In an era where oncology drug development is built on combination approaches, one of the most important clinical trial design attributes to consider is the choice of partner for an immune checkpoint inhibitor.
However, with some recent high-profile combination failures, and considering data presented at ASCO 2018, the question that most oncology-focused pharmaceutical companies are trying to answer is, what is the best combination?
Looking at ongoing clinical development programmes provides an insight into the future clinical application of currently available immune checkpoint inhibitors and analysing the key brands’ phase II and phase III trials reveals the current focus of clinical development.
The two market leaders Opdivo and Keytruda are being tested in the greatest number of ongoing trials, while a more focused approach is being taken with others in the class – Tecentriq’s development, for example, is focused on non-small cell lung cancer (NSCLC) and breast cancer. Both are large potentially lucrative indications, but also ones where Roche has a strong commercial presence and can maximise brand performance.
Some indications have fewer ongoing trials of PD-1/PD-L1 inhibitors (see ongoing trials chart) and therefore may represent untapped opportunities for manufacturers of novel immune checkpoint inhibitors. However, fewer trials does not automatically translate to a relevant market opportunity – the indication may be too niche to create a meaningful return on investment (although it may act as a gateway indication before securing use in larger drug-treatable populations).
Combination strategies are the future but rushing clinical development is risky.
Companies whose immune checkpoint inhibitors improve response rates and survival for patients will reap commercial rewards and one way to demonstrate this is via rational combination trials. But this strategy is not straightforward as evident by the sheer number and range of combinational strategies being explored.
Using NSCLC as an example, in 2013 and 2014, more than 40% of all trials initiated evaluated key immune checkpoint inhibitors as single agents. By 2017 this had risen to 30%. Furthermore, in 2013–2014 there were 6–11 different combination strategies initiated for NSCLC – in 2017 nearly 50 different types of combinations were initiated across approximately 100 trials.
Recently released clinical data suggests that combination approaches need to be planned with care even if early phase data appears promising. Frequently, copy-cat approaches are adopted in the rush to market (whereby one developer demonstrates a positive signal in early phase trials, thereby encouraging others to jump on the bandwagon and embark on a similar strategy without robust testing).
The combination of PD-1 and IDO-1 is a good example. The phase III pivotal study of Keytruda plus epacadostat in malignant melanoma (ECHO-301/KEYNOTE-252) failed to replicate earlier encouraging efficacy. On the back of this failure, multiple IDO-1 developers halted or downsized their IDO-1 programmes and multiple PD-1 and IDO-1 trials were terminated or suspended not only in combination with Keytruda, but with Opdivo too.
Despite the excitement for IDO-1 plus PD-1 earlier in the year, based on the failure of ECHO-301, pharma is pivoting to other combinations. At ASCO 2018, the combination of Opdivo and Nektar Therapeutics’ NKTR-214 in malignant melanoma showed deepening responses, PD-L1-negative tumours also responded, and interestingly treatment turned PD-L1-negative tumours into PD-L1-positive tumours.
Although these findings are very exciting, in the face of the ECHO-301 failure, more data is needed before concrete conclusions can be drawn. Rushing to phase III pivotal trials without robust randomised phase II data can be risky. Nevertheless, based on the ASCO NKTR-214 data, we expect combinations of PD-1/PD-L1s plus other CD122 agents (or similar immune stimulating drugs and cytokines) to be evaluated in future trials, and that trend has already started.
Combination strategies are the future but rushing clinical development is risky.
Combinations of immune checkpoint inhibitors with chemotherapy or angiogenesis inhibitors have been in development for some time and remain a popular strategy. It is highly likely that PD-1/PD-L1s will be used in chemotherapy and angiogenesis combinations across several indications, not least fuelled by physicians’ familiarity with the chemotherapy and angiogenesis inhibitors.
Keytruda leads the way here in terms of the breadth of indications and number of recently initiated late-phase trials for chemotherapy combinations (possibly in part spurred on by the success of Keytruda and chemotherapy in non-squamous NSCLC). At ASCO 2018, data from KEYNOTE-407 – Keytruda in combination with carboplatin, and Abraxane (nab-paclitaxel) or paclitaxel – in first-line squamous NSCLC, regardless of PD-1 expression status was unveiled. The significant improvement in survival it showed means that now Keytruda plus chemotherapy is relevant for first-line squamous and non-squamous NSCLC patients.
In terms of angiogenesis inhibitor combinations, Tecentriq leads the pack, although it is interesting to note that data for Tecentriq and chemotherapy for first-line NSCLC (also released at ASCO 2018) demonstrated improved survival and therefore Tecentriq plus chemotherapy is also a rational combination. Nevertheless, Tecentriq plus Avastin (bevacizumab) is particularly appealing to Roche (albeit before biosimilar bevacizumab enters) and it is a combination which has already shown good clinical data in NSCLC and renal cell carcinoma (IMpower150 and IMmotion151). Roche continue to invest in angiogenesis combinations across indications.
To stand a chance of clinical and commercial success, immune checkpoint inhibitor manufacturers initiating trials today must:
As the field continues to evolve at a rapid pace, it is critical for pharma to maintain a competitive edge through gathering intelligence and building models to understand:
Despite the challenges associated with the class, opportunities remain – although the available ‘white space’ is closing, or at least changing, almost on a weekly basis owing to rapid ongoing development of currently available agents.
The next two years will yield a huge amount of new clinical data for immune checkpoint inhibitors, especially for pembrolizumab and nivolumab and, while multiple novel immune checkpoint inhibitors are in development, two products are of near-term interest. One is Sanofi’s cemiplimab, which should be the next PD-1 agent to secure FDA approval, and the first to secure approval in cutaneous squamous cell carcinoma (an unserved indication). The other is Novartis’ spartalizumab (PDR-001), which is interesting because it is being evaluated in combination with LAG-525 (a LAG-3 inhibitor) and the combination of PD-1 and LAG-3 is rooted in scientific understanding. Furthermore, dual immune checkpoint blockade is a proven mechanism of action (as demonstrated by Opdivo and Yervoy in malignant melanoma).
Looking toward the future, more than 1,000 trials for currently available immune checkpoint inhibitors will complete between 2018 and 2020 and this work will continue to shape the current and emerging clinical environment within this hugely exciting segment of oncology treatment.
Andrew Merron, executive director, oncology at Decision Resources Group
Andrew is the executive director of oncology at Decision Resources Group. He leads the global oncology team of 25 analysts and directors and is responsible for creating and directing broad oncology strategy and translating domain knowledge into actionable solutions. Andrew has more than a decade of experience in commercial oncology analysis; his specific areas of expertise and interests include haematological malignancies, biosimilars, real world evidence, clinical trial design and clinical development strategies. Andrew has a Ph.D. in molecular oncology from the University of London where he designed, created and analysed therapeutic oncolytic adenoviruses.
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