CLINICAL EFFICACY OF GO − Rakyat Biologi

Early clinical studies and accelerated approval of GO

A phase 1 study among 40 adults with relapsed/refractory CD33⁺ AML who received up to 3 doses of GO in 2-week intervals found morphologic elimination of leukemia in 8 (20%) patients, with 3 (7.5%) achieving CR and 2 (5%) achieving CRp. As dose-limiting non-hematologic toxicity was not reached, the highest dose level of 9 mg/m², which provided almost complete saturation of CD33 binding sites, was chosen for further study (128). Three open-label, multicenter single-arm phase 2 trials then evaluated GO in a larger cohort of adults with CD33⁺ de novo AML in first relapse. An interim analysis on 142 patients (median age: 61 [range: 22-84] years) who typically received 2 doses of GO 14 days apart showed an ORR of 29.6% (CR: 16.2%; CRp: 13.4%) (129). Presented with these results, the Oncology Drugs Advisory Committee (ODAC) concluded at the March 14, 2000 meeting that this drug provided a useful therapeutic option in patients >60 years of age with CD33⁺ AML in first relapse who would not be candidates for standard cytotoxic chemotherapy (101). The U.S. Food and Drug Administration (FDA) accepted this recommendation, and GO was given accelerated marketing approval on May 17, 2000 for this indication. Of note, the approval regulations not only required the sponsor to complete the original phase 2 studies in relapsed AML but also mandated the conduct of randomized, controlled trials to confirm the clinical benefit of GO when added to conventional chemotherapy in patients with de novo AML (101).

Subsequent clinical trials and discontinuation of commercial availability of GO

The final report of the 3 pivotal phase 2 trials on 277 patients confirmed the early results in relapsed AML, with 35 (12.6%) and 36 (13.0%) patients achieving CR and CRp, respectively, for an ORR of 25.6%, although remission durations were relatively short (130). Numerous studies have subsequently investigated GO in various clinical situations. As results from most of these trials have been reviewed previously in detail (131-137), we will only

Table 2. Phase 3 studies of GO in newly diagnosed non-APL AML

Study	Reference	Disease	N	Age (median)	Treatment	Results
MRC/NCRI AML15	(146)	AML	1,113	0-71 (49)	± GO (3 mg/m²) on day 1 of the first of two induction courses with either ADE, DA, or FLAG-IDA	No difference in ORR, TRM, relapse, or survival. Improved 5-year OS for favorable-risk subgroup (79% vs. 51%; p=0.0003) with GO; predicted 10% OS benefit for ~70% of patients with intermediate-risk disease
ALFA 0701	(145)	AML	278	59-66 (62)	± GO (3 mg/m²) on days 1, 4, and 7 of DA induction and day 1 of each of 2 courses of DA consolidation	No difference in ORR or mortality. Improved 2-year EFS (40.8% vs. 17.1%, p=0.0003), DFS (50.3% vs. 22.7%, p=0.0003) and OS (53.2% vs. 41.9%, p=0.037) with GO. Survival benefit seen in favorable/intermediate- but not adverse-risk disease
GOELAMS AML 2006 IR	(147)	AML (intermediate risk)	238	18-60 (50)	± GO (6 mg/m²) on day 1 with DA induction and MA consolidation	No difference in ORR, TRM, or 3-year EFS. Improved EFS with GO in patients who did not undergo allogeneic HCT (53.7% vs. 27%, p=0.0308)
MRC/NCRI AML16	(148)	AML, high-risk MDS	1,115	51-84 (67)	± GO (3 mg/m²) on day 1 of the first of two induction courses with either DA or DCLo	No difference in TRM; trend towards reduced risk of persistent disease with GO (17% vs. 21%, p=0.06). Reduced 3-year relapse risk (68% vs. 76%; p=0.007) and superior DFS (21% vs. 16%; p=0.04) and OS (25% vs. 20%; p=0.05) with GO
SWOG S0106	(149, 150)	AML	596	18-60 (47)	± GO (6 mg/m²) on day 4 of the first of up to two induction courses with DA*	Increased TRM in GO arm (5.7% vs. 1.4%; p=0.01). No difference in ORR, DFS, or OS. Possible trend towards improved OS in favorable-risk subgroup with GO (hazard ratio: 0.49 [0.12-2.04])

Abbreviations: ADE, cytarabine/daunorubicin/etoposide; DA, daunorubicin/cytarabine; DClo, daunorubicin/clofarabine; DFS, disease-free survival; EFS, event-free survival; FLAG-Ida, fludarabine/cytarabine/G-CSF/idarubicin; HCT, hematopoietic cell transplantation; MA, mitoxantrone/cytarabine; ORR, overall response rate (CR+CRi); OS, overall survival; TRM, treatment-related mortality, *Daunorubicin was used at 60 mg/m²/day in the control (-GO) arm and 45 mg/m²/day in the GO arm. This table was initially published in Blood (58). Reproduced with permission from The American Society of Hematology.

highlight those trials that are most informative regarding the potential clinical utility of GO.

Treatment of APL

GO is likely most effective in APL. For example, single agent GO resulted in molecular CR in 9 of 11 patients with molecularly relapsed APL tested after 2 doses and in 13 of 13 patients tested after the 3^rd dose (138). Additional case reports corroborate the notion of very high efficacy of GO in the setting of minimal residual disease in APL, including patients with very advanced disease (139, 140). Furthermore, phase 2 trials suggest that GO can substitute for anthracycline therapy even in high-risk disease, and add benefit to therapy with ATRA (141, 142).

Treatment of pediatric non-APL AML

So far, only a few clinical studies have explored GO in childhood AML, primarily in patients with relapsed/refractory disease, and GO has no established role in this patient population. However, a large randomized trial testing the addition of GO to induction chemotherapy was led by the Children’s Oncology Group (AAML0531) and has recently completed accrual of >1,000 participants but preliminary outcome results are expected for 2013 at the earliest.

Treatment of adult non-APL AML

Several phase 2 studies investigated GO monotherapy in unselected patients with newly diagnosed and/or relapsed/refractory non-APL AML. While these studies confirmed single agent activity of GO, the ORRs have typically not exceeded 25-35% and were occasionally quite disappointing, particularly in heavily pretreated patients. Of note, most of these studies followed a 2-weekly schedule of GO administration. Less well explored is the use of GO given at shorter intervals. However, the ALFA group has relatively recently reported the use of GO in fractionated, lower doses (3 mg/m² on days 1,4, and 7) with promising efficacy and acceptable toxicity (143-145), but no direct, controlled comparisons with the traditional administration schedule have been made.

A wealth of studies have explored GO with other therapeutics or chemosensitizers and overall yielded mixed results. As most were small, single arm trials, no firm conclusions can be drawn from the majority of these studies as to the efficacy of GO relative to other drugs, or whether the addition of GO provided any benefit over what would have been achieved with the other therapeutics alone. Recently, however, several well controlled large studies have been conducted that congruently show that GO improves survival in a significant and relatively well defined subset of patients with newly diagnosed non-APL AML when added to conventional chemotherapy (58) (Table 2). In the MRC/NCRI AML15 trial, 1,113 predominantly adult patients were randomized to receive a single dose of GO (3 mg/m²) on day 1 of the first of two induction courses with one of three induction regimens (cytarabine/daunorubicin/etoposide, daunorubicin/cytarabine, fludarabine/cytarabine/G-CSF/idarubicin). While adding GO did not affect ORRs or survival across the entire study cohort, subgroup analyses showed that addition of GO improved OS at 5 years in patients with favorable cytogenetics (79% vs. 51%; p=0.0003) but not in those with unfavorable cytogenetics (8% vs. 11%; p=0.4). There was also a survival benefit for some intermediate-risk patients, as indicated by an internally validated index using cytogenetics, age, and performance status, which predicted that ~70% of these patients had an improved 5-year OS if given GO (146).

In the ALFA 0701 trial, 278 patients with primary AML aged 50-70 years received daunorubicin/cytarabine with or without GO (3 mg/m²) on days 1, 4, and 7; a second course of daunorubicin/cytarabine was given for residual disease on day 15. Patients in remission then received 2 courses of daunorubicin/cytarabine with or without GO (3 mg/m²) on day 1 of each cycle. While there was no statistically significant difference in ORRs and treatment-related mortality (TRM) between the 2 arms, the event-free survival (EFS) at 2 years was significantly superior in the GO arm (40.8% vs. 17.1%, p=0.0003), as was disease-free survival (DFS) (50.3% vs. 22.7%, p=0.0003) and OS (53.2% vs. 41.9%, p=0.037). Subgroup analysis showed that the EFS benefit occurred in patients with favorable/intermediate cytogenetics but not in those with an adverse karyotype (145). In the GOELAMS AML 2006 IR study, adults aged 18-60 years with de novo AML and intermediate karyotype received daunorubicin/cytarabine with or without GO (6 mg/m²) on day 4; GO was also added to consolidation therapy according to the initial randomization (147). Among 238 analyzed patients, there was no difference in ORRs or TRM between the 2 treatment arms. Overall, there was also no statistically significant difference in EFS (GO vs. control: 51% vs. 33%) or OS (53% vs. 46%) at 3 years. However, subgroup analyses showed that in patients who did not undergo allogeneic hematopoietic cell transplantation (HCT), EFS was significantly higher in the GO group (53.7% vs. 27%, p=0.0308). Finally, in the MRC/NCRI AML16 trial, 1,115 adults aged 51-84 years with AML or high-risk myelodysplastic syndromes (MDS; >10% marrow blasts) received either daunorubicin/cytarabine or daunorubicin/clofarabine for 2 cycles with or without GO (3 mg/m²) on day 1 of the first induction course (148). Similar to the other trials, there was no significant difference in ORRs and TRM between the treatment arms, although the patients receiving GO had a slightly lower likelihood of persistent disease (17% vs. 21%, p=0.06). However, use of GO was associated with reduced relapse risk (at 3 years: 68% vs. 76%; p=0.007) and superior DFS (21% vs. 16%; p=0.04) as well as OS (25% vs. 20%; p=0.05). A meta-analysis of AML15 and AML16 on 2,224 patients showed a significant benefit of GO for risk of relapse (odds ratio [OR]: 0.82 [95% confidence interval: 0.72-0.93], p=0.002) and survival (OR: 0.88 [0.79-0.98], p=0.02); the survival benefit was seen in patients with favorable-risk (OR: 0.47 [0.28-0.77]) and intermediate-risk (OR: 0.84 [0.73-0.97]) but not adverse-risk (OR: 1.02 [0.81-1.27]) disease (148).

The results from these European studies differ from the SWOG trial S0106, which was developed with the drug sponsor to fulfill the post-approval commitment to the FDA. Six hundred thirty-seven patients aged 18-60 years with de novo AML were accrued to receive up to 2 cycles of induction chemotherapy with daunorubicin/cytarabine with or without a single dose of GO (6 mg/m²) on day 4 of the first induction (149). Unlike the European studies in which identical doses of conventional chemotherapeutics were used in both arms, S0106 used a lower daunorubicin dose with GO (45 mg/m² vs. 60 mg/m²). Overall, among the 596 evaluable patients, S0106 showed no difference in response or survival in either induction of post-consolidation with the addition of GO, but a trend towards improved OS was seen in patients with favorable-risk leukemias (hazard ratio: 0.49 [0.12-2.04], although S0106 was not powered to detect important outcome differences in this patient subset. As there was an attempt to achieve equi-toxicity with the lower dose of daunorubicin in the GO arm, the S0106 trial is confounded by the lower dose of daunorubicin administered to patients receiving GO, which might mask a greater benefit of the immunoconjugate. Nonetheless, based on the lack of pre-specified overall improvement in outcome, S0106 was prematurely terminated (150).

In contrast to its use in induction therapy, so far no study has documented a benefit of GO when used in consolidation. ECOG used a high-dose cytarabine-containing post-remission strategy incorporating a single dose of GO (6 mg/m²) for patients 17-60 years of age in first CR in a randomized phase 3 trial. Among 352 randomized patients, results of intent-to-treat analyses failed to provide any evidence of a benefit of GO in this trial (151). In the HOVON-43 study, 232 patients 60 years or older who achieved a first CR after intensive induction chemotherapy were randomized to 3 cycles of GO (6 mg/m² every 4 weeks) or no post-remission therapy; again, no differences in relapse probability, survival, or non-relapse mortality were noted (152).

Treatment of the elderly or unfit with non-APL AML

In contrast to the situation when GO is added to intensive chemotherapy, its benefit when combined with low-dose chemotherapy is perhaps more limited. This is suggested by a recent trial conducted by the MRC/NCRI, in which 495 patients were randomized to receive low-dose cytarabine with or without GO at 5 mg/m² on day 1 of every course; in this study, GO almost doubled the CR rate (30% vs. 17%, p=0.006) but did not improve the 12-month overall survival (153).

Withdrawal of GO from commercial market

Following discussions with the FDA, Pfizer voluntarily withdrew the new drug application for GO in the U.S. in 2010 as a result of the outcome of S0106, specifically the lack of overall survival benefit in the entire study cohort and the increased rate of early mortality in the GO arm (154). GO was withdrawn from the U.S. and European markets, but continues to be commercially available in Japan, where it has received full regulatory approval (155).