Anti-PD1/PDL1 + anti-VEGFReuikcs.com/kca/munich/docs/f-04-haanen.pdf · 2017-05-03 · 12th European International Kidney 10 Cancer Symposium 21-22 April 2017 •Combining an antiangiogenic

12th European International Kidney

Cancer Symposium 21-22 April 2017

Anti-PD1/PDL1 + anti-VEGFR

John B.A.G. Haanen MD PhD



My disclosures

• I have provided consultation, attended advisory boards, and/or provided lectures for: Pfizer, MSD, BMS, IPSEN, Roche/Genentech, NEON Therapeutics, Novartis for which NKI received honoraria

• Through my work NKI received grant support from BMS, MSD, Novartis

• I declare no conflict of interest



• Antiangiogenic drugs targeting VEGF pathway are the standard-of-care treatment for patients with advanced renal cell carcinoma (aRCC)

• CRs are uncommon

• Majority develops drug resistance

• short survival

• New combination regimens to improve the efficacy of targeted therapy are highly desirable

• Upregulation of PD-1 on tumour-infiltrating lymphocytes and PD-L1 on tumours has been associated with poor prognosis in patients with aRCC, providing a rationale for immunotherapy targeting the PD-L1/PD-1 pathway

• Anti–PD-L1/PD-1 mAb have shown durable antitumour responses and manageable safety profiles, leading to the approval of nivolumab as a 2nd line treatment in patients with aRCC that has progressed following antiangiogenic therapy

Anti–PD-L1/PD-1 immunotherapy in combination with VEGFR-TKIs in advanced renal cell carcinoma



Manegold et al., J Thor Oncol 2016



Hodi et al. Cancer Immunol Res 2014

Increase in TIL following combined treatment of CTLA4 and VEGF blockade


Cancer Symposium 21-22 April 2017Choueiri & Motzer. NEJM 2017

VEGF and TKI PD-1 and mTOR

Choueiri & Motzer, NEJM 2017



Choueiri et al., Clin Canc Res 2016

Changes in TIL upon anti-PD1 treatment



Ko et al., Clin Canc Res 2009

Sunitinib reduces circulating myeloid derived suppressor cells in mRCC patients



Sunitinib restores CD3 T cell function by decreasing circulating MDSC in mRCC

Ko et al., Clin Canc Res 2009



• Combining an antiangiogenic VEGFR tyrosine kinase inhibitor (TKI) with PD-L1/PD-1 blockade may leverage complementary mechanisms of action to produce additional clinical benefits in aRCC

• Investigations of the therapeutic potential of anti–PD-L1/PD-1 in combination with a VEGFR-TKI are underway, and preliminary evidence of clinical activity has been shown

• Preliminary findings from two phase 1b studies:

• Axitinib (VEGFR-TKI) + avelumab (investigational anti–PD-L1 monoclonal antibody) in patients with aRCC

• Axitinib (VEGFR-TKI) + pembrolizumab (anti-PD1 monoclonal antibody) in patients with aRCC

Anti–PD-L1/PD-1 immunotherapy in combination with VEGFR-TKIs in advanced renal cell carcinoma (cont’d)



Presented By Asim Amin at 2014 ASCO Annual Meeting









Cancer Symposium 21-22 April 2017Ko et al., Clin Canc Res 2009




Keynote-018 study

•Combination of pazopanib + pembrolizumab (McDermott et al., ECC 2015)

•Preliminary antitumor efficacy was seen

•Significant hepatotoxicity was observed



• Combining an antiangiogenic VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI) with a monoclonal antibody that blocks PD-L1/PD-1 may leverage complementary mechanisms of action to produce additional clinical benefits in aRCC

• Investigations of the therapeutic potential of anti–PD-L1/PD-1 in combination with a VEGFR-TKI are underway, and preliminary evidence of clinical activity has been shown

• Preliminary findings from two phase 1b studies:

• Axitinib (VEGFR-TKI) + avelumab (investigational anti–PD-L1 monoclonal antibody) in patients with aRCC

• Axitinib (VEGFR-TKI) + pembrolizumab (anti-PD1 monoclonal antibody) in patients with aRCC

Anti–PD-L1/PD-1 immunotherapy in combination with VEGFR-TKIs in advanced renal cell carcinoma (cont’d)



Javelin 100: Phase 1b study of avelumab + axitinib in aRCC

Presented at ESMO 2016 (Copenhagen) by James Larkin



Baseline characteristics



n=6 Any grade Grade 1 Grade 2 Grade 3 Grade 4

Any event, n (%) 6 (100.0) 1 (16.7) 1 (16.7) 3 (50.0) 1 (16.7)

Dysphonia 4 (66.7) 3 (50.0) 1 (16.7) 0 0

Hypertension 4 (66.7) 0 2 (33.3) 2 (33.3) 0

Palmar-plantar

erythrodysaesthesia

syndrome

4 (66.7) 0 3 (50.0) 1 (16.7) 0

Diarrhoea 3 (50.0) 2 (33.3) 1 (16.7) 0 0

Fatigue 3 (50.0) 3 (50.0) 0 0 0

Headache 3 (50.0) 3 (50.0) 0 0 0

Hypothyroidism 3 (50.0) 1 (16.7) 2 (33.3) 0 0

ALT increased 2 (33.3) 1 (16.7) 1 (16.7) 0 0

Amylase increased 2 (33.3) 2 (33.3) 0 0 0

AST increased 2 (33.3) 1 (16.7) 1 (16.7) 0 0

Hyperthyroidism 2 (33.3) 2 (33.3) 0 0 0

Vomiting 2 (33.3) 2 (33.3) 0 0 0

Lipase increased 1 (16.7) 0 0 0 1 (16.7)

Muscosal

inflammation1 (16.7) 0 0 1 (16.7) 0

Proteinuria 1 (16.7) 0 0 1 (16.7) 0

Treatment-related AEs



• The objective response rate was 100.0% (95% CI, 54.1-100.0) based on 6 partial responses

•Responses were ongoing in 5 of 6 patients (83.3%) at the time of analysis

Clinical activity



• The combination of avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously was selected as the recommended dose for further studies based on an acceptable safety profile and encouraging clinical activity

• All patients (6 of 6) in the study experienced a partial response, with 5 of 6 responses ongoing at the time of analysis

• As of 13 Sept 2016, this study is ongoing and has enrolled 54 patients

• These results support the rationale to further investigate efficacy and safety of combination avelumab + axitinib vs current monotherapies for aRCC

• A pivotal randomised phase 3 trial comparing avelumab + axitinib vs sunitinib was initiated in March 2016 (NCT02684006; Javelin Renal 101)

CONCLUSION



Axitinib in Combination With Pembrolizumab in Patients With Advanced Renal Cell Carcinoma

• Preliminary Safety and Efficacy Results of Keynote-035 study

• Presented at ESMO 2016 (Copenhagen) by Michael Atkins



KEYNOTE-035 Study Schema



Confirmed ORR



Percent Change by BOR



PFS

mPFS 15.1 mo with

only 27% (ESMO Oct

2016)



Treatment Emergent Adverse Events



Conclusions• Preliminary results indicate that, in treatment naïve

patients with advanced RCC, combination of axitinibplus pembrolizumab exhibits anti-tumor activity and anacceptable toxicity profile, with no new or unusualtoxicities.

• There were few treatment discontinuations due tohepatotoxicity

• PDL1 status did not predict tumor response

• PFS, OS and response duration data are not mature



JAVELIN renal 1011

Phase III

Randomized controlled phase III trials with axitinib + avelumab or pembrolizumab in aRCC

Avelumab + axitinib

10mg/kg i.v. every 2 weeks

+ 5mg PO BID

Sunitinib50mg/day 4/2

Primary endpoint: PFS

PD-L1 + VEGFR TK inhibition

R n=583

KEYNOTE 4262

Phase III

Axitinib + pembrolizumab

5mg BID + 200mg i.v.

every 3 weeks

Sunitinib50mg/day 4/2

Co-Primary endpoint: PFS, OS

PD-1 + VEGFR TK inhibition

R n=840



New combinations

Phase I trial of cabozantinib and nivolumab ± ipilimumab

N=66

Estimated completion: December 2017

Primary endpoint: Recommended Phase II dose (RP2D)

Secondary endpoints: Clinical response rate, fraction of patients alive and

progression-free at 2 months

Metastatic GU

tumours

Cabozantinib

Nivolumab

Cabozantinib

Nivolumab

Ipilimumab



Taylor et al. ESMO 2016

New combinations



High activity in mRCC



Summary

• Based on emerging preclinical data there is a goodrational for combining VEGF-R targeting therapy withimmunotherapy (immune checkpoint blockade)

• Results from early clinical trials both efficacy andsafety of combinations of VEGF-R TKI and anti-PD1/PDL1 are promising

• The outcome of RCT comparing these combinationswith SOC need to be awaited to fully appreciate the benefit for mRCC patients

Documents

Anti-PD1/PDL1 + anti-VEGFReuikcs.com/kca/munich/docs/f-04-haanen.pdf · 2017-05-03 · 12th European International Kidney 10 Cancer Symposium 21-22 April 2017 •Combining an antiangiogenic