CLL/SLL

ASCO 2016 Poster Discussion - PI3 Kinase Inhibition in Chronic Lymphocytic Leukemia

The ‘Hematologic Malignancies-Lymphoma and Chronic Lymphocytic Leukemia’ poster discussion session took place on Monday June 6, 2016, between 13:15–14:45. The session was jointly chaired by Susan Mary O’Brien, MD, Associate Director for Clinical Science, at Chao Comprehensive Cancer Center in the University of Irvine, California, and John Leonard, MD, of Weill Cornell Medicine, New-York.

A poster titled ‘PI3 Kinase Inhibition in Chronic Lymphocytic Leukemia’ was discussed, presented by Dr Nicole Lamanna of the Columbia University Medical Center Division of Hematology/Oncology , New York. Dr Lamanna’s presentation explored four abstracts from this year’s ASCO Annual Meeting: 751275137514, and 7515.

Abstract 7514: Results of a Randomized, Double-Blind Placebo-Controlled Phase 3 Study Evaluating Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL and Adverse Prognostic Features

Background: Patients (pts) with relapsed CLL and adverse prognostic features respond poorly to standard treatment. Here we present a subgroup analysis from a phase 3 randomized double-blind placebo-controlled study. We evaluated Progression-Free Survival (PFS) in this pt population enrolled between June 2012 and August 2014.

Methods: All 416 pts (207/209 on the idelalisib (IDELA)/placebo [plb] arms, respectively) had BR for 6 cycles Q 28 days (B = 70 mg/m2 D1, D2 of each cycle; R = 375 mg/m2 C1 and 500 mg/m2 C2-6) and IDELA 150 mg BID or plb. IDELA/plb continued until independent review committee confirmation of disease progression, death, intolerable toxicity, or withdrawal of consent. Mutational analysis was centrally performed. Median time on study was 12 months. 

Results: Improvement in PFS was observed on the IDELA vs plb arm in all adverse-risk categories evaluated (Table). 

Conclusions: IDELA with BR consistently increased PFS in all risk categories evaluated. The safety profile was consistent with prior reported studies. This evidence supports the combination of IDELA with BR as an important treatment option for pts with relapsed CLL and adverse prognostic features. Clinical trial information: NCT01569295.

Adverse Prognostic Feature
(N, IDELA/placebo arms)

Med PFS (months)

IDELA + BR

Plb+ BR

HR (point estimate), p value

All pts (207/209)

23.1

11.1

0.33, P<0.001

Del11q:

.

.

.

    Yes (78/77)

23.1

8.9

0.24, P<0.001

    No (125/129)

23.1

11.1

0.41, P<0.001

Tumor:

.

.

.

    ≤ 5 cm (67/73)

NR

11.1

0.35, P<0.001

    > 5 cm (140/136)

23.1

10.4

0.35, P<0.001

Del 17p or p53:

.

.

.

    Either (69/68)

11.1

8.3

0.50, P=0.002

    Neither (138/141)

24.6

11.1

0.22, P<0.001

IGHV:

.

.

.

    mut (34/36)

NR

11.2

0.22, P<0.001

    unmut (173/173)

21.8

11.0

0.38, P<0.001

Abstract 7515: Updated Results of a Phase III Randomized, Controlled study of Idelalisib in Combination with Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia (CLL)

Background: Idelalisib (IDELA) is an oral PI3Kd inhibitor approved for use with rituximab in pts with relapsed CLL. This open-label study (NCT01659021) compared IDELA + ofatumumab (OFA) v OFA in pts with relapsed CLL. Results of the primary (1°) endpoint analysis were previously reported (Jones et al, ASCO 2015) and are updated here with an additional 8.5 mos of follow-up. In the 1° analysis, the combination yielded superior PFS and the KM estimated median OS was 20.9 and 19.4 mos in the IDELA+OFA and OFA arms. 

Methods: Pts with CLL progressing ≤ 24 mo from last therapy, who had received ≥ 2 cycles of a purine analogue or bendamustine, were randomized 2:1 to either Arm A (IDELA 150 mg BID continuously plus OFA, 300 mg IV wk 1, then 1 g IV q wk x 7 and q 4 wk x 4) or Arm B (OFA, same as Arm A except 2 g was substituted for 1 g dosing) with stratification factors relapsed v refractory, del17p and/or TP53 mutation, and IGHV mutation. The 1° endpoint was PFS based on IRC using modified IWCLL 2008 criteria.

Results: Pt characteristics were balanced in the 2 arms: med age 67; Rai II/III/IV 18/13/51%, med no. prior regimens 3, refractory 49%, del17p/TP53mut 40%, IGHV unmut 78%. Exposure, disposition, and efficacy are shown in the table. Results were consistent across risk groups. Gr ≥ 3 AEs in Arm A included diarrhea/colitis (23.1%), pneumonia (19.7%), and pneumonitis (4.6%). 

Conclusions: With > 8 mos longer follow-up, IDELA + OFA vs OFA continues to show superior PFS and ORR, and now demonstrates superior OS in pts with del17p/TP53mut and a trend of improvement of OS in the ITT population. Clinical trial information: NCT01659021.

 

Arm A (IDELA+OFA)
N = 174

Arm B (OFA)
N = 87

HR / OR2

Months on study (range)

16.1 (1.1 - 28.5)1

5.8 (0 - 25.4)

-

Reason for study D/C3 (%)

78 (44.8)

50 (57.5)

-

    PD/Death

29 (16.7)

19 (21.8)

-

    AE/Physician decision

15 (8.6)

17 (19.5)

-

    Withdrew consent/other

     

Med PFS4, mo

16.4

8.0

HR = 0.27, p < 0.0001

ORR, %

75.3

18.4

OR = 15.9, p < 0.0001

Q15 of OS4 (95% CI), mo

18.2 (12.3, 22.7)

12.7 (6.0, 19.3)

-

Med OS4 (95% CI), mo

NR (25.8, NR)

NR (21.7, NR)

HR = 0.75, p = 0.27

Del17p/TP53mut: Med OS4 (95% CI), mo

25.8 (22.7, NR)

19.3 (10.7, NR)

HR = 0.52, p = 0.03

1IDELA med exposure 12.3 mo (0.2-23.9); 2odds ratio;3per physician; 4KM estimation;51st quartile

Abstract 7513: An Evaluation of the Chronic Lymphocytic Leukemia (CLL) International Prognostic Index as a Prognostic Tool in Patients with Relapsed/Refractory CLL in Idelalisib Phase 3 Randomized Studies

Background: The International Prognostic Index for patients (pts) with CLL (CLL-IPI) is a validated scoring system with prognostic value for overall survival (OS) in untreated CLL, but it has not been studied in relapsed/refractory (R/R) CLL (Kutsch et al. J Clin Oncol.33 (suppl), 2015). The CLL-IPI is a risk-weighted model comprising the risk factors age (relative weight, 1), stage (1), del(17p)/TP53 mutation (−17p/TP53M) (4), IGHV mutation status (2), and β2-microglobulin (2). We hypothesized that idelalisib (IDELA), an agent active in CLL with −17p/TP53M, can overcome the negative impact of high CLL-IPI risk on OS. 

Methods: The CLL-IPI score was analyzed in 460 pts with R/R CLL treated with IDELA + rituximab (R) vs placebo + R (NCT01539512) or IDELA + ofatumumab (O) vs O (NCT01659021). Subgroup analyses of OS were performed in 274 pts treated with IDELA + R or + O (IDELA cohort) and in 186 pts treated with R or O alone (control). Median OS was estimated for low, intermediate, high, and very high CLL-IPI risk groups using the Kaplan-Meier method. The log-rank test was used to compare survival distributions across groups and estimate hazard ratios (HRs) for OS. 

Results: At a median follow-up of 14.7 months, the CLL-IPI score was validated in the pooled cohort of all pts with R/R CLL, with significant differences in OS across CLL-IPI risk groups (P=0.0001; table). In the subgroup analysis, the CLL-IPI score was prognostic for OS in the control (P=0.0007) but not IDELA cohort (P=0.0859). 

Conclusions: Although low-risk pts are uncommon in the R/R setting, the CLL-IPI score is prognostic of OS in R/R CLL. IDELA partially overcomes the negative impact on OS of very high-risk disease driven by −17p/TP53M. Analyses of data derived from another phase 3 study are ongoing. Clinical trial information: NCT01659021 and NCT01539512.

OS

CLL-IPI

Low (0–1)

Intermediate (2–3)

High (4–6)

Very High (7–10)

All (N=460)

n=6

n=38

n=228

n=188

    HR (95% CI)

0

0.22 (0.08–0.6)

0.57 (0.4–0.8)

1

    Log-rank test

P=0.0001

IDELA cohort (n=274)

n=4

n=20

n=141

n=109

    HR (95% CI)

0

0.37 (0.11–1.21)

0.67 (0.41–1.09)

1

    Log-rank test

P=0.0859

Control (n=186)

n=2

n=18

n=87

n=79

    HR (95% CI)

0

0.09 (0.01–0.64)

0.42 (0.28–0.77)

1

    Log-rank test

P=0.0007

Abstract 7512: Long-term Follow-up of the PI3Kδ Inhibitor TGR-1202 to Demonstrate a Differentiated Safety Profile and High Response Rates in CLL and NHL: Integrated-Analysis of TGR-1202 Monotherapy and Combined with Ublituximab

Background: TGR-1202 is a novel, once-daily PI3Kδ inhibitor with a differentiated safety profile from other PI3Kδ inhibitors, and demonstrated activity in patients (pts) with advanced hematologic malignancies. An integrated-analysis is presented of pts dosed with TGR-1202 monotherapy or combined with the glycoengineered CD20 mAb ublituximab (UTX). 

Methods: There were no limits on prior therapies (Tx). TGR-1202 was escalated in 3 + 3 design with expansion cohorts explored. The primary endpoint was safety and efficacy was a secondary endpoint.

Results: A total of 152 pts (81 monotherapy/71 combined with UTX), including 41 Follicular (FL), 40 CLL/SLL, 38 DLBCL, 11 Marginal Zone (MZL), 9 Hodgkins (HL), 8 Mantle Cell (MCL) and 5 other, were exposed to at least one dose of TGR-1202. Median age 65 yrs (22-86); 100 M/52 F; median # prior Tx = 3 (1-14); 53% refractory to immediate prior Tx. Most frequent reported AE's (all grades; Gr 3/4): nausea (44%; 1%), diarrhea (42%; 2%), fatigue (36%; 3%), vomiting (23%; 0%) and neutropenia (19%; 16%). AST/ALT increase was 6% (3% Gr 3/4), pneumonia 6% (5% Gr 3/4) and pneumonitis 1% (<1% Gr 3/4). 64 pts received TGR-1202 for 6+ mos, 33 for 1+ year, with longest on 30+ mos. Discontinuations due to AE’s occurred in 8% of pts. 109 pts received the therapeutic targeted dose and were evaluable for efficacy. Median PFS for TGR-1202 monotherapy was 24 mos and 27 mos in CLL and iNHL, respectively. Median PFS for TGR-1202 + UTX has not been reached for either CLL or iNHL. Majority of DLBCL responses occurred with TGR-1202 + UTX, including 3 CR’s and majority were of GCB subtype. 

Conclusions: TGR-1202 has exhibited a markedly differentiated safety profile from other PI3Kδ inhibitors to date with few discontinuations due to AE’s and limited G 3/4 events. Robust activity was observed in CLL and iNHL. Phase 2 and 3 trials are ongoing both alone and in combo with UTX in CLL, DLBCL, and iNHL. Clinical trial information: NCT01767766 and NCT02006485.

 

Disease

Pts
n

CR
n (%)

PR
n (%)

ORR
n (%)

CLL/SLL

27

1 (4)

23* (85)

24 (89)

iNHL (FL, MZL)

37

4 (11)

14 (38)

18 (49)

aNHL (DLBCL, MCL, Richters)

37

3 (8)

6 (16)

9 (24)

HL

8

-

1 (13)

1 (13)

* 6/23 with persistent lymphocytosis; all on monotherapy.

Dr Lamanna concluded the session by stating that it is an exciting time for patients with CLL – no doubt these and other BCR-directed agents have had tremendous impact on patients. However, there are side effects of the PI3K inhibitors that have led to discontinuation of these agents. There are second generations of these agents in development (TGR1202 and duvelisib for example) that may have decreased adverse events. Finally, we still need to ascertain the best way of using these agents for example, in combination with antibodies or other therapies (if not limited by toxicity) and for what duration? 

References
  1. Burris HA, et al. Long-term follow-up of the PI3Kδ inhibitor TGR-1202 to demonstrate a differentiated safety profile and high response rates in CLL and NHL: integrated-analysis of TGR-1202 monotherapy and combined with ublituximab. J Clin Oncol 34, 2016 (suppl; abstr 7512).
  2. Soumerai JD, et al. An evaluation of the Chronic Lymphocytic Leukemia (CLL) international prognostic index as a prognostic tool in patients with relapsed/refractory CLL in idelalisib phase 3 randomized studies. J Clin Oncol 34, 2016 (suppl; abstr 7513).
  3. Barrientos J, et al. Results of a randomized, double-blind placebo-controlled phase 3 study evaluating idelalisib in combination with bendamustine and rituximab in patients with relapsed/refractory CLL and adverse prognostic features. J Clin Oncol 34, 2016 (suppl; abstr 7514).
  4. Jones JA, et al. Updated results of a phase III randomized, controlled study of idelalisib in combination with ofatumumab for previously treated Chronic Lymphocytic Leukemia. J Clin Oncol 34, 2016 (suppl; abstr 7515).