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Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status

  • Naiyer Rizvi1,
  • Jamie Chaft2,
  • Ani Balmanoukian3,
  • Sarah B Goldberg4,
  • Rachel E Sanborn5,
  • Keith E Steele6,
  • Marlon C Rebelatto6,
  • Yu Gu6,
  • Joyson J Karakunnel6 and
  • Scott Antonia7
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P193

https://doi.org/10.1186/2051-1426-3-S2-P193

Published: 4 November 2015

Keywords

Pericardial EffusionInfiltrate Immune CellPrior LineTumor Cell MembraneDose Escalation Phase

Background

As single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective tumor response rates in PD-L1-positive patients compared with PD-L1-negative patients. Anti-CTLA4 therapies activate T-cells and may increase immune infiltrate and PD-L1 expression in tumor cells and tumor infiltrating immune cells. Thus, combination therapy with durvalumab and tremelimumab could be active in NSCLC regardless of baseline PD-L1 expression.

Methods

This is a phase 1, open-label, dose-escalation/expansion study (NCT02000947) of D+T in patients with Stage III/IV NSCLC (any number of prior lines of therapy; immunotherapy-naïve). The primary endpoint is safety and tolerability; secondary endpoints include investigator-reported RECIST v1.1 response. PD-L1 expression was tested retrospectively using an immunohistochemical assay (Ventana).

Results

As of 1 June 2015, 102 patients received treatment in the dose escalation phase; combinations of durvalumab [3 mg/kg (D3) to 20 mg/kg (D20) every 2 (q2w) or 4 weeks (q4w)] and tremelimumab [1 mg/kg (T1) to 3 mg/kg (T3)] q4w, plus a D15 + T10 combination, were explored. Across all cohorts, 80% and 42% of patients had ≥1 treatment-related AE (any Grade and Grade 3/4, respectively); 28% discontinued treatment due to a related AE. A greater frequency of AEs, without a corresponding increase in tumor response, was seen with increasing T dose. In the combined T1 cohort (D10–D20), 73% and 30% of patients had ≥1 related AE (any Grade and Grade 3/4, respectively); 16% discontinued treatment due to a related AE. There were 3 treatment-related deaths (myasthenia gravis, T1; pericardial effusion, T1; neuromuscular disorder, T3).

84 patients (73 EGFR/ALK wild-type; 77 non-squamous; 48 with ≥2 prior lines of therapy) were evaluable for response (Table 1). The overall response rate (confirmed+unconfirmed) was 25%. Higher response rates were observed in those with 1 vs ≥2 prior therapies. Response rates do not appear dependent on PD-L1 status: 35% (PD-L1-positive), 22% (PD-L1-negative, <25% tumor cell staining) and 33% (PD-L1-negative, 0% tumor cell staining). Similar findings were observed for the combined T1 cohort. D+T also showed good durability of response similar to that seen for monotherapy.
Table 1

Response rates (Confirmed/unconfirmed with ≥16 weeks follow-up)

 

Overall population

EGFR/ALK wild-type population

 

All cohorts

Combined cohort: D10–20 q4w or q2w + T1

All cohorts

Combined cohort: D10–20 q4w or q2w + T1

 

n/N (%)

95% CI

n/N (%)

95% CI

n/N (%)

95% CI

n/N (%)

95% CI

All patients

21/84 (25)

16–36

11/39 (28)

15–45

21/73 (29)

19–41

11/34 (32)

17–51

PD-L1+ (≥25%)

7/20 (35)

15–59

3/9 (33)

8–70

7/17 (41)

18–67

3/9 (33)

8–70

PD-L1- (<25%)

11/49 (22)

12–37

6/23 (26)

10–48

11/45 (24)

13–40

6/19 (32)

13–57

PD-L1- (0%)

9/27 (33)

17–54

6/12 (50)

21–79

9/26 (35)

17–56

6/11 (55)

23–83

All 2L patients

15/32 (47)

29–65

7/16 (44)

20–70

15/31 (48)

30–67

7/15 (47)

21–73

PD-L1+ (≥25%)

6/8 (75)

35–97

2/3 (67)

9–99

6/8 (75)

35–97

2/3 (67)

9–99

PD-L1- (<25%)

7/18 (39)

17–64

4/11 (36)

11–69

7/17 (41)

18–67

4/10 (40)

12–74

PD-L1- (0%)

6/8 (75)

35–97

4/5 (80)

28–100

6/8 (75)

35–97

4/5 (80)

28–100

2L, second line: 1 prior line of therapy, receiving D+T in second line

Conclusions

D+T at selected phase 3 dose (D20, T1) has a manageable tolerability profile and anti-tumor activity in NSCLC. Unlike anti- PD-1/PD-L1 monotherapies, the combination of D+T appears to be active regardless of PD-L1 status, including even in patients with no tumor cell membrane PD-L1 staining, a setting where patients would not be expected to derive significant benefit from anti-PD-1/PD-L1 monotherapy over current standard of care [1, 2].

Authors’ Affiliations

(1)
Columbia University Medical Center, New York, USA
(2)
Memorial Sloan Kettering Cancer Center, New York, USA
(3)
The Angeles Clinic and Research Institute, Los Angeles, USA
(4)
Yale University, Yale Cancer Center, New Haven, USA
(5)
Earle A. Chiles Research Institute, Providence Cancer Center, Portland, USA
(6)
MedImmune, Gaithersburg, USA
(7)
Moffitt Cancer Center, Tampa, USA

References

  1. Paz-Ares L, et al: ASCO. 2015, abstract LBA109Google Scholar
  2. Vansteenkiste J, et al: ECC. 2015, abstract 14LBAGoogle Scholar

Copyright

© Rizvi et al 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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