Immune therapy in NSCLC

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Immune therapy in NSCLC

• Presentation ???
• Supervisor ?????

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Introduction

• Immunotherapys evaluation has expanded into
  other solid tumors than melanoma (Ipilimumab).
• Most patients present with advanced disease and
  are immune suppressed as documented by reports of
  decreases in peripheral and tumor lymphocyte
  counts seen in this patient population.
• Regulatory T cells (Tregs-CD4) play a key role in
  suppressing tumor immune surveillance, found high
  level in NSCLC.

Brahmer , J Clin Oncol. 31(8)1021-8, 2013
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CTLA-4 and PD-1 pathway
Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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VACCINES

• Vaccines for NSCLC effective in minimal dz (s/p
  resection, CCRT, C/T)
• Tumor cell vaccines advantage of exposing the
  hosts immune system to a myriad of tumor
  antigens
• Antigen-based vaccines expose the hosts immune
  system to a specific antigen expressed on the
  tumor cell

Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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Tumor Cell Vaccines

• Belagenpumatucel-L an allogeneic tumor cell
  vaccine with four irradiated NSCLC cell lines
  (H460, H520, SKLU-1, and RH2) modified with
  transforming growth factor ß2 (TGF-ß2) antisense
  plasmid.
• Cohort 1 1.25 107 cell/injection
• Cohort 2 2.5 107 cell/injection
• Cohort 3 5 107 cell/injection
• High-dose cohorts had a
• significantly improved OS
• (p0.0069)

Nemunaitis J et al, J Clin Oncol.  244721-4730,
2006
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Antigen-Specific VaccinesMAGE-A3

• The melanoma-associated antigen-A3 (MAGE-A3)
  expressed melanoma and approximately 35 of
  NSCLCs
• Tumor recurrence rate 30.6 in vaccine vs 43.3
  in placebo
• Disease-free interval, OS NS
• Positive gene signature group had a 43 relative
  risk reduction of cancer recurrence with vaccine
  treatment vs 25 in unselective group.
• Phase III MAGRIT ongoing

Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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Others

• One dose of cyclophosphamide (300 to 600 mg/m2)
  was given 3 days before the first vaccine to
  inhibit Tregs to enhance the immune response.
• BLP-25 Phase III START and INSPIRE trial.

Target MUC-1
Target MUC-1
Target EGFR
Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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CHECK POINT INHIBITORS

• CTLA-4 pathway is important in early T-cell
  activation.
• Ipilimumab blocks the interaction between CTLA-4
  and its ligands, CD80 and CD86, and showed
  promise with C/T.

Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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Phase II Ipilimumab
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Abbreviation

• irPFS immune-related progression-free survival.
• BORR best overall response rate
• ir-BORR immune-related BORR
• DCR disease control rate
• ir-DCR immune-related DCR
• mWHO radiologic review committee by using
  modified WHO criteria

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Response and Safety

• Safety
• Grade 3-4 AEs control 37, concurrent 41,
  phased 39
• Drug related discontinuation control 5,
  concurrent 10, phased 6
• Two treatment related death
• Concurrent 1 septic shock secondary to epideraml
  necrosis
• Control 1 neutropenic sepsis

Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Ipilimumab irPFS phased vs concurrent

• irPFS phased
• HR 0.72, p0.05
• The immune-related best ORR was nearly doubled
  for the phased schedule versus chemotherapy alone
  (32 v 18)

Lynch et al, J Clin Oncol.  302046-2054, 2012
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mWHO-PFS/OS
Lynch et al, J Clin Oncol.  302046-2054, 2012
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Historlogy
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Onging phase III of Ipilimumab
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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PD-1
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Immune Resistance
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Inhibitors for PD-1/PD-L1
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Phase I PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Patient characteristics
Heavily pretreated patients
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Efficacy of PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Response to anti-PD-1 antibody

• Tumor PD-L1 expression may be associated with
  response.
• 36 of patients with tumor PD-L1 expression were
  objective responders.

Brahmer, J Clin Oncol. 31(8)1021-8, 2013
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Safety of PD-1 antibody
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Anti-PD-L1 BMS-936559
Total 207 pts, 75 patients with NSCLC
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Clinical activity of BMS-936559
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Safety
Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Conclusion

• Immunotherapy may play a role in the future of
  lung cancer treatment.
• Checkpoint inhibitors have promising activity in
  NCSLC.
• Check point inhibitors have a unique set of side
  effects consistent with immune mechanism of
  action.
• Randomized studies are ongoing.

Present by Julie R. Brahmer MD, at 2013 ASCO
Annual meeting
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Thank you for listening!