PRO Labeling claims in Antineoplastic agents Caron M, Emery MP MAPI Research Trust, Lyon, France

Table 2: List of Antineoplastic Agents approved with with a PRO labeling claim - FDA (Source: PROLabels - March 2010) Objectives Type of Other PROs Date of To review PRO labeling claims achieved in antineoplastic products in Europe and in the US. Type Brand endpoint Primary measured Approval INN MAH Therapeutic Indication(s) Labeling claim of PRO Agency Name (PROs in endpoint(s)* not included (for this (in label) label) in label indication)

Sarcoma, Kaposi - Panretin gel is indicated for topical S1. The patients’ assessment of their overall satisfaction with treatment of cutaneous lesions in patients with AIDS-related the drug effect on all treated lesions significantly favored Treatment Panretin gel over vehicle (p=0.0001). S2. Responses to Ligand Kaposi's sarcoma. Panretin gel is not indicated when satisfaction, systemic anti-KS therapy is required (e.g., more than 10 Panretin gel were seen both in previously untreated patients Alitretinoin Panretin® Pharmaceuticals Inc. and in patients with prior systemic and/or topical KS treatment. Subjective Secondary Response rate None 02/02/1999 FDA new KS lesions in the prior month, symptomatic lymphedema, The physician's and the patient's subjective assessments of Methods (CA, USA) symptomatic pulmonary KS, or symptomatic visceral all treated lesions both showed a response rate of 47% for assessments of involvement). There is no experience to date using Panretin panretin and 11% for all treated lesions gel with systemic anti-KS treatment. vehicle (p=0.0003). PROLabels database was searched with neoplasm and oncology as keywords to identify antineoplastic agents with PRO labeling claims approved or revised in Europe since 1995 and Osteolytic metastases - Aredia is indicated, in conjunction Study 1: Decreases in pain scores from baseline Novartis with standard antineoplastic therapy, for the treatment of occurred at the last measurement for those Aredia Percentage of patient in the US since 1998. FDA and EMEA websites and guidances were reviewed. osteolytic bone metastases of breast cancer and osteolytic patients with pain at baseline (P=.026) but not in the Pamidronate Pharmaceutical lesions of multiple myeloma. The Aredia treatment effect Pain and narcotic developping any Aredia placebo group. Study 2: The changes from baseline Secondary None 22/09/1998 FDA Anti-emetic and analgesic products were not included, as well as generic drugs (such as Docetaxel Teva, Docetaxel Winthrop, Temomedac, Temozoline Teva, Topotecan Actavis). disodium Corporation appeared to be smaller in the study of breast cancer in the bone pain score and analgesic score was use skeletal-related event patients receiving hormonal therapy than in the study of (NJ, USA) significantly worse for placebo patients than for Aredia (SRE) those receiving chemotherapy, however, overall evidence patients in these trials. of clinical benefit has been demonstrated. Astra Zeneca Prostatic neoplasms - CASODEX 50 mg is an androgen receptor Survival, inhibitor indicated for use in combination therapy with a luteinizing Assessment of the Quality of Life questionnaires did Health-related Bicalutamide Casodex® Pharmaceuticals LP hormone-releasing hormone (LHRH) analog for the treatment of not indicate consistent significant differences between Secondary time to NS** 19/12/2008 FDA Stage D2 metastatic carcinoma of the prostate. o CASODEX 150 mg the two treatment groups. quality of life (DE, USA) daily is not approved for use alone or with other treatments. progression Gemcitabine Eli Lilly and Company Carcinoma, Non-Small-Cell Lung - Gemzar is indicated in In both studies no significant differences were observed Health-related Gemzar® combination with cisplatin for the first-line treatment of patients in QOL between the Gemzar plus cisplatin arm and the Secondary Survival NS** 25/08/1998 FDA Results (IN, USA) with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic quality of life hydrochloride (Stage IV) non-small cell lung cancer. comparator arm.

® In the first study, patients treated with Gemzar had statistically Among the 130 antineoplastic products approved, 19 were identified with PRO claims - eleven in the U.S, eight in Europe (including one in both agencies - Hycamtin ) - for fourteen significant increases in clinical benefit response (table 4). Clinical benefit response was achieved by 14 patients treated with Clinical benefit different indications: non-small cell lung carcinoma, prostatic neoplasms, small cell lung carcinoma, Kaposi sarcoma, chronic myeloid leukemia, astrocytoma, pleural malignant mesothelioma, Gemzar and 3 patients treated with 5-FU. One patient on the response Gemzar arm showed improvement in all 3 primary parameters Primary Pancreatic Neoplasms - Gemzar is indicated as first-line (pain intensity, analgesic consumption, and performance status). Performance (clinical improvement breast neoplasms, head & neck neoplasms, thyroid neoplasms, stomach neoplasms, colorectal neoplasms, osteolytic metastases and ovarian neoplasms (see Table 1 and Table 2). treatment for patients with locally advanced (nonresectable Eleven patients on the Gemzar arm and 2 patients on the 5-FU status, Pain (all 3 included Gemcitabine Eli Lilly and Company arm showed improvement in analgesic consumption and/or pain based on analgesic ® Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma intensity, Pain: Gemzar intensity with stable performance status. Two patients on the in “clinical consumption, pain NS** 25/08/1998 FDA Survival was primary endpoint for 13 products. Other primary endpoints included time to progression, response rate and response duration. hydrochloride (IN, USA) of the pancreas. Gemzar is indicated for patients previously Gemzar arm showed improvement in analgesic consumption Use of rescue treated with 5-FU. or pain intensity with improvement in performance status. One benefit intensity, performance ® patient on the 5-FU arm was stable with regard to pain intensity medication PROs included in labels were primary endpoints in only two cases: one product used in prostatic neoplasms (Novantrone - improvement in pain) and one product approved for pancreatic and analgesic consumption with improvement in performance response”) status, and weight ® status. No patient on either arm achieved a clinical benefit change) neoplasms (Gemzar - clinical benefit response including pain intensity, use of rescue medication and performance status). Both products were approved at the FDA. response based on weight gain. - The second study showed a clinical benefit response rate of 27%. Health-related quality of life was clearly mentioned in the label of 8 products (5 approved by the EMEA including 3 approved after the publication of the EMEA and FDA guidances, Physical, functional, and 3 by the FDA, all approved before the publication of the guidances). Of these 8 products, 3 approved by the EMEA and 1 by the FDA had an indication for non small cell lung carcinoma. Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM and treatment- (Functional Assessment of Cancer Therapy - Biologic specific biologic Response Modifier) instrument were used to assess response modifier Table 1: List of Antineoplastic Agents approved with a PRO labeling claim - EMEA (Source: PROLabels - March 2010) Leukemia, myeloid, chronic - Gleevec™ (imatinib patient-reported general effects of interferon toxicity in scales from the Imatinib ™ Novartis 1067 patients with CML in chronic phase. After one Survival Gleevec mesylate) is indicated for the treatment of newly FACT-BRM Secondary None 22/01/2002 FDA mesylate (Switzerland) diagnosed adult patients with Philadelphia chromosome month of therapy to six months of therapy, there was (progression-free) positive chronic myeloid leukemia (CML) in chronic phase. a 13%-21% decrease in median index from baseline (Functional Type of Other PROs Date of in patients treated with interferon, consistent with Assessment of Type increased symptoms of interferon toxicity. There was Cancer Therapy - Brand endpoint Primary measured Approval no apparent change from baseline in median index INN MAH Therapeutic Indication(s) Labeling claim of PRO Agency for patients treated with Gleevec. Biologic Response Name (PROs in endpoint(s)* not included (for this Modifier) instrument. (in label) label) in label indication) In study 1, patients receiving irinotecan reported significantly better results for the global health status, on two of five Global health Pharmacia & Upjohn Colorectal neoplasms - CAMPTOSAR is indicated for functional subscales, and on four of nine symptom subscales. status, functional Breast neoplasms - TAXOTERE in combination with Irinotecan ® patients with metastatic carcinoma of the colon or rectum As expected, patients receiving irinotecan noted significanly Aventis Pharma S.A. In both arms, quality of life measured by the Health-related Time to Camptosar Co, division of Pfizer and symptom Secondary Survival None 14/06/1996 FDA ® doxorubicin is indicated for the treatment of patients with EORTC questionnaire was comparable and stable Secondary None 27/11/1995 EMEA hydrochloride whose disease has recurred or progressed following initial more diarrhea than those receiving best supportive care. In Study Docetaxel Taxotere Inc (NY, USA) 2, the multivariate analysis on all 15 subscales did not indicate (France) locally advanced or metastatic breast cancer who have not during treatment and follow-up. quality of life progression fluorouracil-based therapy. subscales of the previously received cytotoxic therapy for this condition. a statistically significant difference between irinotecan and infusional 5-FU. EORTC QLQ-C30

Carcinoma, Non-Small-Cell Lung - TAXOTERE in Survival data, median time to progression and Health-related response rates for two arms of the study are 1) Proportion of patients Aventis Pharma S.A. combination with cisplatin is indicated for the treatment of quality of life, achieving castrate levels Docetaxel Taxotere® patients with unresectable, locally advanced or metastatic illustrated in the table p.29 of the SPC which Secondary Survival (overall) None 27/11/1995 EMEA is reported below. Results on the secondary Pain, Performance of serum testosterone (France) non-small cell lung cancer, in patients who have not 2) proportion of patients previously received chemotherapy for this condition. endpoints (including quality of life) were supportive of the primary end-points results. status maintaining castrate levels Bone pain, urinary serum testosterone from Leuprolide Atrix Laboratories, ® Eligard® Prostatic neoplasms - ELIGARD is indicated for See Table 5 of approved label pain and urinary Secondary the day they actually None 23/01/2002 FDA Patients treated with TPF experienced significantly acetate Inc. (CO, USA) the palliative treatment of advanced prostate cancer achieved castrate levels Head and neck neoplasms - TAXOTERE (docetaxel) in less deterioration of their Global health score Pain, swallowing, speech, symptoms Aventis Pharma S.A. Survival to study end; and 3) ® combination with cisplatin and 5-fluorouracil is indicated compared to those treated with PF (p=0.01, Global health, Secondary and coughing domains from proportion of patients Docetaxel Taxotere for the induction treatment of patients with inoperable locally using the EORTC QLQ-C30 scale). Pain intensity 23/10/2006 EMEA (France) Pain (progression-free) the EORTC QLQ-H&N35 showing acute-on-chronic advanced squamous cell carcinoma of the head and neck. score improved during treatment in both groups and breakthrough indicating adequate pain management. module responses following initial suppression. Patients who received docetaxel every three weeks demonstrated significantly longer overall Study 1: A palliative response was achieved in 29% survival compared to those treated with mitoxantrone. of patients randomized to N+P compared to 12% of Prostatic neoplasms - TAXOTERE (docetaxel) in The increase in survival seen in the docetaxel patients randomized to P alone (p=0.011). An overall Aventis Pharma S.A. weekly arm was not statistically significant compared Health-related Docetaxel Taxotere® combination with prednisone or prednisolone is indicated Secondary Survival (overall) None 27/11/1995 EMEA palliative response was achieved in 38% of patients for the treatment of patients with hormone refractory to the mitoxantrone control arm. Efficacy endpoints quality of life, randomized to N+P compared to 21% of patients (France) for the docetaxel arms versus the control arm are metastatic prostate cancer. Pain randomized to P (p=0.025). The median duration of summarized in the table p.30 of the SPC. No primary palliative response for patients randomized statistical differences were observed between to N+P was 7.6 months compared to 2.1 months treatment groups for Global Quality of Life. for patients randomized to P alone (p=0.0009). The median duration of overall palliative response for Study 1: Additional PRO enpoint Overall, quality of life (QoL) and clinical benefit Health-related Current HRQL (measured patients randomized to N+P was 5.6 months compared to 1.9 months for patients randomized to P alone was improvement in quality of life Stomach neoplasms -TAXOTERE (docetaxel) in results consistently indicated improvement in favor quality of life, using the EQ-5D thermometer) (EORTC-Q30C, Specific Prostate combination with cisplatin and 5-fluorouracil is indicated of the TCF arm. Patients treated with TCF had a Immunex (p=0.0004). Study 2: Approximately 60% of patients Bone pain, urinary Prostatic neoplasms - Novantrone in combination with on each arm required analgesics at baseline. The best Primary and Module, and LASA scales). Study 2: ® Aventis Pharma S.A. for the treatment of patients with metastatic gastric longer time to 5% definitive deterioration of global Global health Time to and curative analgesic ® Improvement Docetaxel Taxotere Secondary 27/04/2006 EMEA Mitoxantrone Novantrone Corporation corticosteroids is indicated as initial chemotherapy for percent change from baseline in mean analgesic use pain and urinary Additional PRO was quality of life ?? FDA adenocarcinoma, including adenocarcinoma of the health status on the QLQ-C30 questionnaire consumption were also the treatment of patients with pain related to advanced secondary in pain (France) status, progression was -17% for 61 patients with available data on the symptoms (Functional living index-cancer, FLIC; gastroesophageal junction, who have not received prior (p=0.0121) and a longer time to definitive worsening (WA, USA) hormone-refractory prostate cancer. chemotherapy for metastatic disease. of Karnofsky performance status (p=0.0088) Performance among the secondary N + H arm, compared with +17% for 61 patients on H Sexual and Urologic Functioning; compared to patients treated with CF. status parameters. alone (p = 0.014). A time trend analysis for analgesic Functional limitations scale; Impact use in individual patients also showed a trend favoring the N + H arm over H alone but was not statistically of pain on daily activities). Carcinoma, Non-Small-Cell Lung - Tarceva is indicated for Tarceva resulted in symptom benefits by significantly Quality of life of patients significant. The best percent change from baseline ® Roche Registration the treatment of patients with locally advanced or metastatic Erlotinib Tarceva prolonging time to deterioration in cough dyspnoea Symptoms: cough, Secondary Survival assessed using 19/09/2005 EMEA in mean pain intensity was -14% for 37 patients with Limited (UK) non-small cell lung cancer after failure of at least one prior and pain, versus placebo. dyspnoea and pain available data on the N + H arm, compared with +8% chemotherapy regimen. EORTC QLQ-C30. for 38 patients on H alone (p = 0.057). A time trend analysis for pain intensity in individual patients showed Quality of life outcomes differed according to EGFR no difference between treatment arms. Carcinoma, Non-Small-Cell Lung - IRESSA is indicated mutation status. In EGFR mutation-positive patients, Astra Zeneca significantly more IRESSA-treated patients Health-related Survival Gefitinib Iressa™ for the treatment of adult patients with locally advanced Secondary None 24/06/2009 EMEA (Sweden) or metastatic non small cell lung cancer (NSCLC) with experienced an improvement in quality of life and quality of life, (progression-free) Mead Jonhson, Quality of life was also evaluated using lung cancer symptoms vs carboplatin/paclitaxel In the ECOG study, the Lung Cancer Specific Symptoms the EORTC core questionnaire QLQ-C30 activating mutations of EGFR TK. Carcinoma, Non-Small-Cell Lung - TAXOL, in combination subscale favored the TAXOL 135 mg/m²/24 hour plus Lung Cancer (see Table 3). Symptoms ® a Bristol Myers Paclitaxel Taxol with cisplatin, is indicated for the first-line treatment of cisplatin arm compared to the cisplatin/etoposide arm. Specific Subscale Secondary Survival and the lung module LC-13. Both 30/06/1998 FDA Squibb Co., non-small cell lung cancer in patients who are not candidates questionnaire were administered at In the first study, improved short term QoL with For all other factors, there was no difference in the (FACT-L) for potentially curative surgery and/or radiation therapy. randomization and every 6 weeks Carcinoma, Non-Small-Cell Lung - Paxene is indicated for cisplatin/paclitaxel vs cisplatin/tenoposide was (NJ, USA) treatment groups. Norton Healthcare considered important result in a palliative population. thereafter. Paclitaxel Paxene® the treatment of patients with non-small cell lung carcinoma Health-related Secondary Survival (duration) None 19/07/1999 EMEA Limited (UK) (NSCLC) who are not candidates for potentially curative In the second study, a greater proportion of Following Thyrogen administration, little change from surgery and/or radiation therapy, in combination with cisplatin. paclitaxel-treated patients had improvements quality of life baseline was observed in any of the eight QOL in short-term QoL. Thyroid neoplasms -Thyrogen (thyrotropin alfa for domains of the SF-36. Following thyroid hormone injection) is indicated for use as an adjunctive treatment withdrawal, statistically significant negative changes A statistically significant improvement of the Genzyme Thyrotropin ® for radioiodine ablation of thyroid tissue remnants in patients were noted in five of the eight QOL domains (physical Health-related Success clinically relevant symptoms (pain and dyspnoea) Thyrogen Corporation Secondary None 14/12/2007 FDA Eli Lilly Mesothelioma, malignant pleural - ALIMTA in combination alfa who have undergone a near-total or total thyroidectomy for functioning, role physical, vitality, social functioning of ablation associated with malignant pleural mesothelioma and mental health). quality of life Pemetrexed ® with cisplatin is indicated for the treatment of chemotherapy (MA, USA) well-differentiated thyroid cancer and who do not have Alimta Nederland B.V. in the ALIMTA/cisplatin arm (212 patients) versus Symptoms: pain, Secondary Survival None 20/09/2004 EMEA evidence of metastatic thyroid cancer. The difference between treatment groups was isodium naïve patients with unresectable malignant pleural the cisplatin arm alone (218 patients) was (The Netherlands) mesothelioma. dyspnoea statistically significant (p<0.05), favoring Thyrogen demonstrated using the Lung Cancer Symptom over thyroid hormone withdrawal. Scale. Topotecan GlaxoSmithKline Small Cell Lung Carcinoma - Hycamtin is indicated for Changes on a disease-related symptom scale in Disease-related Response rates and Malignant glioma - Temodal capsules are indicated for the In this study, achieving a radiological objective Hycamtin® the treatment of small cell lung cancer sensitive disease patients who received HYCAMTIN or who received Secondary None 30/11/1998 FDA Schering Plough response or maintaining progression-free status Health-related Survival hydrochloride (NC, USA) after failure of first-line chemotherapy. CAV are presented in Table 3. symptoms response duration Temozolomide Temodal® treatment of patients with malignant glioma, such as Secondary None 26/01/1999 EMEA Europe (Belgium) glioblastoma multiforme or anaplastic astrocytoma, was strongly associated with maintained or quality of life (progression-free) showing recurrence or progression after standard therapy. improved quality of life. * Several studies used for approval ** NS: Not Specified (Medical Review or Scientific Discussion not available) Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom Survival (overall), Patient-completed FACT-L SmithKline Small Cell Lung Carcinoma - Topotecan monotherapy is benefit for oral topotecan + BSC. Oral and intravenous response rate, questionnaire to assess Topotecan ® indicated for the treatment of patients with relapsed small Hycamtin Beecham plc topotecan were associated with similar symptom Symptoms Secondary response duration disease related symptoms 13/01/2006 EMEA hydrochloride cell lung cancer [SCLC] for whom re-treatment with the palliation in patients with relapsed sensitive SCLC in (UK) first-line regimen is not considered appropriate. patient self-reports on an unblinded symptom scale and time to at baseline and at the end assessment in both studies. progression of each course of treatment. Conclusions Ovarian Neoplasms - Yondelis in combination with Pharma Mar S.A. No statistically significant differences were found Health-related Survival Trabectedin Yondelis pegylated liposomal doxorubicin (PLD) is indicated for between treatment arms in global measures of Secondary NS** 28/10/2009 EMEA PROs are rarely used as primary endpoints in approval of antineoplastic agents except for assessing palliative response. When assessed, health-related quality of life is used as a (Spain) the treatment of patients with relapsed platinum-sensitive Quality of Life. quality of life (progression-free) ovarian cancer. supportive endpoint, and more often associated with non-small cell lung carcinoma, especially in Europe.

ISPOR May 2010, Atlanta-USA