Ofatumumab plus idelalisib as front-line therapy for CLL: Results from a phase II trial

Small molecule inhibitors like idelalisib have shown promising activity in the relapsed chronic lymphocytic leukemia (CLL) setting, especially when combined with anti-CD20 monoclonal antibodies, such as rituximab or ofatumumab. Blockade of PI3K signaling with idelalisib in combination with rituximab is an approved treatment by the US Food and Drug Administration (FDA). Given the positive outcome of that combination for relapsed CLL, this study aimed to explore the potential of idelalisib and ofatumumab in the treatment of naïve patients with CLL.

On 9 April 2019, Benjamin Lampson from Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA, and colleagues, published in Blood Advances results from a phase II clinical trial that investigated the efficacy and safety of idelalisib plus ofatumumab as first-line treatment for CLL.

In this multicenter, single-arm, open-label, non-randomized phase II trial, idelalisib plus ofatumumab treatment was administered in previously-untreated patients with CLL. The primary endpoint of the study was overall response rate (ORR) after 10 months of therapy. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS) and complete response (CR) rate after 10 combination treatment cycles. The study and treatment was ceased early due to an increased rate of death due to infections.

Study design & baseline characteristics

• N = 27 treatment-naïve patients with CLL or small lymphocytic lymphoma (SLL), aged ≥ 18 with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Study enrolment started on 16 June 2014 and permanent study cessation occurred on 14 March 2016 (database lock 19 March 2018)

*One patient was later reclassified as lymphoplasmacytic lymphoma
Total number of patients	N = 27
Median age (range)	69 (57−84) years
Sex Male	77.8% (n = 21)
Diagnosis CLL SLL	85.2% (n = 23)* 14.8% (n = 4)
ECOG 0 1	85.2% (n = 23) 14.8% (n = 4)
High-risk features 17p deletion only TP53 mutation only Both TP53 and 17p NOTCH1 mutation Bulky adenopathy Median β2 microglobulin (range)	3.7% (n = 1) 7.4% (n = 2) 7.4% (n = 2) 11.1% (n = 3) 29.6% (n = 8) 5.2 (2.4−14.6) mg/L

• Treatment plan:
  • First: idelalisib monotherapy (150 mg orally, twice daily) for two 28-day cycles
  • Then: ofatumumab + idelalisib combination treatment for six cycles
    • Ofatumumab: 300 mg intravenously (IV) on cycle 3, Day 1; then 1000 mg once per week for seven weeks; and then 1000 mg every four weeks for 16 weeks (six months in total)
  • Finally: idelalisib treatment until disease progression (PD) or unacceptable toxicity
  • Treatment discontinuation was allowed due to adverse events (AEs) until the AE was resolved to ≤ Grade 1. Then idelalisib was resumed at 100 mg twice daily, with the option to resume the starting dose after ≥ 4 weeks
  • Protocol amendment: If at any point a Grade 2 or 3 transaminitis developed patients were required to hold idelalisib and receive 1 mg/kg prednisone
• Computed tomography (CT) scans and bone marrow biopsies were obtained at the end of cycle 2 and before the start of cycle 10. CT scans were also obtained at end of cycles 4 and 8

Key findings

• Median follow-up (range): 39.7 (13.1−8) months
• In the intention-to-treat (ITT) population:
  • ORR: 88.9% (24 out of 27 patients):
    • CR: n = 1
    • Partial response (PR): n = 21
    • PR with lymphocytosis: n = 2
    • Stable disease (SD): n = 3
  • All patients with TP53-associated mutations responded to therapy (n = 5)
• All patients with lymph node enlargement at baseline and at least one post-baseline assessment before second-line therapy had a reduction in nodal burden
• Median PFS: 23 (95% CI, 18−36) months
• Three-year PFS rate: 28% (95% CI, 12−47%)
• Median time from treatment discontinuation to PD (range): 9.0 (0.2−34.0) months
• Median time to next treatment: 6.8 months
• Median OS: not reached
• Three-year OS: 88% (95% CI, 68−96%)
• Univariate Cox regression analysis revealed:
  • TP53-associated disease (17p deletion, TP53 mutation or both) was linked to a shorter PFS:
    • Median PFS of patients with TP53-related disease (range): 17.6 (4.6−23.2) months
    • Median PFS of patients without TP53-related disease (range): 24.3 (0.9−42.3) months
    • Comparison: HR = 4.37; (95% CI, 1.11−17.15); P = 0.035
  • Duration of therapy < 12 months was associated with a shorter PFS:
    • Median PFS of patients treated for < 12 months (range): 17.6 (0.9−38.3) months
    • Median PFS of patients treated for ≥ 12 months (range): 35.7 (19.5−42.3) months
    • Comparison: HR = 2.86; (95% CI, 1.12−8.08); P = 0.038
  • Among the 19 patients who experienced PD or death, treatment duration correlated with time to PD or death (r = 0.67; P = 0.002)

Safety

• All 27 patients received idelalisib
• Treatment discontinuation due to AEs occurred in n = 15 patients
  • Treatment was discontinued in the remaining 12 patients after the request of Gilead Pharmaceuticals in March 2016
• Treatment-emergent AEs (TEAEs) that led to discontinuation were:
  • Transaminitis: n = 5
  • Enteritis/colitis: n = 5
  • Pneumonitis: n = 2
  • Rash: n = 2
  • Autoimmune haemolytic anemia: n = 1
• AEs of interest:
  • Transaminitis occurred in 63% of patients (Grade ≥ 3 in 52% of patients)
  • Neutropenia occurred in 48% of patients Grade ≥ 3 in 33% of patients)
  • Colitis/diarrhea occurred in 37% of patients (Grade ≥ 3 in 15% of patients)
  • Pneumonitis occurred in 11% of patients (Grade ≥ 3 in 7% of patients)
  • Opportunistic infections occurred, including two cases of P jirovecii pneumonia, one case of Aspergillus pneumonia, one of cytomegalovirus colitis, and one of herpes simplex virus esophagitis
• Patients who also completed the combination treatment (idelalisib + ofatumumab): n = 13
• Median time on therapy for all patients (range): 8.1 (0.3−6) months
• Median time on therapy for patients who discontinued treatment (range): 7.7 (0.7−22) months
• No patients died during treatment, but three died during follow-up:
  • Due to malnutrition: n = 1
  • Due to renal failure: n = 1
  • Due to ischemic stroke: n = 1

Conclusion

• Idelalisib plus ofatumumab led to a high ORR but short PFS in previously-untreated patients with CLL/SLL
• The treatment led to unacceptable toxicity with high rates of therapy discontinuation due to the common occurrence of transaminitis, enteritis/colitis, and/or infections
• Similar safety concerns have also been raised from other trials where idelalisib was used as first-line treatment for B-cell malignancies (unpublished data from Gilead Pharmaceuticals, 2016)
• Despite the early discontinuation of the trial, the authors reported all the useful and informative data from the study