La gestione del paziente ALK traslocato, dopo la prima linea Milano 20 Novembre 2015 – Palazzo...

La gestione del paziente ALK traslocato,dopo la prima linea

Milano 20 Novembre 2015 – Palazzo Pirelli

Antonio PassaroDivisione di Oncologia Toracica

Istituto Europeo di Oncologia, Milano

http://www.ieo.it/Italiano/Pages/Default.aspx

• Primary and acquired resistance on Crizotinib

• Potential Strategies for Overcoming Resistance to ALK inhibitors

• 2ndgeneration ALK inhibitors

• Clinical CNS data with 2ndgeneration ALK inhibitors

• Algorithm

Sai-Hong Ou at 2015 ASCO Annual Meeting

Camidge et al., ASCO 2011

% D

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Dec

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ease

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Progressive disease

Stable disease

Partial response

Complete response

100100

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6060

4040

2020

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Objective response details

(all evaluable patients)N=116

ORR (95% CI) 61% (52, 70)

Median response duration 48 weeks

Median time to response 8 weeks

Disease control rate at 8, 16 weeks 79%, 67%

Primary Resistance

1.01.0

0.80.8

0.60.6

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0 5 10 15 20

Months119 73 29 8 1# at risk

Median PFS = 10.0 months (95% CI: 8.2, 14.7)

Censored

95% Hall-Wellner Band

Acquired Resistance

Camidge et al., ASCO 2011

Limited efficacy of crizotinib1-3

• ORR 60%

• Median PFS 8–10 months

Nearly all patients developresistance4,5

• Mostly within 1–2 years

• Frequent CNS relapse6

Different mechanisms of resistance4,5

• ALK resistance mutations

• Alternative pathways

1. Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019; 2. Kim D-W, et al. ESMO; 2012. Abstract 1230PD; 3. Shaw AT et al. ESMO; 2012. Abstract LBA1_PR; 4. Katayama R, et al. Sci Transl Med. 2012;4:120ra17; 5. Doebele RC, et al. Clin Cancer Res. 2012;18:1472-1482; 6. Takeda M, et al. J Thorac Oncol. 2013;8:654-657.

Shaw A, et al. ASCO; 2013. Abstract 8010

Katayama et al. Clin Cancer Res 2015;21:2227-2235

Presented By Christine Lovly at 2015 ASCO Annual Meeting

1. Second generation ALK inhibitors

2. ALK TKI + HSP90 inhibitors

3. ALK TKI + chemotherapy

4. Co-targeting of potential bypass tracks:

• Receptor tirosine kinases (EGFR, IGF-1R)

• Downstream signaling mediators

5. ALK TKI + immuno therapy

Adapdet from C Lovly at 2015 ASCOPresented By Christine Lovly at 2015 ASCO Annual Meeting

1) Better affinity for ALK• Improved quality and duration of response to TKI• Delay in ALK non-gatekeeper resistance emergence (ALK amplification)?

2) Better affinity for crizotinib resistant second-site mutated ALK • Delay in ALK mutation-dependent resistance emergence• Treatment option in mutation-dependent resistance

3) Improvement in pharmacokinetics to brain tissue and CSF

Activity in enzymatic and cell-based assays1,2

Long-lasting responses in EML4-ALK +murine models including crizotinib-

resistance1

AssayLDK378IC50 (nM)

CrizotinibIC50 (nM)

Enzymatic ALK IGF-1R c-Met

0.158

3200

3400

8

Cell-based EML4-ALK - L1196M - G1269S - G1202R - C1156Y

2060

140490130

120810

16001020350

Crizotinib-resistant H2228 tumor model with ALK C1156Y mutation

1. Li N, et al. AACR-NCI-EORTC; 2011. Abstract B232; 2. Shaw AT, et al. ESMO; 2012. Abstract 440O; Adapted from Shaw A, et al. ASCO; 2013. Abstract 8010.

Patients with at least 1 postbaseline assessment of target lesions (investigator assessment)

Bes

t %

Ch

ang

e fr

om

Bas

elin

e

Best % Change from Baseline in Target LesionsLDK378 400–750 mg/day

–100

–80

–60

–40

–20

0

60

40

20

80

100

PFS event

Prior crizotinibCrizotinib- naïve

ORR •Crizo-pretreated: 59%•Crizo-naive: 62%

FD

A ap

pro

val: 29-04-2014

Adapted from Shaw A, et al. ASCO; 2013. Abstract 8010.

Censoring timesNSCLC with prior ALKi (n = 163)NSCLC ALKi naive (n = 83)All NSCLC (N = 246)

Kaplan-Meier medians, monthsNSCLC with prior ALKi: 6.93NSCLC ALKi naive: 18.40All NSCLC: 9.03

80

70

10

0 3 6 9 12

60

15

50

40

30

20

0

90

100

18 21 24 30 33 3627Time, months

Time, monthsNSCLC with prior ALKi

NSCLC ALKi naiveAll NSCLC

0163

83

246

Number of patients still at risk

3108

69

177

679 55

134

952 43 95

1229 32 61

1513 17 30

182 6

8

211 2

3

240 0

0

270 0

0

300 0

0

330 0

0

360 0

0

Prob

abili

ty, %

Efficacy ParameterPatients with NSCLC

Treated with Prior ALKi (n = 163)

ALKi-Naive Patients with NSCLC

(n = 83)

All Patients with NSCLC

(N = 246)

ORR, n (%)(95% CI)a

92 (56.4)(48.5–64.2)

60 (72.3)(61.4–81.6)

152 (61.8) (55.4–67.9)

CR 3 (1.8) 1 (1.2) 4 (1.6)

PR 89 (54.6) 59 (71.1) 148 (60.2)

SD, n (%) 29 (17.8) 14 (16.9) 43 (17.5)

Progressive disease, n (%) 16 (9.8) 0 16 (6.5)

Unknown, n (%) 26 (16.0) 9 (10.8) 35 (14.2)

Median PFS (95% Cl), mo

6.9 ( 5.6–8.7)

18.4 (11.1–NE)

9.0 (6.9–11.0)

Median DOR(95% Cl), mo

8.3 (6.8–9.7)

17.0 (11.3–NE)

9.7 (8.3–11.4)

Investigator-Assessed Results for Patients with NSCLC at 750-mg Dose

aORR was complete response + partial response.DOR, duration of response; NE, not estimable.Novartis, data on file (ASCEND-1 [2101] clinical data as of April 14, 2014).

All Patients with NSCLC All Gradesn (%)

Grades 3/4 n (%)b

Total 246 (100.0) 200 (81.3)

Diarrhea 213 (86.6) 15 (6.1)

Nausea 205 (83.3) 15 (6.1)

Vomiting 150 (61.0) 11 (4.5)

ALT increased 109 (44.3) 73 (29.7)

Fatigue 106 (43.1) 12 (4.9)

Abdominal pain 94 (38.2) 3 (1.2)

Decreased appetite 93 (37.8) 4 (1.6)

AST increased 81 (32.9) 25 (10.2)

Constipation 75 (30.5) 0 (0.0)

Cough 71 (28.9) 0 (0.0)

Dyspnea 62 (25.2) 10 (4.1)

Upper abdominal pain 59 (24.0) 2 (0.8)

Headache 51 (20.7) 4 (1.6)

Back pain 50 (20.3) 1 (0.4)

Most Common AEs for All Patients (N = 246; ≥15 for all grades)a

Novartis, data on file (ASCEND-1 [2101] clinical data as of April 14, 2014).

Shaw AT, et al. NEJM 2014.Gainor JF, et al. Clin Cancer Res 2015

Alectinib


ALKi-Naive ALK+ NSCLC•Diagnosed by IHC with confirmatory FISH or RT-PCR•≥1 prior CT•ALKi naive

Phase I Dose Escalation Alectinib

•20 mg to 300 mg BID fasting; 240 mg or 300 mg BID nonfasting •N = 24

Primary endpoint: DLT, MTD

RP2D

Phase II Dose Expansion Alectinib

•300 mg BID•N = 46

Primary endpoint: ORR

Study Design and Demographics

DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RP2D, recommended phase 2 dose.Seto T, et al. Lancet Oncol. 2013;14:590-598.

Seto T, et al. Lancet Oncol. 2013;14:590-598.

Phase I Results

•No DLTs reported; RP2D was 300 mg BID

•17 of 20 evaluable patients (85%) had a PR

Phase II Results

•ORR 93.5% (2 CRs and 41 PRs)– All responders had >30% reduction in tumor size. 65% reached

criteria for PR within 3 weeks

•Median PFS was not reached (median follow-up 7.6 m)

•15/46 patients in the phase II portion had known BMs– 12/15 received prior radiation for BMs

– Prolonged disease control (>6 months) was observed in 7/15 patients (47%)

•Most frequent AEs: Dysgeusia (30%), increased AST (28%), and increased blood bilirubin (28%)

– Drug-related visual disorders were rare, and GI events were mild

Waterfall Plot of Best Response from Baseline

20Seto T, et al. Lancet Oncol. 2013;14:590-598. Nakagawa et al. ASCO 2013.

Median duration of treatment

Gadgeel SM et al. Lancet Oncol 2014

Overall RR 54.5% across all cohorts for all patients

Overall RR 59.5% for cohorts of 460 mg dose or higher

NP28673: Study design

Efficacy and safety of the ALK inhibitor alectinib in ALK+ non-small-cell lung cancer (NSCLC) patients who have failed prior crizotinib: an open-label, single-arm, global phase 2 study (NP28673)


High response rate in patients with crizotinib-resistant ALK+ NSCLC


Presented By Sai-Hong Ou at 2015 ASCO Annual MeetingSai-Hong Ou at 2015 ASCO Annual Meeting

Few reported grade 3/4 adverse events with alectinib


Zhang, AACR 2010; Rivera AACR 2012; Gettinger, ESMO 2012

Gettinger, ESMO 2012

ALK patient responses observed at 60 mg and above

EGFR patient response observed at 120 mg

• AEs: nausea, fatigue (G1 or 2), no rash• One DLT identified at 240 mg, MTD has not yet been identified• AP26113 (180mg) showed activity in crizotinib-resistant brain metastasis (1pt)

Leena Ghandi at 2015 ASCO Annual Meeting

• Crizotinib across all ALK+ NSCLC trials1-3

– ORR: ~60% across all studies – Median PFS: 8 to 10 months

• Majority of responders will become resistant to crizotinib, with most relapses occurring within 1 year1

• Progression may occur due to molecular resistance or metastatic spread to the CNS2,4,5

– 1/3 of patients treated with crizotinib will develop mutations3

– CNS is a common site of metastases in ALK+ NSCLC patients2,5,6

Common Sites of Metastases in Patients with Treated with ALK inhibitor5

A 2012 study by Weickhardt et al reports 46% of patients have first progression in brain5

1. Shaw AT, et al. N Engl J Med. 2013;368:2385-2394; 2. Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019; 3.Kim D, et al. Ann Oncol. 2012;Abstract 1230PD; 4. Doebele RC, et al. Clin Cancer Res. 2012;18:1472-1482; 5. Weickhardt A, et al. J Thorac Oncol. 2012;7:1807-1814; 6. Takeda M, et al. J Thorac Oncol. 2013;8:654-657

Clinical CNS data with 2ndgeneration ALK inhibitors

Mehra et al., ASCO (2012), abstr 3007 - Gettinger et al., ESMO (2012), abstr 4390- Nishio et al., ESMO (2012), abstr 4410

6 wks6 wks6 wks6 wksBaselineBaselineBaselineBaseline CeritinibCeritinib

AP26113AP26113

AlectinibAlectinibBaselineBaselineBaselineBaseline

8 wks8 wks8 wks8 wksBaselineBaselineBaselineBaseline

33 wks33 wks33 wks33 wks

AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC

Leena Gandhi at 2014 ASCO Annual Meeting

Efficacy in Patients with Baseline BMs ALKi Treated(n = 75)

ALKi Naive (n = 19)

ORR, n (%) (95% CI)a

42 (56) (44–68)

15 (79) (55–94)

CR/PR, n (%) 1 (1)/41 (55) 0 (0)/15 (79)

SD, n (%) 19 (25) 2 (11)

Median DOR, months (95% CI) 7 (5–11) 13 (3–NE)

Median PFS, months (95% CI) 8 (6–10) 10 (5–NE)

IDCR (CR + PR + SD), n (%) (95% CI)b,c

49 (65) (54–76)

15 (79) (54–94)

CR/PR, n (%) 4 (5)/10 (13) 3 (16)/5 (26)

SD, n (%) 35 (47) 7 (37)

Median IC PFS, months (95% CI) NE (7.4–NE) 6.0 (4.2–9.4)

In ASCEND-1, a total of 124 patients had BMs at baseline.

aWhole-body response denotes best OR in all sites of disease, including the brain; bRECIST 1.0; cAnalyses include patients evaluated by MRI (n = 74) and CT (n = 20). IDCR, intracranial disease control rate; IC PFS, intracranial PFS; NE, not estimable.

35Mehra R, et al. SNO; 2014. Abstract BM-32.

Patients with Measurable BMs by MRI/CTALKi Treated

(n = 28)ALKi Naive

(n = 8)

IDCR (CR + PR + SD), n (%) (95% CI)

17 (61) (41–79)

5 (63) (25–92)

OIRR (CR + PR), n (%) (95% CI)

10 (36) (19–56)

5 (63) (25–92)

CR, n (%) 0 (0) 0 (0)

PR, n (%) 10 (36) 5 (63)

SD, n (%) 7 (25) 0 (0)

In ASCEND-1, a total of 36 patients had measurable BMs at baseline.

OIRR, overall intracranial response rate..

Mehra R, et al. SNO; 2014. Abstract BM-32.

*Intracranial PFS calculated as time to progression in brain + deaths due to any cause. Analyses include patients evaluated by MRI (n = 74) and CT (n = 20).

Median: non-estimable (95% CI 7.4-non-estimable)Intracranial* PFS rate at 12 months: 54.9% (95% CI 21.8-79.0)

Median: 6.0 months (95% CI 4.2-9.4)Intracranial* PFS rate at 12 months: 24.5% (95% CI 13.6-37.2)


Time (Months) 0 3 6 9 12 15 18 21

NSCLC with prior ALKi 75 46 29 20 9 5 0 0

NSCLC ALKi naive 19 13 10 7 3 1 1 0

100

90

80

70

60

50

Pro

bab

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%)

40

30

20

10

0

0 3 6 9 12 15 18Time (Months)

21

NSCLC with prior ALKi (N = 75)NSCLC ALKi naive (N = 19)

Shaw AT, et al. SNO; 2014. Abstract BM-32

Median: non-estimable (95% CI 5.6-non-estimable)Intracranial DOR rate at 12 months: 53.3% (95% CI 6.8-86.3)

Median: 6.9 months (95% CI 2.9-non-estimable)Intracranial DOR rate at 12 months: 31.7% (95% CI 6.7-61.4)


Time (Months) 0 3 6 9 12 15 18 21

NSCLC with prior ALKi 14 11 8 3 2 0 0 0

NSCLC ALKi naive 8 6 4 2 1 0 0 0

100

90

80

70

60

50

Pro

bab

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y (

%)

40

30

20

10

0

0 3 6 9 12 15 18Time (Months)

21

NSCLC with prior ALKi (N = 14)NSCLC ALKi naive (N = 8)

Responders


Retrospective, independent readings. Analyses include patients evaluated by MRI (n = 74) and CT (n = 20).NCRNPD, noncomplete response nonprogressive disease; UNK, unknown.

0 5 10 15 20 25 30 35 40 45 50

Duration of Exposure (weeks)

55 60 65 70 75 80 85 90 95100

UNKSDNCRNPDPDCRPR

BIOR

Subgroup: Prior ALKi-Treated Patients (N = 75)++++++++

+++

+++

++++

+++++

++

0 5 10 15 20 25 30 35 40 45 50

Duration of Exposure (weeks)

55 60 65 70 75 80 85 90 95100

UNKSDNCRNPDPDCRPR

BIOR

Subgroup: ALKi-Naive Patients (N = 19)+

+

+

+

+

+

+

+

+

+ Ongoing patients + Ongoing patients


Median ceritinib treatment exposure among patients with baseline brain metastases evaluable by MRI/CT• ALK inhibitor naive (n = 19), 49.6 weeks (range: 7.9-83.0)• Previously treated with ALK inhibitor (n = 75), 40.6 weeks (range: 0.4-95.1)

AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC

Leena Gandhi at 2014 ASCO Annual Meeting

• The mPFS on crizotinib was 8.2 months (95% CI: 7.4–10.6)

• The mPFS on ceritinib was 7.8 months (95% CI: 6.5–9.1)

• The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days

Gainor JF, et al. Clin Cancer Res 2015 [Epub ahead of print].

In the overall study population, median OS was 49.4 months (35.5–63.1) from the time of metastatic diagnosis

Gainor JF, et al. Clin Cancer Res 2015 [Epub ahead of print].

Crizotinib yields significant clinical benefit for ALK+ lung cancer patients Mechanisms of drug resistance include: – CNS drug penetration– Molecular adaptation

50% of patients developed CNS metastasis during Crizotinib

Appr. 60% of RR with 2nd generation ALK-TKIs in Crizotinib-refractory patients

2nd generation ALK-TKIs may prevent CNS pharmacological failure and delay intracranial PD

c

Clinical Trial or Ceritinib Compassionate USE

Modified from B. Besse, et al. 2015

Now in Italy

Grazie.

[email protected]

La gestione del paziente ALK traslocato, dopo la prima linea Milano 20 Novembre 2015 – Palazzo...

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