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 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

This abstract was based on an integrated analysis of patients who received TGR-1202 as a single-agent or in combination with ublituximab (UTX; a glycoengineered CD20 monoclonal antibody). TGR-1202 is a novel PI3Kδ inhibitor with a differentiated safety profile from other PI3Kδ inhibitors.

In a 3 + 3 design, TGR-1202 was escalated and expansion cohorts were assessed; safety was the primary endpoint and efficacy was assessed as a secondary endpoint. 

  • In total of 152 pts included: monotherapy = 81; combination = 71 combined with UTX
  • Exposed to at least 1 dose of TGR-1202, by subtype: FL = 41; CLL/SLL = 40; DLBCL = 38; MZL = 11; HL = 9; MCL = 8; other = 5
  • Median age = 65 years (range, 22–86); 100 male/52 female; median number of prior therapies = 3 (range, 1–14); 53% refractory to immediate prior therapy
  • The majority of reported AEs (all grades; Grade 3–4): nausea (44%; 1%), diarrhea (42%; 2%), fatigue (36%; 3%), vomiting (23%; 0%), and neutropenia (19%; 16%)
  • AST/ALT elevation was 6% (3% Grade 3–4), pneumonia 6% (5% Grade 3–4), and pneumonitis 1% (<1% Grade 3–4)
  • Number of pts who received TGR-1202 for: >6 months = 64; >1 year = 33; with the longest being >30 months
  • Discontinuations due to AEs were reported for 8% of pts
  • Therapeutic target dose was reached in 109 pts who were evaluable for efficacy
  • Median PFS for TGR-1202 monotherapy in CLL and iNHL = 24 months and 27 months
  • Median PFS for TGR-1202 + UTX in CLL has not been reached for either CLL or iNHL
  • Most responses in DLBCL pts occurred with TGR-1202 + UTX, including 3 CRs; most were GCB subtype 

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


TGR-1202 activity was robust in CLL and iNHL. Phase 2 and 3 trials are ongoing both alone and in combo with UTX in CLL, DLBCL, and iNHL.

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

A validated prognostic scoring system for OS in newly diagnosed CLL is the International Prognostic Index (CLL-IPI). It is risk-weighted and includes factors such as age, stage, (both relative weight 1), IGHV mutation status, β2-microglobulin (both relative weight 2), and del(17p)/TP53 mutation (relative weight 4).  This system, however, has not been investigated in patients with R/R disease.

The hypothesis of abstract 7513 was that IDELA can overcome the negative impact of high CLL-IPI on OS risk. CLL-IPI was assessing in 460 patients with R/R CLL and who had received IDELA plus rituximab (R) vs. placebo (PBO) plus R (NCT01539512) or IDELA plus OFA vs. OFA alone (NCT01659021).

274 patients who received IDELA + R +OFA (IDELA cohort) and 186 patients who received either R or OFA alone (control cohort) were included in subgroup analyses. Median OS per Kaplan-Meier method was estimated for low, intermediate, high, and very high CLL-IPI risk group patients. 

  • Median follow-up = 14.7 months
  • CLL-IPI score was validated in the pooled cohort of all pts with R/R CLL; significant differences found in OS across CLL-IPI risk groups (= 0.0001)
  • CLL-IPI score was prognostic for OS in the control (= 0.0007) but not IDELA cohort (= 0.0859) 

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

 Key messages from this abstract were:

  • In relapsed patients, low and intermediate risk CLL-IPI scores are rare
  • Treatment with IDELA overcame the negative prognostic impact of high-risk CLL-IPI - possible because of the activity of IDELA in CLL with adverse prognostic characteristics such as del(17p)/TP53 mutation
  • OS of R/R patients with del(17p) is significantly improved with BCR-directed agents and BCL2 inhibitors vs. chemoimmunotherapy and so are potential candidates to become standard of care in this setting

It was concluded that CLL-IPI score is prognostic of OS in R/R CLL. Analyses of data derived from another phase 3 study are ongoing.

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

CLL patients with adverse prognostic characteristics (i.e. del(17p)/TP53 mutation, del(11q), IGHV mutation, high tumor burden) and who relapse have very poor responses to conventional therapy. During this talk, results from a subgroup analysis from a phase III randomized, double-blind, placebo-controlled were presented (NCT01569295). Progression Free Survival (PFS) was evaluated in patients enrolled from June 2012 and August 2014. 

  • 416 pts (207 of 209 in the idelalisib [IDELA]/placebo [PBO] arms, respectively) received 6 cycles Q28 days of bendamustine plus rituximab (BR; B = 70mg/m2 D1 and D2 of each cycle; R = 375mg/m2 C1 and 500 mg/m2 C2–6)
  • IDELA 150mg BID or PBO continued until Independent Review Committee (IRC) confirmation of progressive disease, death, intolerable toxicity, or withdrawal of consent
  • Mutational analysis was centrally performed
  • Median time on study = 12 months 

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

 Key take home messages from abstract 7514 were:

  • IDELA plus BR was superior to BR alone in patients with R/R CLL and adverse prognostic characteristics
  • Median PFS for patients with adverse prognostic characteristcs, especially del(17p)/TP53 mutation and IGHV unmutated, with IDELA plus BR was reported to be similar to that observed with IDELA plus rituximab
  • A limitation of this study was a lack of a single-agent IDELA arm
  • It currently is not certain if IDELA plus BR will be adopted in the relapsed setting (a similar conclusion was drawn from the Helios study) 

It was concluded that IDELA plus BR increased PFS in all the assessed risk categories and that the safety profile observed was in accordance with previous studies. This combination provides an alternative treatment option for patients with adverse prognostic characteristics who experience relapse.

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

IDELA, an oral PI3Kδ inhibitor is approved in combination with rituximab to treat patients with relapsed CLL. The next abstract discussed by Dr Lamanna was results of an open-label study comparing IDELA plus ofatumumab (OFA) to OFA alone in relapsed CLL patients (NCT01659021).

The primary results of this trial have been reported previously reported (Jones et al, ASCO 2015). In the primary analysis, Kaplan–Meier estimated median OS with IDELA plus OFA was 20.9 months compared to 19.4 months in the OFA arm. Moreover, IDELA plus OFA resulted in superior PFS.

In the current talk, the results were updated with an extended follow-up of 8.5 months.

  • Enrollment criteria included progression ≤24 months from last therapy and had received ≥2 cycles of a purine analogue or bendamustine
  • Pts were randomized 2:1 to either Arm A (IDELA 150mg BID continuously plus OFA 300mg IV wk 1, then 1g IV q wk x 7 and q 4 wk x 4) or Arm B (OFA same as Arm A except 2g was substituted for 1g dosing)
  • Stratification factors: relapsed vs. refractory, del(17p) and/or TP53 mutation, and IGHV mutation
  • The primary endpoint was PFS based on independent review committee (IRC) using modified iwCLL 2008 criteria
  • Patient characteristics were balanced between the two treatment groups: median age = 67 years; median number of prior regimens = 3; refractory = 49%; del(17p)/TP53 mutation = 40%; IGHV unmutated = 78%
 

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

Results were found to be consistent across risk groups. ≥Grade 3 AEs in Arm A included diarrhea/colitis (23.1%), pneumonia (19.7%), and pneumonitis (4.6%). 

Dr Lamana summarized the key take home messages of abstract 7515:

  • IDELA plus antibody (either rituximab, ofatumumab, etc.) is superior to antibody alone
  • It remains uncertain if there is any difference than that previously documented with IDELA plus rituximab
  • The number of AEs experienced by patients was higher in the combination arm but consistent with previous reports

It was concluded that with more than 8 months longer follow-up, IDELA plus OFA continued to demonstrate superior PFS and ORR compared to single-agent OFA. Moreover, the combination resulted in superior OS in patients with adverse prognostic characteristics, del(17p)/TP53 mutation, and a trend towards improved OS in the intention to treat population. 

Overall conclusion

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).