Current and Future Challenges of Innovative Oncology Drug Development. 19-21 October 2016 – Innsbruck, Austria

Combination therapy in immuno-oncology: Regulatory aspects - EU perspectiveJorge Camarero (AEMPS)

disclaimers

the views presented are personal and may not be

understood or quoted as being made on behalf of or

reflecting the position of AEMPS, EMA or one of its

committees or working parties

data presented have been sourced from European Public

Assessment Reports (EPARs) and published literature

EU-approved immunotherapies in oncology

Ipilimumab: Melanoma

Nivolumab: Melanoma, NSCLC, renal cellcarcinoma, cHL (CHMP positive opinion in October)

Pembrolizumab: Melanoma, NSCLC

Anti-PD therapy has become the backbone of cancer immunotherapyand a major modality of cancer treatment

EU-potential indications immunotherapies in oncology

Bladder cancer

Head and neck cancer

Ovarian cancer

Hematological malignancies

etc

Targets for anti-tumour immunity

Smyth et al. Nat Rev Clin Oncol. 2016

Why is so promising?

• Anti-PD therapy modulates immune responses at the tumor site

- Highly dependent of mutational load

- Renal cancer? (low number of mutations)

• Anti-PD therapy targets a specific defect of the immune response during the fight against cancer, while such events occur minimally in cancer-free tissues

- less toxic

• Repairs ongoing immune responses

- longer survival than chemotherapy

But, right now,

immunotherapy does not cure

cancer, so, why not combine

with others?

Combination• What do we understand by combination?

- Combination of two immunotherapies

- Combination with chemotherapy, radio, other

• Is there any differences from a regulatory point of view?

- Overall, the goal is the same: increase the

benefit over the monocomponents

- Better efficacy, worse safety?

Sharma P. Science. 2015 Apr 3;348(6230):56-61.

Evolution of combination

Melero et al. Nat Rev Cancer. 2015

EU experienceImmuno-oncology combinations

OPDIVO as monotherapy or in combination with ipilimumab is

indicated for the treatment of advanced (unresectable or

metastatic) melanoma in adults

nivolumab + ipilimumab

CheckMate 067: phase 3 double-blind RCT of

nivolumab or nivolumab + ipilimumab vs. ipilimumab

in subjects with previously untreated unresectable or

metastatic melanoma

Study CA209069: phase 2 double-blind RCT of

nivolumab + ipilimumab vs. ipilimumab in subjects with

previously untreated, unresectable or metastatic melanoma

CheckMate 067 PFS and OS co-primary endpoints

ORR secondary endpoint

CheckMate 067

Treatment ArmMedian PFS mo

(95% CI)HR (95% CI)

vs IpiHR (95% CI)vs Nivo

Nivo + Ipi (n = 314) 11.5 (8.9-16.7) 0.42 (0.31-0.57)* 0.74 (0.60-0.92)†

Nivo (n = 316) 6.9 (4.3-9.5) 0.57 (0.43-0.76)* —

Ipi (n = 315) 2.9 (2.8-3.4) — —

PD-L1 expression?

CheckMate 067

Discrepancy between ORR and PFS?

CheckMate 067 (ORR)

CheckMate 067 Safety

What about OS?

• No OS data from CheckMate 067 yet

- Maybe at the end of this year (follow-up 28 months)

• There are OS data from other studies

- CA209066 (first-line nivolumab monotherapy in BRAF

wild-type [WT] subjects)

- Updated OS data from CA209069 (first-line

combination of nivolumab and ipilimumab regardless

of BRAF status)

Conclusions from EU regulatory view

• Only longer PFS with combo in PD-L1 negative

• Higher ORR for combo regardless PD-L1 expression

• No OS data yet

- Indirect simulations seem to mimic PFS outcomes

• Combo is more toxic

What would you do?

EMA solution

OPDIVO as monotherapy or in combination with ipilimumab is

indicated for the treatment of advanced (unresectable or

metastatic) melanoma in adults

-an increase in progression-free survival (PFS) for the

combination of nivolumab with ipilimumab is established only in

patients with low tumour PD-L1 expression (see sections 4.4 and

5.1).

Obligation to conduct post-authorisation measures

•Post-authorisation efficacy study (PAES): The MAH should submit the final Study report for study CA209067: a Randomized, Double-Blind Study in Subjects Treated With nivolumab Monotherapy, ipilimumab Monotherapy, And nivolumab combined With Ipilimumab. (By March 2017)

•The value of biomarkers to predict the efficacy of nivolumab and/or nivolumab + ipilimumab combination therapy should be further explored

EMA solution

Combo with chemotherapy, does it make sense?

Kaplan-Meier Plot of OS (all treated patients) – Study CA209037

Combination• When

First line, second, after immunotherapy?

• How

Combination, maintenance, sequential administration

• Who

All comers, only PD-L1 expressors?

• Where

Lung, melanoma, renal, any indication?

Benefit from combination

Should we use the conventional endpoints?

• Pros

- They are validated- Broadly accepted- Experience

• Cons

- Appropiated for immunotherapy- OS feasible- Benefit in the long run

Long term survival

Study CA184024 (Ipi + DTIC vs DTIC)

PFS in immunotherapyPFS renal cancer with nivolumab

Potential solutions

• Statistical approaches

- Weighted Log-Rank Test

- Restricted Mean Survival Time

- Percentage at fixed time

• New criteria to assess

- Immune-related response criteria

Challenges for regulators

• Little experience with immuno combinations. (Nivolumab and Ipilimumab)

• Many uncertantities in the long run

• Lack of validated criteria to evaluate the real benefit

• Role of biomarkers

• Complexity of clinical trials

• Can we afford the price?

Regulators tools

accelerated assessmentRapid assessment of medicines in the centralised procedure that are of major interest for public health, especially ones that are therapeutic innovations. Accelerated assessment usually takes 150 evaluation days, rather than 210.

conditional marketing authorisationsThe approval of a medicine that address unmet medical needs of patients on the basis of less comprehensive data than normally required. The available data must indicate that the medicine’s benefits outweigh its risks and the applicant should be in a position to provide the comprehensive clinical data in the future.

primeEMA will provide early and enhanced support to optimise the development of eligible medicines, speed up their evaluation and contribute to timely patients' access.

Thank you!

Jorge Camarero PhD, MSc, PharmDAgencia Española de Medicamentos y Productos Sanitarios (AEMPS)Calle Campezo 1 • Edificio 8 • E-28022 Madrid • España/SpainTel: (+34) 918225152Fax: (+34) 918225161jcamarero@aemps.eswww.aemps.gob.es