new research on treatment options for melanoma · 2014-09-16 · new research on treatment options...

NEW RESEARCH ON TREATMENT OPTIONS FOR MELANOMAHighlights from ASCO 2014Chicago, Illinois — May 31-June 3, 2014

Scientific Reviewers:

Volume 2 Number 1, August 2014Immunotherapies in Metastatic Melanoma

Long-term survival of ipilimumab-naive patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. (Hodi et al) .................................................................p. 2Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma. (Sznol et al) ...................p. 4Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma. (Ribas et al) .........p. 6Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory and IPI-naive melanoma. (Hamid et al) .................................................................................................p. 6A randomized phase II study of ipilimumab (IPI) with carboplatin and paclitaxel (CP) in patients with unresectable stage III or IV metastatic melanoma. (Jamal et al) ....................................................................................p. 8

Targeted Therapies in Advanced Melanoma

COMBI-d: A randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. (Long et al)...............................................p. 9Phase I study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (IPI) for V600E/K mutation-positive unresectable or metastatic melanoma. (Puzanov et al) ............p. 10A phase Ib/II study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity. (Sosman et al)......................................................................p. 11

Locoregional Therapies for Melanoma

Primary overall survival (OS) from OPTiM, a randomized phase III trial of talimogene laherparepvec (T-VEC) versussubcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB/C and IV melanoma. (Kaufman et al).......................................................................................p. 12

Treatment of Non-cutaneous Melanoma

Long-term survival benefit from ipilimumab treatment in metastatic uveal melanoma patients. (Deo et al) ..............p. 13Phase II study evaluating ipilimumab as a single agent in the first-line treatment of adult patients with metastatic uveal melanoma (MUM): The GEM-1 trial. (Piulats Rodrigues, et al) .................................................p. 13Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups. (Zimmer et al) ........................................p. 13

Adjuvant Therapy for Melanoma

Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial. (Eggermont et al).............................................................................p. 14Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): An individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients. (Suciu et al)......................p. 16

This report was made possible through the support of Bristol-Myers Squibb Canada.

Tina Cheng, MSc, MD, FRCPCAssociate Professor of Oncology,Faculty of Medicine, University of CalgaryDivision of Medical Oncology,Tom Baker Cancer Centre

Rahima Jamal, MD, FRCPCHematologist and OncologistAssociate Professor, Université de Montréal,CHUM—Notre-Dame Hospital

Robyn J. Macfarlane, MD, FRCPCMedical Oncologist, Nova Scotia Cancer CentreAssistant Professor of Medicine, Dalhousie University

Xinni Song, MD, FRCPCMedical Oncologist,The Ottawa Hospital Cancer CenterAssistant Professor, University of Ottawa

Long-term Survival with the Anti-PD-1 Agent NivolumabHodi F, et al. Long-term survival of ipilimumab-naive patients with advanced melanoma treatedwith nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. Presented at ASCO 2014,Abstract #9002.

Objectives: To assess the safety and efficacy of the anti-PD-1 agent nivolumab in patients with advanced melanoma.

Methods and 107 ipilimumab-naive patients with previously treated, advanced melanoma.

• Subjects received one of five nivolumab doses (0.1, 0.3, 1, 3, or 10 mg/kg IV) every two weeks for up to a maximum of 96 weeks.

• The initial primary endpoints were safety and tolerability-related and subsequently amended to collect overall survival data.

• Initial secondary endpoints were preliminary efficacy and dose-response relationships.

• Subgroup analyses of response based on key patient prognostic factors were conducted.

• This analysis included data for up to three years of follow-up.

• Baseline characteristics included:

o Median age 61 years, 67% male, 97% ECOG status 0-1.

o 62% had at least two prior regimens of systemic therapy; 25% had ≥ 3 prior therapies.

o 65% had received prior immunotherapy, 5% had received a BRAF inhibitor.

o 78% had visceral metastases at baseline; 36% had elevated LDH.

2

Figure 1. Overall Survival for Nivolumab in Ipilimumab-naive Patients

Figure 2.Overall Survival by Response Type

study population:

Months Since Treatment InitiationPatientsat Risk

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

Total 107 97 86 71 63 54 50 47 44 31 25 22 22 19 18 9 3 2 1 0

Overall Survival (%)

1009080706050403020100

Data as of September 2013.

• N = 93; 14 patients not included due to lack of tumor assessment by week 8.• 11/107 (10%) patients demonstrated and iR-type response.Subgroups: CR/PR, SD, PD: Patients with standard RECIST v1.0 responses.iR-type responses: Patients with best reduction in target lesions from baseline ≥ 30% in the presence of new lesions or afterinitial PD, or patients with PD for ≥ 3 tumor assessments with best change in tumor burden ≤ 20% from baseline.

1 year OS 63%

3 year OS 41%

2 year OS 48%

Median OS,Died/Treated mo (95% CI)

64/107 17.3 (12.5, 36.7)Patients at Rate, %

OS risk, n (95% CI)6 mo 86 82 (74, 88)1 yr 63 63 (53, 71)2 yr 44 48 (38, 57)3 yr 22 41 (31, 51)

Censored

Months Since Treatment Initiation0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57


1009080706050403020100

CR/PRiR-type responsePDSD

Censored

Patients who experience iR-typeresponses can have similar OSoutcomes as those with RECISTresponses

SD n = 18

PD n = 30

CR/PR n = 34

iR-type response n = 11

3

FACULTY COMMENTARY. This phase I/II dose escalation cohort expansion study studied heavily pretreated patients across a doserange of nivolumab from 0.1 to 10 mg (100-fold difference); 37 out of the 107 patients received a dose above 3mg/kg. This is thelongest duration of follow-up for any study of an anti-PD-1 agent to date. The overall survival data in this phase I study, as withother studies with anti-PD-1 agents, are encouraging and suggest that these agents offer an additional survival benefit. Further, thisagent offers acceptable tolerability and no new safety signals have emerged over the three years of follow-up. We awaitconfirmation of these data in prospective, phase III studies.

AUTHORS’ CONCLUSIONS: In pretreated, advanced melanoma, nivolumab monotherapy was associated with durable ORR inone third of patients. Median overall survival and 1-, 2- and 3-year survival rates compare favorably with other agents. Activity wasseen across patient populations/prognostic factors. Nivolumab was well tolerated, with no new safety signals. There are severalongoing trials with this agent, including three phase 3 monotherapy trials in previously treated or treatment-naive patients, aswell as other studies combining nivolumab with ipilimumab and other immuno-oncology agents.

Table 1. Select Drug-related Adverse Events with Nivolumab

Figure 4.Response Characteristics with Nivolumab Treatment

Results:

• For the 3 mg/kg dose (which was the doseselected for phase III studies):

o Objective response rate (ORR) was 41% (7/17).

o Median progression-free survival was 9.7 months.

o Median overall survival was 20.3 months

• For all nivolumab doses:

o Overall survival was 17.3 months (Figure 1).

o Survival rates at 1, 2 and 3 years were 63%, 48% and 41%, respectively.

o The survival curves by type of response are shown in Figure 2; patients with iR-type responses can have survival responses similar to those with RECIST responses.

o Objective response is shown in Figure 3, subdivided by presence or absence of visceral metastases.

o Median duration of response to nivolumab was 22.9 months (Figure 4).

o Responses were ongoing in 19 of 34 responders at the time of analysis.

o 44% of responding patients showed a response at first tumor assessment (8 weeks).

o For many patients, response persisted following discontinuation of therapy.

• There were no new safety signals noted withnivolumab therapy in this extended follow-up.

Figure 3. Objective Response to Nivolumab, by Presence or Absence of Visceral Mets

Category Any Grade % (n) Grade 3-4 % (n)Any select AE 54 (58) 5 (5)Skin 36 (38) 0Gastrointestinal 18 (19) 2 (2)Endocrinopathies 13 (14) 2 (2)Hepatic 7 (7) 1 (1)Infusion reaction 6 (6) 0Pulmonary 4 (4) 0Renal 2 (2) 1 (1)

Weeks Since Treatment Initiation

Median DOR 22.9 months

Months

0

0 4 8 12 16 20 24 28 32 36

8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160

Patients

Change in Tum

or Size (%)

Time to and duration of responsewhile on treatmentResponse duration followingtreament discontinuationTime to reponseOngoing response

NoYes

• 10 patients that were not evaluable for tumor burden are not presented.Horizontal dashed line denotes -30% change from baseline.

Patients-100-80-60-40-20020406080100120140160

Visceral Metastases

Efficacy and Safety of Nivolumab-Ipilimumab Combination TherapySznol M, et al. Survival, response duration, and activity by BRAF mutation (MT) status ofnivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapyin advanced melanoma. Presented at ASCO 2014, Abstract #LBA9003.

Objectives: To report updated safety, survival and clinical activity of concurrent ipilimumab and nivolumab for patients with advanced melanoma.

Methods and The initial trial included 53 patients randomized to concurrent therapy (cohorts 1 to 3) and 33 patients administeredstudy population: sequential therapy (cohorts 6 and 7). This analysis includes a newer group, cohort 8, which includes 41 patients who

were also prescribed concurrent therapy. The doses and regimens for each cohort are shown in Table 1. Note that survival data are not yet available for the newest cohort.

Across the concurrent cohorts, baseline characteristics included:

• Median age 58 years, 53% male, 94% ECOG status 0-1, 53% stage M1c.

• 17% had at least two prior regimens of systemic therapy.

• 23% had received prior immunotherapy (no prior ipilimumab), 5% had received a BRAF inhibitor.

• 38% had elevated LDH.

4

Table 1. Dosing Regimens Used in the Study

Figure 1. Characteristics of Response

Regimen Dose (mg/kg) Treatment ScheduleCohort No. N Nivolumab Ipilimumab Induction Maintenance

Concurrent1 14 0.3 32 17 1 32a 16 3 13 6 3 3

8* 41 1 3

Sequenced6 17 1 Prior7 16 3 Prior

Nivo Q3W x 8+

IPI Q3W x 4Nivo + IPI Q12W x 8

Nivo Q3W x 8+

IPI Q3W x 4

Nivo 3 mg/kgQ2W

(Max. 48 doses)

Nivo Q2W (Max of 48 doses)

*Insufficient data at this follow-up point to report survival endpoints.

Weeks

Months

0

0 4 8 12 16 20 24 28

10 20 30 40 50 60 70 80 90 100 110 120 130

Cohort

Time to and duration of response while on treatmentResponse duration followingtreament discontinuationTime to reponseOngoing response

Nivo 0.3 / IPI 3Cohort 1

Nivo 1 / IPI 3Cohort 2

Nivo 3 / IPI 1Cohort 2a



5

Table 2. Safety Overview

Figure 2.Overall Survival in Concurrent CohortsResults (for the concurrent regimens):

• Objective response rate (ORR) was 53% inconcurrent cohorts 1-3 and 43% in concurrentcohort 8.

• Complete response was 18% in concurrent cohorts1-3 and 10% in concurrent cohort 8.

o In the selected dosing regimen of nivolumab 1 mg/kg + ipilimumab 3 mg/kg, ORR was 53% in cohort 2 and 43% in cohort 8, with complete responses in 18% in cohort 2 and 10% in cohort 8.

• The median duration of response had not beenreached. 18 of the 22 responses were ongoing(Figure 1).

• Overall survival was 85% at one year and 79% attwo years (Figure 2).

o Among those in the nivolumab 1 mg/kg + ipilimumab 3 mg/kg cohort, one-year survival was 94% and two-year survival was 88%.

• There were no significant differences in efficacywhen analyzed by BRAF mutation status.

• There was a high incidence of grade 3/4 adverseevents (Table 2).

o 22/94 patients (23%) discontinued treatment due to treatment-related adverse events.

o There was 1 death deemed to be drug-related (fatal multi-organ failure as a result of colitis in cohort 8).

FACULTY COMMENTARY: The data presented from this study show exceptional efficacy of this combination in advancedmelanoma, with a higher rate of grade 3-4 toxicity. However, immune-related adverse events appear to be manageable withstandard management guidelines. Further data and follow-up are needed to provide additional information regarding the optimaluse of immunotherapy with checkpoint inhibition or immune blockade therapy. If the result is confirmed with longer follow-upand subsequent phase II and III trials, the ratio of risk/benefit favors the benefit. A three-arm, phase-III study has completedenrollment; results are expected to be presented soon.

AUTHORS’ CONCLUSIONS: Concurrent therapy with nivolumab and ipilimumab resulted in unprecedented two-year overallsurvival rates (overall 79% in cohorts 1-3 and 88% among those treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg). Themajority of objective responses are ongoing. There was a high incidence of grade 3-4 adverse events, but no new safety signals andstandard safety guidelines are available to manage/reverse AEs. Phase II and III trials investigating concurrent nivolumab andipilimumab combination vs. nivolumab vs. ipilimumab in patients with advanced melanoma have completed enrollment.

Concurrent AllCohorts 1-3 Cohort 8 Concurrentn = 53 n = 41 n = 94

Any Gr Any Gr Any GrAE, % Gr 3/4 Gr 3/4 Gr 3/4

All Related AEs 96 62 95 61 96 62

Select AEsGastrointestinal 43 9 34 20 39 14Hepatic 30 15 12 12 22 14Skin 79 4 73 15 77 9Endocrine 17 4 22 2 19 3Renal 6 6 0 0 3 3

OtherUveitis 6 4 2 2 4 3Pneumonitis 6 2 2 2 4 2Lipase increased 26 19 15 10 21 15Amylase increased 21 6 12 7 17 6

Months0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

14 13 11 10 8 7 7 7 7 7 5 2 2 2 1 1 0

Survival (%

)

100

90

80

70

60

50

40

30

20

10

0

Nivo 1 mg/kg + IPI 3 mg/kg (n=17)Concurrent cohorts 1-3 (n=53)

Censored

Patientsat RiskNivo 0.3 IPI 3

17 17 16 15 15 14 14 13 9 4 3 3 3 2 0 0 0Nivo 1 IPI 316 16 15 15 15 13 4 2 0 0 0 0 0 0 0 0 0Nivo 3 IPI 16 6 6 6 6 6 6 6 3 0 0 0 0 0 0 0 0Nivo 3 IPI 353 52 48 46 44 40 31 28 19 11 8 5 5 4 1 1 0Concurrent

1 year OS 85%

1 year OS 94%

2 year OS 79%

2 year OS 88%

Efficacy and Safety of Pembrolizumab (MK-3475) in Advanced Melanoma (KEYNOTE Study-001)Ribas A, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients with melanoma. Presented at ASCO 2014, Abstract #LBA9000.

Hamid O, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory and IPI-naive melanoma. Presented at ASCO 2014, Abstract #3000.

Objectives: To evaluate the safety and efficacy of pembrolizumab (formerly MK-3475) in patients with advanced melanoma.

Methods and This was a somewhat complicated, multi-cohort study design (the KEYNOTE study), which included study population: ipilimumab-naive, ipilimumab-treated and ipilimumab-refractory subgroups with different dosing levels of MK-3475

(2 mg/kg or 10 mg/kg).

There were 411 patients enrolled (190 ipilimumab-naive and 221 ipilimumab-treated). The number in the randomized cohorts was 276, of whom 103 were ipilimumab-naive. Overall baseline characteristics included:• Median age 61 years, 60% male, 73% ECOG status 0, 56% stage M1c.• 23% were treatment-naive.• 48% had at least two prior regimens of systemic therapy.• 23% and 30% of the ipi-naive and ipi-treated groups had previously received other immunotherapy, respectively.• 35% had elevated LDH.• 8% had brain metastasis.

6

Table 1. Safety Overview

Table2. Treatment-related AEs with Incidence > 5%

IPI-N IPI-T Totaln = 190 n = 221 n = 411

Time on therapy, weeks, mean (range) 34 (0.1-97) 28 (0.1-90) 30 (0.1-97)

Number of doses, median (range) 11 (1-47) 9 (1-46) 10 (1-47)

Grade 3-5 treatment-related AE, n (%) 26 (14) 25 (11) 51 (12)

Serious treatment-related AE, n (%) 20 (11) 12 (5) 32 (8)

Treatment-related AE leading to discontinuation, n (%) 7 (4) 10 (5) 17 (4)

Treatment-related death, n (%) 0 (0) 0 (0) 0 (0)

Total N = 411 Total N = 411Adverse Event, % Any Grade Grade 3/4 Adverse Event, % Any Grade Grade 3/4

Fatigue 36 2 Myalgia 9 0Pruritis 24 < 1 Headache 8 < 1Rash 20 < 1 Hypothyroidism 8 < 1Diarrhea 16 < 1 Decreased appetite 7 < 1Arthralgia 16 0 Dyspnea 7 < 1Nausea 12 < 1 Chills 6 0Vitiligo 11 0 Pyrexia 6 0Asthenia 9 0 ALT increased 5 < 1Cough 9 0 Total 83 12

Figure 1. Individual Tumor Responses (by RECIST Criteria)

Change From Baseline in Sum

of

Longest Diameter of Target Lesion, %

IPI-treatedIPI-naive

Individual Patients Treated With Pembrolizumab-100

-80

-60

-40

-20

0

20

40

60

80

100

72%

7

Results:

• The mean duration of therapy was 30 weeks overall(34 weeks for the ipilimumab-naive subgroup and28 weeks for the ipilimumab-treated group).

• 12% of the patients overall experienced grade 3-5,treatment-related adverse events (14% of theipilimumab-naive group and 11% of the ipilimumab-treated group) (Table 1). o Discontinuation rates due to treatment-related

AEs were 4% in the ipilimumab-naive group and 5% in the ipilimumab-treated group.

o The most common individual grade 3-4 adverse event was fatigue, which occurred in 2% of patients. All others occurred at a rate of < 1% (Table 2).

o There were no treatment-related deaths in this study.

• Figure 1 shows the individual tumor responses(waterfall plot) by RECIST criteria.o The median duration of response had not been

reached at the time of analysis; 88% of the responses were ongoing (Figure 2).

o The majority of patients had a response at the first assessment (at 3 months).

o Efficacy in terms of objective response rates was similar across analyzed subgroups, including pembrolizumab dose and whether or not patients had prior exposure to ipilimumab.

– The exception was baseline tumor size, wherethose who had tumors below median size hadhigher response rates than those who hadhigher-than-median tumor sizes.

• Median overall survival had not yet been reached.One-year overall survival was 69% (74% foripilimumab-naive and 65% for ipilimumab-treated)(Figure 3).o There were no differences in OS between

pembrolizumab doses.

• Median progression-free survival was 5.5 months(5.6 among ipilimumab-naive patients and 5.4 among ipilimumab-treated patients).o There were no differences in PFS between

pembrolizumab doses.

FACULTY COMMENTARY: This is the largest study conducted to date with an anti-PD-1 agent in advanced melanoma. Althoughthe duration of follow-up is relatively short for this study, the efficacy and safety data are very encouraging. Studies with anti-PD-1 agents in advanced melanoma have consistently shown positive efficacy data with overall survival. Incidences of Grade3-4 toxicities are low. There were no apparent safety differences regardless of whether the patients had received prior ipilimumabor not. As with the other anti-PD-1 inhibitors, we await confirmatory phase III study data.

AUTHORS’ CONCLUSIONS: Pembrolizumab, across all dose regimens tested, provided a favorable benefit-risk profile,suggesting it is a promising treatment option for patients with advanced melanoma. Responses were durable for both ipilimumab-naive and ipilimumab-treated patients, with a 69% overall survival rate at one year. The safety profile was manageable across all doses. There were no significant differences in outcomes among the different dosing regimens and the 2 mg/kg regimen is the recommended dose for subsequent study.

Time, monthsn at risk

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

411 388 347 324 307 281 250 208 156 95 78 62 27 6 0


100908070605040302010

0

Median OS not reached.69% OS rate at 12 months (74% for IPI-naive, 65% for IPI-treated).62% OS rate at 18 months.

Figure 3. Overall Survival

Figure 2. Time to and Durability of Response

Individual Patients Treated with Pem

brolizum

ab

10 30 50Time, weeks

6 months 12 months 18 months

70 90

88% of responsesongoing.Median responseduration notreached (range, 6+ to 76+ weeks)

IPI-treatedIPI-naiveComplete ResponsePartial ResponseProgressionOn Treatment

8

Carboplatin-paclitaxel + Ipilimumab in Metastatic MelanomaJamal R, et al. A randomized phase II study of ipilimumab (IPI) with carboplatin and paclitaxel(CP) in patients with unresectable stage III or IV metastatic melanoma. Presented at ASCO 2014,Abstract #9066.

FACULTY COMMENTARY: The results of this small Canadian study are interesting and provide proof that this type of combinationapproach to patients with BRAF-wild-type disease may be safe and helpful in bridging patients’ treatment from chemotherapy toimmunotherapy in those with significant tumor bulk or rapid disease progression. Consideration should be given to a largerprospective study investigating this combination.

AUTHORS’ CONCLUSIONS: The safety results from this study suggest that toxicity is manageable when carboplatin-paclitaxelis added to ipilimumab, with most patients completing the full course of treatment. The median survival in this study had notbeen reached, and the one-year overall survival compares favorably to the ipilimumab/DTIC arm and the ipilimumab alone arm inthe pivotal trials (where one-year overall survival was less than 50%). These results suggest that the combination of ipilimumaband carboplatin-paclitaxel may be appropriate for BRAF-wild-type melanoma patients with rapidly progressing disease.

Objectives: To determine the efficacy and safety of cytoreduction with carboplatin and paclitaxel (CP) in combination with immunotherapy with ipilimumab among patients with metastatic melanoma.

Methods and This study included 30 patients who either had no prior treatment or one BRAF-targeted regimen. They were study population: randomized to receive either concurrent (arm A) or sequential (arm B) CP (AUC6 + 175mg/m2 x 5) with ipilimumab

(3mg/kg x 4) given every 3 weeks either concurrently or delayed by one week.

The subjects mostly (n = 24) had cutaneous melanoma. Others were mucosal (n = 2), ocular (n = 3) and unknown primary (n = 1).

Median age was 55 years, 57% had stage M1c disease,40% had elevated LDH, six patients (20%) hadpreviously been treated with vemurafenib.

Results:

• Median follow-up period was 24 weeks.

• 85% of the patients completed the full course oftreatment.

• Response rates (RR) and disease control rates(DCR) for 30 evaluable patients at 24 weeks were13.3% and 36.7% by mWHO, and 26.7% and 56.7% byirRC, respectively (Table 1).

• One-year overall survival was 67%.

• Grade 3-5 adverse events (regardless of causality)are shown in Table 2.

o Seventeen percent (5/30) of patients received steroids for an immune-related (ir) AE: 2 patients with Grade 3 colitis, 2 patients with Grade 2 endocrinopathy, and 1 patient with Grade 2 rash.

o There were no treatment-related deaths on trial.

Table 2. Grade 3-5 Adverse Events

Grade 3/4/5Adverse event All IPI related C/P related

Hepatotoxicityhigh ALT 1 1high AST 1 1 1nausea 1 1

GI Disorders diarrhea 3 3 2colitis – C. Diff. 1 1hypophosphatemia 2 2 2

Electrolyte hypokalemia 1 1 1hypomagnesemia 1 1anemia 2 2

Hematologic febrile neutropenia 2 2thrombocytopenia 5 5

Neurologicalseizure 1vasovagal reaction 1

Infection pneumonitis 1 1 1abdominal 1

Painthoracic 2lower extremity 1generalized 2 1

Psychiatric insomnia 1

Constitutionalfatigue 2 1 1fever 1 1

Vascular disorder pulmonary embolism 1

Table 1. Best Overall Responses

All Arm A Arm BmWHO irRC mWHO irRC mWHO irRC

CR 0 1 0 0 0 1PR 4 7 2 2 2 5SD 7 9 4 5 3 4PD 19 13 4 3 15 10RR (%) 13.3 26.7 20 20 10 30DCR (%) 36.7 56.7 60 70 25 50Rate of PD (%) 63.3 43.3 40 30 75 50n 30 30 10 10 20 20

9

Dabrafenib + Trametinib vs. Dabrafenib Alone (COMBI-d)Long GJ, et al. COMBI-d: A randomized, double-blinded, phase III study comparing thecombination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-linetherapy in patients with unresectable or metastatic BRAFV600E/K mutation-positive cutaneousmelanoma. Presented at ASCO 2014, Abstract #9011.

FACULTY COMMENTARY: These preliminary findings show that response rate and PFS with the combination of BRAF and MEKinhibition is superior to BRAF inhibition alone. The combination also improved OS, but p-value did not cross the stopping boundaryfor interim analysis. However, these data are not yet mature with median OS not met at the time of analysis; we await the finalanalysis of overall survival. The difference between the two arms may not have been as large as the investigators had anticipated,but combination of BRAF and MEK inhibition can still be of clinical importance to patients with BRAF-mutated melanoma.

AUTHORS’ CONCLUSIONS: Compared to dabrafenib monotherapy, the combination of dabrafenib and trametinib resultedin a 25% reduction in risk of progression, 37% reduction in risk of death at interim analysis and a significantly improvedresponse rate. The toxicities encountered were manageable. This study is ongoing, with an updated survival analysis planned at70% death events.

Objectives: To confirm the superiority of dabrafenib + trametinib compared to dabrafenib alone in patients with BRAFV600E/K mutant metastatic melanoma.

Methods and A total of 423 patients were randomized 1:1 to receive dabrafenib 150 mg twice daily + trametinib 2 mg once daily or study population: dabrafenib 150 mg twice daily + placebo once daily as first-line therapy.

• Across the two treatment arms, baseline characteristics were balanced between the study and placebo arms. The data for the combination arm were as follows:

o Median age 55 years, 53% male.

o 67% stage M1c, 73% ECOG 0, 36% elevated LDH.

• Primary endpoint was investigator-assessed progression-free survival (PFS).

• The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response, and safety.

Results:

• The median PFS for the combination group was 9.3 months, compared to 8.8 months in themonotherapy arm (HR 0.75, p = 0.035) (Figure 1).

o The six-month PFS was 70% with the combination and 57% with monotherapy.

o The combined CR/PR rate was 67% with the combination and 51% with dabrafenib monotherapy (p = 0.0015).

o Six-month overall survival was 93% in the combination arm and 85% in the monotherapy arm (HR 0.63, p = 0.023) (Figure 2).

Figure 2.Overall Survival: Dabrafenib vs. Dabrafenib-Trametinib

Figure 1. Progression-free Survival: Dabrafenib vs. Dabrafenib-Trametinib

Time from randomization (months)0 2 4 6 8 10 12 14

Proportion alive and progression-free

0.80.91.0

0.70.60.50.40.30.20.10.0

Patients at RiskDabrafenib + trametinib

Dabrafenib211212

196173

164136

138107

8268

3331

910

00

DabrafenibMed. PFS 8.8 months6-month PFS = 57%

Dabrafenib + TrametinibMed. PFS 9.3 months6-month PFS = 70%

HR 0.75 (95% CI: 0.57, 0.99)p = 0.035

Time from randomisation (months)0 2 4 6 8 10 12 14 16 18 20

Proportion alive

0.80.91.0

0.70.60.50.40.30.20.10.0

Patients at RiskDabrafenib + trametinib

Dabrafenib211212

208205

199190

185174

160142

10290

4441

00

00

20

1111

Dabrafenib6 month OS = 85%Died (events): 55 (26%)

Dabrafenib + Trametinib6 month OS = 93%Died (events): 40 (19%)

HR 0.63 (95% CI: 0.42, 0.94)p = 0.023Median follow-up 9 months

10

Feasibility of Dabrafenib ± Trametinib + Ipilimumab in Advanced MelanomaPuzanov I, et al. Phase I study of the BRAF inhibitor dabrafenib (D) with or without the MEKinhibitor trametinib (T) in combination with ipilimumab (IPI) for V600E/K mutation–positiveunresectable or metastatic melanoma. Presented at ASCO 2014, Abstract #2511.

FACULTY COMMENTARY: It is too early to draw any conclusions from these results, other than to agree with the authors that theipilimumab-dabrafenib-trametinib triplet is too toxic for concurrent administration, but combination of ipilimumab-dabrafenibseemed to be tolerable. Many questions remain unanswered, including what difference it might make if the therapies wereadministered sequentially, with induction BRAF inhibition followed by immunotherapy; which immunotherapeutic agent would beoptimal to use in the combination setting (e.g., would an anti-PD-1 agent be better tolerated in combination?); and will favorableresponse data translate into meaningful survival benefits? This is an intriguing area of study, but one which is still in its earlystages.

AUTHORS’ CONCLUSIONS: Dabrafenib and ipilimumab, at standard doses, have been well tolerated in combination. Thecombination appears to be highly active, although longer follow-up is needed. The concurrent administration of dabrafenib,trametinib and ipilimumab was associated with unacceptable toxicity. Sequential administration is being considered.

Objectives: To characterize the safety, efficacy, pharmacokinetics and pharmacodynamics of dabrafenib, with or without trametinib, when administered in combination with ipilimumab.

Methods and 3 patients were initially included in the first phase of the trial for the doublet of dabrafenib 150 mg bid + study population: ipilimumab 3 mg/kg every three weeks for 4 cycles. Following this 12-week phase, a planned expansion cohort of

30 patients was intended for the doublet arm (of which 9 had been enrolled at the time of this presentation) and a dose-finding arm for the triplet of ipilimumab, dabrafenib and trametinib was also initiated. Seven patients were enrolled in this analysis.

A total of 12 patients were therefore evaluable for the doublet cohort and seven for the triplet cohort.

Results:

• There were no dose-limiting toxicities observedwith the initial phase of dabrafenib-ipilimumabdoublet (Table 1).

o Changes in transaminases have been infrequent.

o The expansion cohort for the doublet is going ahead as planned.

• Preliminary clinical activity with the doublet isshown in Figure 1.

• The triplet arm (n = 7) was discontinued due tounacceptable toxicity.

o Among the seven patients, there were two cases of colitis (grade 3)—of which one had grade 4 intestinal perforation and one grade 2 intestinal perforation—and one grade 4 renal failure.

Figure 1. Initial Anti-tumor Activity of the Dabrafenib-ipilimumab Doublet

Table 1. Adverse Event Summary with the Dabrafenib-ipilimumab Doublet

Related AEs grade 1-2 (> 1 patients) Patients, n (%)Any adverse event 8 (100)Pyrexia 7 (88)Chills 6 (75)Rash maculo-papular 4 (50)Hand-foot syndrome 4 (50)Pruritus 4 (50)Nausea 2 (25)Vomiting 2 (25)Fatigue 2 (25)Hyperhidrosis 2 (25)

All AEs grade 3 (no grade 4) Patients, n (%)Any adverse event 4 (50)Liver function test abnormal (AST, ALT) 1 (13)Squamous-cell carcinoma of skin 1(13)Flu-like symptons 1 (13)Transient ischemic attack 1 (13)

Time since the first dose (months)0 2 3 4 5 6 7 8 9 10 11

Percent Change from

Baseline

20

010

-30-20-10

-40-50-60-70-80-90-100

11

Novel Combined Targeted Therapy for NRAS-mutant MelanomaSosman JA, et al. A phase Ib/II study of LEE011 in combination with binimetinib (MEK162) inpatients with NRAS-mutant melanoma: Early encouraging clinical activity. Presented at ASCO2014, Abstract #9009.

FACULTY COMMENTARY: There is no approved targeted therapy for patients with NRAS-mutated melanoma and many of thesepatients do poorly in terms of clinical outcomes. Although these are only preliminary results, response rate and duration ofresponse from the combination of MEK inhibitor and CDK4/6 inhibitor seemed promising. This combination should be studied infuture clinical trials.

AUTHORS’ CONCLUSIONS: Combined LEE011 and binimetinib demonstrated promising preliminary antitumor activity inpatients with advanced NRAS-mutant melanoma. The combination was associated with frequent AEs, necessitating doseinterruptions and reductions. Exploration of intermittent dosing schedules to establish a more tolerable recommended phase IIdose are underway.

Objectives: To determine the maximum tolerated dose and/or recommended phase II dose, safety and tolerability, pharmacokinetics and clinical efficacy of the combination of LEE011 (CDK4/6 inhibitor) and binimetinib (MEK inhibitor).

Methods and This was a phase Ib study involving 22 patients with metastatic or locally advanced NRAS-mutant melanoma study population: (15-20% of cutaneous melanoma and associated with poor prognosis).

• Patients were randomized to one of four dosingschedules (Table 1).

• Median age at baseline was 58 years, 59% weremale.

• 55% had elevated LDH, 81% were stage M1c.

• 32% had 2-3 prior systemic anti-cancer therapies;50% had prior immunotherapy.

Results:

• Dose-limiting toxicities (DLT) were observed incohorts 1, 3 and 4:

o Cohort 1: 1 patient with DLT.

– Grade 3 acute renal injury.

o Cohort 3: 1 patient with DLT.

– Intracranial bleed & death.

o Cohort 4: 2 patients with DLTs.

– Grade 4 atrial fibrillation and grade 3 edema.

– Grade 4 symptomatic CPK elevation.

• The maximum tolerated dose was determined tobe LEE011 200 mg qd and binimetinib 45 mg bid.

• There was no evidence of drug-drug interactionswith these two agents.

• Partial responses were observed in 7 of 22 patients (33%).

o Individual responses are shown in Figure 1.

o Several patients had early tumor shrinkage with major symptomatic improvement.

o The 12 patients remaining in the study have had exposure to the study drugs ranging from 2 to 8 months (Figure 2).

Figure 1. Individual Patient Responses

Figure 2. Individual Patients’ Duration of Exposure

*Ongoing as of April 14, 2014.

* * * * * * * * * * * *

K denotes patient with KRAS-mutant pancreatic cancer.

K

N = 21

LEE 300 mg + MEK 30 mgLEE 300 mg + MEK 45 mg


Treatment Group

Best Percentage Change from

Baseline

100

-80

-60

-40

-20

0

20

40

60

80

-100

Duraction of Exposure, d0 26 56 84 112 140 168 195 224 252



Arrowhead indicates patient ongoing as of April 14, 2014. K denotes patient with KRAS-mutant pancreatic cancer.

KN = 22

Table 1. Dosing Schedules Used in This Study

Cohort n Binimetinib dose LEE011 dose1 9 45 mg bid 200 mg qd

2 4 45 mg bid 250 mg qd

3 4 30 mg bid 300 mg qd

4 6 45 mg bid 300 mg qd

12

Talimogene Laherparepvec (T-VEC) for the Local Treatment of Advanced MelanomaKaufman HL, et al. Primary overall survival (OS) from OPTiM, a randomized phase III trial oftalimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of unresected stage IIIB/C and IVmelanoma. Presented at ASCO 2014, Abstract #9008a.

FACULTY COMMENTARY: This is an interesting trial showing benefit of this locally injected immunotherapy in patients withadvanced melanoma. It should be noted that this is not an easy treatment to administer, requiring time and training. Thecomparator used in this study—GM-CSF—may not be appropriate, as this is not a treatment that many clinicians would offerpatients. Also, the population included in this study is not as sick as those typically seen in immunotherapy trials. The subgroupanalyses suggest that this agent may be considered for selected patients with a low burden of disease or for those who declinesystemic treatment.

AUTHORS’ CONCLUSIONS: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanomain a well designed trial. The systemic effect of T-VEC is demonstrated by responses in uninjected lesions. T-VEC monotherapyprovides a novel potential therapeutic approach to metastatic melanoma. Combination treatment approaches including T-VEC arerational; a trial evaluating T-VEC + ipilimumab is accruing.

Objectives: To report the overall survival findings from the OPTiM trial evaluating T-VEC in advanced melanoma.

Methods and OPTiM was a randomized, phase III trial of T-VEC vs. GM-CSF in 436 patients with unresected stage IIIB-IV melanoma.

• Baseline characteristics included:

o 57% male, 70% ECOG PS 0.

o 22% stage IV M1c disease, 11% elevated LDH.

• Patients were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108

pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d).

• The primary endpoint (previously reported) was durable response rate, defined as CR or PR beginning within 12 months of initiation of therapy and lasting continuously for at least six months. Overall survival was a key

secondary endpoint.

Results:

• Overall response rate was 26.4% with T-VEC vs.5.7% with GM-CSF (p < 0.0001).

o Complete responses were seen in 10.8% of T-VEC patients and 0.7% of those in the GM-CSF arm.

o The durable response rate was 16.3% for T-VEC and 2.1% for GM-CSF (p < 0.0001).

• Responses were also seen in lesions that were notinjected.

• Median overall survival was 23.3 months in the T-VEC group and 18.9 months in the GM-CSF arm(HR 0.79, p = 0.051) (Figure 1).

o Exploratory subanalyses showed that the largest impact on overall survival with T-VEC vs. GM-CSF was among patients with earlier stages of disease (i.e., IIIB/C, IVM1a vs. IVM1b/c) (Figure 2) and among those taking T-VEC as first-line therapy rather than second or subsequent line of therapy.

Figure 1. Overall Survival

Figure 2.Overall Survival by Disease Stage

study population:

0 5 10 15 20 25 30 35 40 45 50 55 60

Kaplan-Meler Percent

80%

100%

60%

40%

20%

0%

Patientsat Risk

Study Month

T-VECGM-CSF

295141

269124

230100

18783

15963

T-VECGM-CSF

14552

12546

00

3615

165

20

6627

9536

Median (95% CI)Events / N (%) in Months189/295 (64) 23.3 (19.5, 29.6)101/141 (72) 18.9 (16.0, 23.7)

DifferenceSurvival T-VEC GM-CSF % (95% CI)12-mo 73.7% 69.1% 4.6 (-4.7, 13.8)24-mo 49.8% 40.3% 9.5 (-0.5, 19.6)36-mo 38.6% 30.1% 8.5 (-1.2, 18.1)48-mo 32.6% 21.3% 11.3 (1.0, 21.5)

0 5 10 15 20 25 30 35 40 45 50 55 60

Kaplan-Meler Percent

Stage IIIB/C, IVM1a

80%

100%

60%

40%

20%

0%

Risk set, nStudy Month Study Month

T-VECGM-CSF

Hazard Ratio: 0.57 (95% CI: 0.40, 0.80)Log Rank: p < 0.001 (descriptive)

16386

15778

14665

12955

11343

10435

9330

7322

5117

2310

102

10

00

T-VECGM-CSF

Events / N (%) Median (95% CI), mo80/163 (49) 41.1 (30.6, NE)

57/86 (66) 21.5 (17.4, 29.6)

0 5 10 15 20 25 30 35 40 45 50 55 60

Stage IVM1b/c

80%

100%

60%

40%

20%

0%

Risk set, nT-VEC

GM-CSF

Hazard Ratio: 1.07 (95% CI: 0.75, 1.52)Log Rank: p =0.71 (descriptive)

13155

11246

8435

5828

4620

4117

3216

2214

1510

135

63

10

00

T-VECGM-CSF

Events / N (%) Median (95% CI), mo109/131 (83) 13.4 (11.4, 16.2)

44/55 (80) 15.9 (10.2, 19.7)

13

Overview of Research Investigating Non-cutaneous MelanomaDeo MA, et al. Long-term survival benefit from ipilimumab treatment in metastatic uvealmelanoma patients. Presented at ASCO 2014, Abstract #3060.

Piulats Rodrigues JM, et al. Phase II study evaluating ipilimumab as a single agent in the first-linetreatment of adult patients with metastatic uveal melanoma (MUM): The GEM-1 trial. Presentedat ASCO 2014, Abstract #9033

Zimmer L, et al. Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to furtherevaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and raresubgroups. Presented at ASCO 2014, Abstract #9031.

FACULTY COMMENTARY: Non-cutaneous melanomas are under-represented in clinical trials, making evidence-based medicine forthese patients problematic. Although the research presented at ASCO 2014 for non-cutaneous melanoma did not provide manyencouraging results, it is notable that these patients are being evaluated. It is important to consider these melanoma subtypes forfuture clinical trials.

Key Findings:

Deo et al: In this retrospective analysis (n = 24 in asingle French centre), patients with metastatic uvealmelanoma demonstrated a 4% response rate toipilimumab. However, the median overall survival was9.7 months, which compares favorably to historicalcontrols in this population (~6 months). As well, one-year OS was 45%, which is similar to the OSreported for cutaneous melanoma.

Piulats Rodrigues et al (GEM-1 trial): In thisprospective, open-label phase II study for uvealmelanoma (n = 32), ipilimumab was administered asinduction (10 mg/kg iv q 3 weeks for 4 doses) andmaintenance (q 12 weeks until progression,intolerance or withdrawal).

As shown in Table 1, there was a low overall responserate (7% PR by mWHO or irRC criteria). The medianoverall survival was 9.8 months. Progression-freesurvival rates at 6 and 12 months were 27% and 19%,respectively.

Zimmer et al (DeCOG trial): This was a multicenter,phase II clinical trial of ipilimumab in patients withdifferent subtypes of metastatic melanoma(cutaneous [n = 83], mucosal [n = 7], ocular [n = 53] orunknown primary melanoma [MUP, n = 13]). Patientswere to receive four cycles of ipilimumab 3 mg/kgevery three weeks.

As shown in Figure 1, the 12-month overall survivalrates were 38% for cutaneous, 14% for mucosal, 22% for ocular melanomas and 27% for MUP.

Figure 1. Overall Survival by Subtype of Metastatic Melanoma (DeCOG)

Table 1. Best Responses with Ipilimumab in Metastatic Uveal Melanoma (GEM-1)

mWho irRC

Response N (%) N (%)

Complete Response 0 0

Partial Response 2 (7) 2 (7)

Stable Disease 10 (32) 13 (39)

Progressive Disease 13 (42) 10 (32)

Not Evaluable 6 (19) 6 (19)

Months

p-value: 0.24

cutaneous

CutaneousMucosalMUPOcular

MUP

mucosal ocular

0

8371253

427730

262311

18

36

13

23

CutaneousMucosal

MUPOcular

No. at risk6 12 2418 30

OS

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Cutaneous Mucosal OcularMelanoma Melanoma MUP Melanoma Total

Median survival, 2.6 (2.5-2.7) 2.8 (1.5-5.7) 3.1 (2.3-4.1) 2.8 (2.5-2.9) 2.6 (2.5-2.7)months (95% CI)

1-year survival, % 38 (27-48) 14 (1-46) 27 (5-57) 22 (12-35) 30 (23-38)(95% CI)

2-year survival, % 22 (13-33) 0 27 (5-57) 7 (1-18) 16 (10-23)(95% CI)

14

Ipilimumab for the Adjuvant Treatment of MelanomaEggermont AM, et al. Ipilimumab versus placebo after complete resection of stage III melanoma:Initial efficacy and safety results from the EORTC 18071 phase III trial. Presented at ASCO 2014,Abstract #LBA9008.

Objectives: To evaluate ipilimumab as an adjuvant therapy for resected stage III melanoma.

Methods and This was a randomized, double-blind trial in 951 patients who underwent complete resection of stage III study population: cutaneous melanoma.

• Patients were randomized 1:1 to receive ipilimumab 10 mg/kg (n = 475) or placebo (n = 476) every 3 weeks for 4 doses, then every 3 months for up to 3 years until completion, disease recurrence, or unacceptable toxicity.

• The primary endpoint was recurrence-free survival (RFS), which is reported in this analysis.

• The study is ongoing: overall survival and updated safety analyses will be forthcoming.

• The current analysis was done with a median duration of follow-up of 2.7 years.

Figure 1. Recurrence-free Survival with Adjuvant Ipilimumab vs. Placebo

Figure 2. Recurrence-free Survival in Subgroup Analyses

MonthsPatientsat Risk

0 12 24 4836 60

Ipilimumab 475234NO

276 205 67 5 0Placebo 476294 260 193 62 4 0

Patients Alive

Without Relapse (%

)

1009080706050403020100

Ipilimumab PlaceboEvents/patients 234/475 294/476HR (95% CI)* 0.75 (0.64–0.90)Log-rank p value 0.00132-year RFS rate (%) 51.5 43.83-year RFS rate (%)** 46.5 34.8

*Stratified by stage**Date are not yet mature

Ipilimumab 10 mg/kgPlacebo

Median: 26.1 months

Median: 17.1 months

Events/Patients HR & CI*Ipilimumab Placebo (Ipilimumab : Placebo)

AJCC 2002 (CRF)

Stage IIIA 34/98 36/88 0.91 (0.49–1.68)

Stage IIIB 99/213 121/207 0.77 (0.54–1.08)

Stage IIIC 101/164 137/181 0.73 (0.52–1.02)

Type of LN+

Microscopic 83/210 108/193 0.68 (0.47–0.99)

Macroscopic 151/265 186/283 0.83 (0.63–1.10)

Ulceration

No 116/257 131/244 0.84 (0.61–1.17)

Yes 106/197 146/203 0.67 (0.48–0.93)

Unknown 12/21 17/29 1.08 (0.40–2.87)

Total 234/475 294/476 0.76 (0.64–0.91)**(49.3%) (61.8%)

Ipilimumabbetter

Placebobetter

0.25 0.5 1.0 2.0 4.0

Treatment effect: p < 0.01*95% CI for total, 99% CI elsewhere**Unstratified analysis

15

FACULTY COMMENTARY: Based on these results, it appears that immunotherapy with ipilimumab has activity in the adjuvantsetting, although the overall survival data are still not available. The tolerability of this agent is perhaps more of a concern for somepatients at this stage of disease than in the metastatic setting, anecdotally, healthier patients may be less willing to compromisequality of life. However, it is possible that the AE rates and severities in this study, which began in 2008, may be higher than wemight expect if the trial were to start today, as the management of ipilimumab-related adverse events was not well understood inthe earlier days of this trial. The use of placebo as the comparator in this study has been questioned, given that there are datashowing a small but significant benefit of interferon in the adjuvant setting. However, interferon use is not favored in Europe, wheremany of this study’s patients were recruited. Using interferon as a control would not have been acceptable in those centres. TheECOG 1609/NCIC CTG MEC3 study is currently evaluating ipilimumab vs. interferon in the adjuvant melanoma setting.

AUTHORS’ CONCLUSIONS: Adjuvant ipilimumab therapy (10 mg/kg) was associated with a significant improvement in RFSrelative to placebo. Data for overall survival will be reported at a later date. The safety profile of ipilimumab is generallyconsistent with that observed in advanced melanoma, although the incidence of some AEs was higher in this study. Most of theimmune-related AEs were managed with established treatment algorithms. There is currently a second phase III study ongoing inthe adjuvant setting, comparing ipilimumab 3 mg/kg or 10 mg/kg to interferon.

Table 2. Management and Resolution of Immune-related Adverse Events

Table 1. Summary of Immune-related Adverse EventsResults:

• Median RFS was 26.1 months for ipilimumab and17.1 months for placebo (p = 0.0013, Figure 1).

o 2- and 3-year RFS were 51.5% and 46.5% for ipilimumab and 43.8% and 34.8% for placebo, respectively.

o RFS results were consistent across subgroups (Figure 2).

• Most patients in this trial discontinued theirtherapy:

o 91.7% in the ipilimumab group discontinued: 48.8% due to adverse events and 28.0% due to disease progression.

– 42.0% of ipilimumab-treated patients receivedat least one dose of maintenance therapy;28.9% received at least seven doses (1 year oftherapy).

o 83.1% of the placebo group discontinued: 57.6% due to disease progression and 1.7% due to adverse events.

• The immune-related adverse events observed inthis study are shown in Table 1.

• Most AEs were manageable and resolved. Theexception was endocrinopathies, which remainedunresolved in 44% of patients who experiencedthese AEs (Table 2).

• There were five deaths attributed to ipilimumab:three due to colitis; one due to myocarditis andone due to Guillain-Barré syndrome.

% PatientsIpilimumab (n = 471) Placebo (n = 474)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4

Any irAE 90.4 36.5 5.5 38.6 2.3 0.2

Dermatologic 63.3 4.5 0 20.9 0 0Rash 34.4 1.3 0 11.0 0 0

Gastrointestinal 46.3 14.9 1.1 17.7 0.6 0.2Diarrhea 41.4 9.6 0 16.7 0.4 0Colitis* 15.9 6.8 0.8 1.3 0.2 0

Endocrine 37.6 7.9 0.6 6.5 0 0Hypophysitis 18.3 4.7 0.4 0.4 0 0Hypothyroidism 8.9 0.2 0 0.8 0 0

Hepatic 25.1 7.9 2.8 4.4 0.2 0LFT increase 19.7 3.8 1.5 4.0 0 0

Neurologic 4.5 1.1 0.8 1.9 0 0

Other 23.6 7.4 0.4 4.4 1.7 0

LFT=liver function test. *Gastrointestinal perforations: ipilimumab, 6 related (1.3%); placebo, 3 unrelated (0.6%).

Ipilimumab (n = 471) Placebo (n = 474)

Skin irAEN with event 129 14Resolved, n (%) 115 (89.1) 13 (92.9)Median, weeks (95% CI) 5.5 (4.1–8.1) 2.6 (0.1–39.7)

Gastrointestinal irAEN with event 144 18Resolved, n (%) 135 (93.8) 17 (94.4)Median, weeks (95% CI) 4.0 (2.7–5.1) 0.9 (0.4–1.9)

Hepatic irAEN with event 77 5Resolved, n (%) 73 (94.8) 4 (80.0)Median, weeks (95% CI) 5.0 (3.7–8.4) 12.0 (1.1 –NR)

Endocrine irAEN with event 134 5Resolved, n (%) 75 (56.0) 4 (80.0)Median, weeks (95% CI) 31.0 (13.9–186.0) 12.6 (3.4–NR)

NR=not reached.

16

Meta-analysis of Interferon Studies for Adjuvant Treatment of MelanomaSuciu S, et al. Predictive importance of ulceration on the efficacy of adjuvant interferon-a (IFN): An individual patient data (IPD) meta-analysis of 15 randomized trials in more than 7,500 melanoma patients. Presented at ASCO 2014, Abstract #9067.

FACULTY COMMENTARY: The observation that adjuvant therapy with interferon works best among patients with ulceration may behelpful in selecting potential patients for adjuvant therapy. We await definitive evidence on this matter from ongoing phase III trials.

AUTHORS’ CONCLUSIONS: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse andimproves overall survival, but does not identify the optimal dose or duration of IFN. The overall survival benefit was confined topatients with ulcerated tumours. The biological basis of this action is incompletely defined and is being studied in the ongoingEORTC 18081 and ECOG-ACRIN Intergroup Trial E1609.

Objectives: To assess the evidence of interferon vs. no interferon for adjuvant treatment of melanoma.

Methods and Meta-analytic methods were used to assess event-free survival (EFS) and overall survival (OS) among clinical trials study population: evaluating interferon as adjuvant therapy.

• 15 trials were included, involving more than 7,500 patients.

Results:

• There was a small, but statistically significantbenefit for IFN for both EFS (odds ratio [OR] 0.86, 95% CI 0.81-0.91) and OS (OR 0.90, 95% CI0.85-0.97).

• The between-group differences were largestamong those patients with ulceration.

o 5- and 10-year EFS among patients with ulceration were 32.9% and 27.2% for interferon, and 26.9% and 20.4% for no interferon, respectively (Figure 1).

o 5- and 10-year OS among patients with ulceration were 46.0% and 38.5% for interferon, and 38.1% and 28% for no interferon, respectively (Figure 2).

Figure 1. Event-free Survival by Ulceration Status

Figure 2.Overall Survival by Ulceration Status

Years0 3 1 4 6 7 8 10 11+2 5 9

Estim

ated percentage still event-free

100

90

80

70

60

50

40

30

20

10

0

Annual event rates:years 1-10 years 11+

IFN 23.5% SD 0.9 4.0% SD 2.3No IFN 29.6% SD 1.4 2.4% SD 2.4

EFS 5-yr 10-yr

IFN 32.9% 27.2%

No IFN 26.9% 20.4%

32.9%

26.9%

allocated IFN (% ± SD)allocated no IFN (% ± SD)

27.3% 20.1%

20.4% 19.9%

63.3% SD 3.3(logrank2P = 0.0006)

Ulceration: YES

Years0 3 1 4 6 7 8 10 11+2 5 9

Estim

ated percentage still event-free

100

90

80

70

60

50

40

30

20

10

0



43.2%

40.7%


35.5% 34.7%

34.6%34.3%0.4% SD 2.6(logrank2P > 0.1; NS)

Ulceration: NO

Years0 3 1 4 6 7 8 10 11+2 5 9

Estim

ated percentage still alive

100

90

80

70

60

50

40

30

20

10

0



OS 5-yr 10-yr

IFN 46.0% 38.5%

No IFN 38.1% 28.0%

46.0%

38.1%


36.5% 37.1%

28.0% 27.4%

9.7% SD 3.5(logrank2P = 0.0002)

Ulceration: YES

Years0 3 1 4 6 7 8 10 11+2 5 9

Estim

ated percentage still alive

100

90

80

70

60

50

40

30

20

10

0



53.7%

53.2%


43.4% 42.5%

-1.9% SD 2.5(logrank2P > 0.1; NS)

Ulceration: NO

44.7% 44.4%

This document has been produced by STA HealthCare Communications. The opinions expressed in this program do not necessarily reflect those of the publisher or sponsor. The informationpresented in this document may have been derived from unpublished papers, preliminary study reports, or oral communications and, as such, may contain incomplete or non-peer-reviewed data.Healthcare professionals should take into account the patient’s individual condition and consult officially approved product monographs before making any diagnosis or following any procedurebased on suggestions made in this document. Copyright 2014. All rights reserved.

new research on treatment options for melanoma · 2014-09-16 · new research on treatment options...

Documents