Efficacy and safety of the triplet regimen obinutuzumab-atezolizumab-lenalidomide for patients with R/R follicular lymphoma

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin’s lymphoma  and while patients with FL largely respond to initial chemoimmunotherapy, most eventually relapse and experience subsequent increased refractoriness to further lines of therapy. New treatment regimens and combinations have been investigated in an effort to address relapsed or refractory (R/R) FL, including phosphoinositide 3-kinase inhibitors, anti-CD20 monoclonal antibodies, and immunomodulators.

These agents include lenalidomide (len), an immunomodulatory agent; obinutuzumab (G), an anti-CD20 monoclonal antibody; and atezolizumab (atezo), a programmed death-ligand 1  inhibitor. Results from phase II/III trials have shown that len in combination with rituximab or G may enhance antitumor activity in patients with FL and with similar safety profiles when compared with any of these agents used alone. Another promising combination is atezo plus G, which has shown clinical activity in R/R FL. Len in combination with atezo may also have a synergistic effect in patients with FL via dual activation of NK cells.

In a recent study, Morschhauser, et al. conducted a phase Ib/II trial (BO29562; NCT02631577) to assess the safety and efficacy of the triplet regimen G-atezo-len as induction and maintenance therapy in patients with R/R FL.¹

Patient eligibility criteria

Patients with documented CD20-positive FL (Grade 1–3a) aged ≥18 years were eligible for inclusion if they had received ≥1 prior anti CD20-antibody containing immunochemotherapy. Patients with Grade 3b or a history of transformation to diffuse large B-cell lymphoma were excluded.

Study design

This was an open label, multicenter phase Ib/II randomized study with an initial 3+3 dose escalation to determine the recommended phase II dose (RP2D) for len when combined with fixed doses of G and atezo. The dose escalation phase was followed by an expansion phase. The study design and treatment plan are shown in Figure 1.

C, cycle; CR, complete response; D, day; EOI, end of induction; G, obinutuzumab; IV, intravenous, Len, lenalidomide; MRD, minimal residual disease; PO, oral dose transfer; PR, partial response, RP2D, recommended phase II dose; SD, stable disease.
*Adapted from Morschhauser, et al.¹

 

Study endpoints

Primary endpoint for phase Ib

To determine the RP2D for len in combination with G plus atezo based on the incidence of dose limiting toxicities during Cycle 2 of study treatment.

Endpoints for phase II

The primary endpoint was to evaluate efficacy, which was defined as complete remission (CR) by positron emission tomography-computed tomography at end of induction (EOI), CR was assessed by independent review committee.

Secondary endpoints:

• CR at EOI, investigator assessed using positron emission tomography-computed tomography
• CR at EOI, independent review committee and investigator assessed using CT alone
• Safety and tolerability of the treatment regimen through the incidence of adverse events (AEs)

Exploratory endpoints:

• duration of response
• progression free survival (PFS)
• overall survival  
• objective response rate and CR at EOI among patients with and without progression of disease within 24 months

Results

Baseline characteristics and patient disposition

Enrollment was stopped after 38 patients following sponsor assessment (unrelated to safety findings). The median age was 61.5 years, and 79% of patients had Ann Arbor Stage III/IV disease at diagnosis (Table 1).

Table 1. Baseline characteristics of the safety population*

CD20, cluster of differentiation 20; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; ECOG, Eastern Cooperative Oncology Group; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; POD24, progression of disease within 24 months; ULN, upper limit of normal. *Adapted from Morschhauser, et al.1
Characteristics, % (unless otherwise stated)	N = 38
Median age (range), years	61.5 (38–79)
Male	50
ECOG Performance Status 0–1	100
Ann Arbor stage III/IV at diagnosis	79
FLIPI risk group (low [0–1]; intermediate [2]; high [>3])	16; 58; 26
Elevated LDH >1 × ULN	24
Prior lines of therapy (1; >2)	53; 47
Prior treatment
Bendamustine	32
CHOP	63
Obinutuzumab	3
Rituximab	92
Refractory to last line of treatment	45
Refractory to last line of anti-CD20 antibody	29
POD24 on first line treatment	37
Bulky disease (>7cm)	16
Bone marrow infiltration	35
Extranodal involvement	53

At the time of final analysis, 38 patients had completed the trial, with 4 patients in the 15 mg len cohort and 34 patients in the 20 mg len cohort. At the final cut-off date, 27 patients had completed maintenance treatment: two patients in the len 15 mg cohort and 25 in the len 20 mg cohort.

Treatment exposure and follow up

• No dose limiting toxicities were reported with either len 15 or 20 mg during Cycle 2 of the dose-escalation phase, len 20 mg was selected as the RP2D for the expansion phase.
• At the time of the primary analysis, median follow-up was 30.0 and 14.2 months in the len 15 and 20 mg cohorts, respectively.
• At the time of the final analysis, the overall median treatment duration was 26.4 months in the len cohort.
• Treatment exposure during induction and maintenance for the len 20 mg cohort is presented in Table 2.

Table 2. Treatment exposure during induction and maintenance (len 20 mg cohort final analysis)*

Atezo, atezolizumab; G, obinutuzumab; Len, lenalidomide. *Adapted from Morschhauser, et al.1
	Dose intensity >90%		Dose intensity ≥75%
Induction phase (n = 34)	Maintenance phase (n = 28)	Induction phase (n = 34)	Maintenance phase (n = 28)
G	91.2	100	100	100
Atezo	71.9	85.7	90.6	85.7
Len	76.5	85.7	88.2	92.9

Efficacy

A total of 32 patients were evaluated for efficacy in the len 20 mg cohort (Table 3).

Table 3. Response rates at EOI (len 20 mg cohort; primary and subgroup analyses)*

CR, complete response; CT, computed tomography; D/R, double refractory; EOI, end of induction; INV, investigator; IRC, independent review committee; MRI, magnetic resonance imaging; N/R, non-refractory; ORR, objective response rate; PD, progressive disease; PET, positron emission tomography; POD 24, progression of disease within 24 months PR, partial response; SD, stable disease. *Adapted from Morschhauser, et al.1
AE		PET-CT scan	CT-MRI scan
		n, %	n, %
IRC-assessed (n = 32)
Primary analysis	ORR	78.1	81.3
CR	71.9	31.3
PR	6.3	50.0
SD	6.3	3.1
PD	9.4	12.5
D/R	ORR	66.7	–
CR	66.7	–
N/R	ORR	85	–
CR	75	–
POD24	ORR	58.3	–
CR	50	–
Non-POD 24	ORR	90	–
CR	85	–
INV assessed (n = 32)
Primary analysis	ORR	84.4	87.5
CR	75	50.0
PR	9.4	37.5
SD	3.1	3.1
PD	3.1	3.1

Response according to minimal residual disease (MRD) status

Among the MRD-evaluable patients (n = 21) at EOI, 16 (76.2%) were MRD negative. Out of these patients, 93.8 % achieved a CR and 6.3% achieved a PR. Within the MRD-positive patients at EOI (n = 5), one patient (20%) had SD, three patients (60%) had disease progression, and one patient was not evaluable for response.

Efficacy at 36 months

• The 36-month PFS rate (median, 35.9 months) was 68.4% (95% confidence interval [CI], 48–82)
• There were 14 INV-assessed progression events
• For patients who received G-atezo-len as maintenance treatment 24 had durable clinical responses for >1 year and 18 patients had clinical response lasting >36 months
• The median duration of response was 38 months (95% CI, 35-not estimable)
• The 36-month OS rate was 90.0% (95% CI, 72–97)

Adverse events (AEs)

All treated patients had Grade ≥1 AEs, and 84.2% patients had Grade 3–5 AEs, the most common hematologic AEs being neutropenia, thrombocytopenia, and anemia, observed in 45%, 26%, and 18% of patients, respectively.

The most common any grade (predominantly Grade 1/2) non-hematologic AEs were diarrhea, constipation, asthenia, cough, and infusion-related reactions observed in 58%, 40%, 37%, 37%, and 34% of patients, respectively. The most common non-hematologic Grade ≥3 AEs were increased lipase and increased alanine aminotransferase affecting 8% and 5% patients, respectively. Overall, a total of 28 serious AEs were reported in 47.4% patients.

Also, 28.9% patients had study drug withdrawal due to an AE. In total, 13 AEs resulted in study drug withdrawal. Three of these (acute myeloid leukemia [AML], ischemic stroke [IS], and increased lipase [IL]) were categorized as Grade 4 AEs. Four of these AEs (AML, IS, lung disorder, and malignant lung neoplasm) were classed as serious AEs. AML, IS, and malignant lung neoplasm resulted in permanent discontinuation of all three study drugs but not discontinuation from the study itself.

AEs that resulted in dose modification/interruption of any study drug were observed in 89.5% of patients. These included hyperthyroidism, hematologic toxicities, and thrombocytopenia. There were two fatal AEs, one due to Merkel cell carcinoma and one due to sarcomatoid carcinoma; both events were unrelated to any study drug. A summary of AEs is listed in Table 4.

Table 4. Adverse events *

AE	G-atezo-len 15 mg (n = 4)	G-atezo-len 20 mg (n = 34)	All patients (N = 38)
Any AE, %	100	100	100
Grade 3–5 AE, %	100	84.2	84.2
Grade 5 (fatal) AE, %	0	5.9	5.3
Serious AE, %	50.0	47.1	47.4
AE leading to discontinuation of any study drug, %	25.0	29.4	28.9
AE leading to study discontinuation, %	0	5.9	5.3
AE leading to dose interruption of any treatment, %	100	88.2	89.5
Atezolizumab-related AESI, ≥5%
Hyperthyroidism	0	14.7	13.2
Hypothyroidism	0	11.8	10.5
ALT increased	25.0	5.9	7.9
AST increased	25.0	5.9	7.9
Lipase increased	0	8.8	7.9
Hepatocellular injury	0	5.9	5.3
Rash	0	5.9	5.3
Rash maculopapular	0	5.9	5.3
Squamous cell carcinoma	0	5.9	5.3
AE, adverse event; ALT, alanine amino transferase; AST, asparate amino transferase; G-atezo-len, obinutuzumab-atezolizumab-lenalidomide. *Adapted from Morschhauser, et al.1

Conclusion

The study provides evidence of activity for the immunomodulatory triplet combination G-atezo-len in R/R FL. This combination regimen demonstrated marked efficacy and an acceptable and manageable toxicity profile when used as induction and maintenance therapy.

Most response rates were durable, lasting >3 years). Furthermore, most of the MRD evaluable patients were MRD negative. This confirms the high molecular response rate. Moreover, achievement of CR and results of 3-year PFS for the triplet combination were also promising.

The reported adverse events were manageable and the occurrence of two deaths during the study were considered as misdiagnosed histological transformation in the deceased patients at the time of selection for the study.

The small sample size, however, limits the power of study outcomes to draw definitive conclusions. Nevertheless, these results do suggest that the triplet combination treatment has contributed to the durability of responses.