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) [email protected]
