conventional doxorubicin or 450mg/m2 of epirubicin. Adjuvant anthracycline use allows for few additional months of anthracycline treatment in the event of recurrence, despite the potential efficacy. These problems may prevent adequate dosing, compromising efficacy and, equally importantly, negatively impacting quality of life at a time when it is most important to the patient. High plasma levels of free drug are thought to contribute to the cardiotoxicity seen throughout the anthracycline class.1 This can occur within four to 24 hours post-infusion. Thus, the toxicity to the myocardium can begin with the first dose of the regimen. Agents that retain the efficacy of a conventional anthracycline, whilst allowing for continued dosing to maintain response or stable

Phospholipids are amiphathic in nature, containing a hydrophobic tail and a hydrophilic head. When placed in water, the fatty acid tails associate and exclude water, orienting the hydrophilic heads towards the water. This leads to a bilayer configuration,4 and the resultant vesicular structure is

1. A J Weiss and R W Manthei, "A Hypothesis Concerning the Effect of Changes in Scheduling Upon the Cardiotoxicity of Adriamycin", Oncology, 40 (1983), pp. 223­226. 2. A Gabizon and F Martin, "Polyethylene Glycol-coated (pegylated) Liposomal Doxorubicin: Rationale for Use in Solid Tumours", Drugs, 54 (1997), pp. 15­21. 3. A Gabizon, R Catane, B Uziely, et al., "Prolonged Circulation Time and Enhanced Accumulation in Malignant Exudates of Doxorubicin Encapsulated in Polyethylene-glycol Coated Liposomes", Cancer Res., 54 (1994), pp.

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Figure 1. Structure of the Caelyx TM Liposome

vehicles for delivering encapsulated drugs because the lipid bilayer separates an internal aqueous core from the external space. The liposomes used for drug delivery are generally small in size (< 300nm) and are composed of naturally occurring or synthetic phospholipids with or without cholesterol.5 CaelyxTM is a liposomal formulation of conventional doxorubicin in which segments of hydrophilic methoxypolyethelene glycol (MPEG) are grafted onto the surface of each liposome (see Figure 1). The pegylated coating of the CaelyxTM liposome creates a physical barrier that inhibits the close approach of other liposomes or cells, thereby protecting it from detection and phagocytosis. Escaping detection by the immune system leads to prolonged circulation time.3 CaelyxTM liposomes, with an average diameter of 80nm, can move through the discontinuous endothelium of tumour vasculature and concentrate within the tumour tissue.6 Prolonged circulation time and an ability to concentrate in the tumour tissue are characteristics of the unique pegylated liposomal formulation of CaelyxTM.

CaelyxTM Activity in Recurrent Ovarian Cancer

Table 1. Progression-free and Overall Survival in Recurrent Epithelial Ovarian Cancer

CaelyxTM Topotecan

Intent-to-treat population median progression-free survival (weeks) median overall survival (weeks) Platinum-sensitive subpopulation median progression-free survival (weeks) median overall survival (weeks)

(n = 239) 16.1 60.0 (n = 109) 28.9* 108.0*

(n = 235) 17.0 56.7 (n = 111) 23.3 71.1

*p <.05 Source: A N Gordon, J T Fleagle, D Guthrie, et al, "Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus Topotecan", J. Clin. Oncol., 19 (2001), pp. 3,312­3,322.

Figure 2. Overall Survival Advantage with CaelyxTM in Platinum-Sensitive Advanced Ovarian Cancer

In June 2000, CaelyxTM received marketing authorisation in the US and subsequently in Europe, based on the results of a pivotal, randomised, controlled, Phase III trial, which compared the efficacy of CaelyxTM with topotecan in the treatment of advanced ovarian cancer following failure of a platinum-containing regimen.7 In this study, patients (n = 474) were administered 50mg/m2 CaelyxTM q28d or topotecan 1.5mg/m2/day x 5 days q 21d for up to one year. Median overall survival with CaelyxTM was 60 weeks, compared with 56.7 weeks with topotecan (see Table 1). Overall response rate was 19.7% for the CaelyxTM group and 17.0% for the topotecan group. Although the platinum-sensitive subgroups demonstrated similar response rates (CaelyxTM 28.4%; topotecan 28.8%), there was a significant difference in favour of CaelyxTM for both progression-free and overall survival (see Figure 2 and Table 1). Haematologic toxicity was more frequent and usually

termed a liposome. Liposomes have been used as

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4. M Ostro and P Cullis, "Use of Liposomes as Injectable-drug Delivery Systems", Am. J. Hosp. Pharm., 46 (1989), pp. 1,576­1,587. 5. F Martin, "Pegylated Liposomal Doxorubicin: Scientific Rationale and Preclinical Pharmacology", Oncology, 11 (1997), pp. 11­20. 6. CAELYX (Doxorubicin HCl liposome injection): A Novel Approach to Chemotherapy", Institute S-PR (ed), data on file, 1998. 7. A N Gordon, J T Fleagle, D Guthrie, et al, "Recurrent Epithelial Ovarian Carcinoma: A Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus Topotecan", J. Clin. Oncol., 19 (2001), pp. 3,312­3,322.

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CaelyxTM ­ A Novel Anthracycline

Grade 3 or 4 in the topotecan-treated patients. The haematologic toxicity in the topotecan arm lead to a greater utilisation of haematopoietic growth factors (granulocyte or granulocyte-macrophage colonystimulating factor, erythropoietin, blood transfusions and dosing modifications) when compared with the CaelyxTM arm. In addition, alopecia was also significantly higher in the topotecan arm compared with the CaelyxTM arm (all grades: 49% versus 16%, respectively, p < 0.001). A comparative economic analysis based on this study demonstrated that the total patient management costs per person in the topotecan arm was significantly higher than the CaelyxTM arm in both US- and UKbased analyses (p < 0.05).8 The total cost per person in the topotecan arm was US$2,909 higher (95% confidence interval (CI): US$779 to US$3,415) than the total cost per person in the CaelyxTM arm in the UK-based analysis. The main differences in toxicity management in the UK-based analysis were for blood transfusions and hospitalisations. Comparable efficacy, a favourable safety profile, convenient dosing regimen and cost-effectiveness support the role of CaelyxTM as a valuable treatment option in patients with advanced ovarian cancer after failure of a first-line platinum-based regimen. The efficacy and cost-effectiveness of CaelyxTM in this population led the UK National Institute for Clinical Excellence (NICE) to conclude that CaelyxTM is likely to be the drug of choice for many women with advanced ovarian cancer for whom first-line chemotherapy has failed.9

CaelyxTM Activity in Metastatic Breast Cancer

Phase II ­ Proof of Concept Table 2. Response in the Phase II Metastatic Breast Cancer Study Overall response (complete + partial) Complete response Partial response Stable disease Progressive disease 31% 6% 25% 31% 38%

Source: M R Ranson, J Carmichael, K O'Byrne, et al., "Treatment of Advanced Breast Cancer with Sterically Stabilized Liposomal Doxorubicin: Results of a Multicenter Phase II Trial", J. Clin.Oncol., 15 (1997), pp. 3,185­3,191.

response, 31% achieved a complete or partial response Table 2. No cumulative myelosuppression was noted with multiple cycles of therapy. Nausea and vomiting were rare with CaelyxTM and alopecia was absent in the majority of patients. This is a marked difference from the toxicity profile of conventional doxorubicin and this study provided positive proof of concept and the rationale for the Phase III programme.

Phase III ­ Efficacy and Tolerability in Metastatic Breast Cancer

The first Phase III trial enrolled 301 women with taxane-refractory metastatic breast cancer. Patients were randomised to receive CaelyxTM (50mg/m2 q28d) or a comparator regimen consisting of either vinorelbine (30mg/m2 weekly) or mitomycin C (10mg/m2 d1 and d28) plus vinblastine (5mg/m2 d1, d14, d28 and d42) every six to eight weeks.11 The choice of the comparator was prespecified by site, with 85% of comparator patients receiving vinorelbine. Progression-free survival (PFS), the primary endpoint, and overall survival were comparable, with a trend in favour of CaelyxTM (PFS: median, 2.9 months CaelyxTM, 2.5 months comparator hazard ratio (HR) = 1.26; 95% CI, 0.98 to 1.62; p = 0.11, (see Figure 3); OS: median 11.0 months CaelyxTM, 9.0 months comparator HR = 1.05; 95% CI, 0.82 to 1.33; p = 0.71). Notably, in women > 55 years of age, PFS was significantly prolonged in patients receiving CaelyxTM (median: 3.3 months versus 2.5 months, p < 0.05). Palmar-plantar erythrodysesthaesia (PPE: 37%, 19% Grade 3/4) and stomatitis (22%, 5% Grade 3/4) were

The efficacy of CaelyxTM in metastatic breast cancer has been evaluated in two large, randomised, Phase III clinical trials, as well as a positive proof-ofconcept Phase II trial. The multicentre Phase II trial examined the safety, tolerability and efficacy of CaelyxTM in patients with metastatic breast cancer.10 Patients could have received one prior nonanthracycline-containing regimen. A total of 71 patients were enrolled and, of the 64 assessable for

8. D Smith, J Adams, S Johnston, et al., "A Comparative Economic Analysis of Pegylated Liposomal Doxorubicin Versus Topotecan in Ovarian Cancer in the USA and the UK", Ann. Oncol., 13 (2002), pp. 1,590­1,597. 9. Guidance on the use of pegylated liposomal doxorubicin hydrochloride (PLDH) for the treatment of advanced ovarian cancer. London: National Institute for Clinical Excellence, 2002. 10. M R Ranson, J Carmichael, K O'Byrne, et al., "Treatment of Advanced Breast Cancer with Sterically Stabilized Liposomal Doxorubicin: Results of a Multicenter Phase II Trial", J. Clin.Oncol., 15 (1997), pp. 3,185­3,191. 11. A Keller, R Mennel, V Georgoulias, et al., "A Randomized Phase 3 Trial of Caelyx/Doxil (pegylated liposomal doxorubicin HCL) Versus Standard Salvage Therapy in Women with Taxane-resistant Advanced Breast Cancer", ibid., submitted, 2002.

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Figure 3: Progression-Free Survival in Taxane-Refractory Metastatic Breast Cancer Trial

The second Phase III trial enrolled 509 women with metastatic breast cancer.12 This first-line study was designed to show the non-inferiority of CaelyxTM (50mg/m2 q28d) compared with conventional doxorubicin (60mg/m2 q21d) in terms of efficacy (PFS) and superiority of CaelyxTM compared with conventional doxorubicin in terms of cardiac safety. In the first-line treatment of metastatic breast cancer, PFS was comparable in both the CaelyxTM and conventional doxorubicin groups (6.9 months versus 7.8 months, respectively, HR = 1.00; 95% CI 0.82­1.22 (see Figure 4). Fifty-eight patients (10 CaelyxTM, 48 conventional doxorubicin) met the protocol-defined left-ventricular ejection fraction (LVEF) criteria for cardiotoxicity during treatment and/or follow-up (see Figure 5). The overall risk of developing cardiotoxicity was significantly higher for patients receiving conventional doxorubicin than for those receiving CaelyxTM (p < 0.001; HR = 3.16). Only two patients treated with CaelyxTM but 12 patients treated with conventional doxorubicin developed congestive heart failure. A commonly used definition of a cardiac event is a resting LVEF value of 35% or less.13 This value has been shown to correspond to a 30% risk of death or development of heart failure within 24 months in a prospective analysis of over 2,000 asymptomatic patients with ejection fractions of 35% or less. A supplemental analysis was done to examine the cumulative percentage of cardiac events, defined as last LVEF < 35%, versus cumulative anthracycline dose (see Figure 6). Two patients on CaelyxTM versus 12 patients on conventional doxorubicin met this criterion. As observed in the primary analysis, the risk of developing a cardiac event was lower with CaelyxTM than with conventional doxorubicin. In fact, of the 12 conventional doxorubicin patients who had LVEF < 35%, five developed signs and symptoms of congestive heart failure on study or in follow-up, as compared with neither of the two CaelyxTM patients. Notably, the increase in risk of developing cardiotoxicity on conventional doxorubicin versus CaelyxTM was observed in all subgroups analysed,

12. N Wigler, M Inbar, M O'Brien, et al., "Reduced Cardiac Toxicity and Comparable Efficacy in a Phase III Trial of Pegylated Liposomal Doxorubicin (Caelyx/Doxil) Versus Doxorubicin for First-line Treatment of Metastatic Breast Cancer", Proc. Am. Soc. Clin. Oncol., (2002), p. 177a. 13. "Effect of Enalapril on Mortality and the Development of Heart Failure in Asymptomatic Patients with Reduced Left Ventricular Ejection Fractions", The SOLVD Investigators, N. Engl. J. Med., 327 (1992), pp. 685­691.

Figure 4: Progression-Free Survival in First-Line Monotherapy in Metastatic Breast Cancer Trial

Figure 5: Rate of Cardiac Events Versus Cumulative Anthracycline Dose, Intent-to-Treat Population

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the most common adverse events associated with CaelyxTM, whereas nausea/vomiting (32%, 1% Grade 3/4) and asthaenia (22%, 0% Grade 3/4) were more commonly associated with the comparator regimens.

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CaelyxTM ­ A Novel Anthracycline

including those at a high risk for developing congestive heart failure (see Table 3). In the subgroup that received prior adjuvant anthracycline therapy, the risk of developing cardiotoxicity was seven times higher with conventional doxorubicin than with CaelyxTM. The incidence of alopecia with CaelyxTM was onethird that seen with conventional doxorubicin (see Table 4). Nausea (53% versus 37%) and vomiting (31% versus 19%) were more common with conventional doxorubicin than with CaelyxTM. As in the first Phase III trial, PPE was the most common adverse event associated with CaelyxTM (48%, 17% Grade 3, 0% Grade 4). CaelyxTM has shown comparable efficacy in terms of PFS, compared with standard regimens in the treatment of metastatic breast cancer. Additionally, the safety profile of CaelyxTM was consistently favourable with respect to the competitive agents used in these studies.

CaelyxTM Toxicity Management

Figure 6: Rate of Cardiac Events (defined as last LVEF < 35%) Versus Cumulative Anthracycline Dose

Table 3: Cumulative Anthracycline Dose and Cardiotoxicity in Subgroups

Number of Patients

n 55 years old CaelyxTM Conventional doxorubicin Prior adjuvant anthracycline CaelyxTM Conventional doxorubicin Cardiac risk factor CaelyxTM Conventional doxorubicin

Censored

Cardiotoxicity events 6 18

HR

95% CI for HR 0.81-5.18

159 152

153 134

2.04

CaelyxTM is generally well tolerated by the majority of patients, offering reduced alopecia, myelosuppression, nausea and vomiting compared with conventional doxorubicin, topotecan or vinorelbine. However, PPE, stomatitis and mucositis are characteristic of CaelyxTM therapy. PPE is characterised by an intense, often painful, macular reddening that, in more severe manifestations, may include painful desquamation or ulceration. PPE primarily involves the palms of the hands and soles of the feet, but may also occur in the axilla, groin or other parts of the body where tightfitting garments press against the skin. Simple lifestyle alterations, focused on staying cool and avoiding trauma to the hands and feet can prevent or ameliorate PPE during CaelyxTM therapy. Patients must be educated in the early recognition and reporting of symptoms of PPE. In cases of PPE that interfere with normal physical activities, stepwise dose delays and/or dose reductions are required. A dose delay of up two weeks for the resolution of symptoms may be necessary in severe cases. In addition, a reduction of 25% after dose delay can be implemented with the aim of preventing recurrence of symptoms. The same dosing modification strategies may also be employed in the case of Grade 3 or 4 mucositis or stomatitis.

CaelyxTM Clinical Utility

38 40 122 121

37 29 117 100

1 11 5 21

7.27

0.93-56.80

2.7

1.01-7.18

Table 4: Incidence of Alopecia in the First-Line Study of CaelyxTM in Metastatic Breast Cancer

CaelyxTM Conventional Doxorubicin

Alopecia*

(n = 254) All 20%

Pronounced 7%

(n = 255) All 66%

Pronounced 54%

* Alopecia was graded using two protocol-defined severities, mild hair loss (Grade 1) and pronounced or total hair loss (Grade 2)

regimen and reduced cardiotoxicity, alopecia, myelosuppression, nausea and vomiting, CaelyxTM is ideally suited for specific patient populations including the following: · patients at increased cardiac risk, including those who present with hypertension, prior mediastinal irradiation or a history of heart disease; · elderly patients; · patients for whom the risk of specific toxicities is of significant concern (alopecia, nausea and vomiting); and · patients who received prior anthracycline therapy.

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With its convenient once-per-month dosing

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Figure 7: Length of Therapy for Commonly Used Dose Schedules

enables physicians to now rechallenge patients potentially sensitive to anthracyclines and permits long-term therapy in responding patients.

Conclusions

With comparable efficacy, CaelyxTM successfully addresses the treatment challenges posed by conventional anthracyclines, including the following: · significantly reduced risk of cardiotoxicity; · important reductions in alopecia, myelosuppression, nausea and vomiting; · treatment of high-cardiac-risk patients; · treatment to maintain response or stable disease; and · once-per-month dosing. CaelyxTM expands the possibilities for anthracycline use into areas previously unattainable due to maximum exposure limitations, contraindications or comorbidities. CaelyxTM offers new possibilities for the use of anthracyclines in the treatment options for breast cancer. s

Contact Information Schering-Plough Pharmaceuticals 2000 Galloping Hill Road Kenilworth, New Jersey 07033-0530 United States Tel: (1) 908 298 4000 http://www.sch-plough.com

Using the standard dosing regimens of CaelyxTM (50mg/m2 q28d), conventional doxorubicin (60mg/m2 q21d) and epirubicin (100mg/m2 q21d 5fluorouracil, epirubicin and cyclophosphamide (FEC) 100 regimen) it is possible to administer only six months of treatment of either conventional doxorubicin (540mg/m2) or epirubicin (900mg/m2) before reaching the cumulative dose guidelines. CaelyxTM can be administered for almost twice as long before cardiac monitoring is recommended (450mg/m2 nine months in anthracycline-naïve patients (see Figure 7). Importantly, no maximum cumulative dose has been reached for CaelyxTM. This important distinction from conventional anthracylines

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