KSR: What was the catalyst for your increased focus on immuno-oncology (IO)?
SA: IO has witnessed a long history of highs and lows. Although conventional cytokines and vaccine immunotherapies were approved for certain cancers, high toxicities, low efficacies and conflicting evidence limited their widespread adoption. Cancer immunotherapy research regained momentum with the finding that blocking inhibitory receptors on T cells can reinvigorate their antitumour function.
This led to the discovery of the first checkpoint protein, CTLA4, and the approval of ipilimumab, a CTLA4-blocking antibody for melanoma, laying the foundation for modern day IO. Subsequently, the discovery of another checkpoint axis, PD-1/PD-L1, along with the finding that anti-PD-1 afforded higher response rates and survival than anti-CTLA4 — and that their combination resulted in even greater benefits — opened the floodgates of IO.
Deep durable responses, including complete responses in a fraction of patients and improved long-term survival rates with these therapies compared with standard treatment options, then led to a series of approvals in multiple tumours, including melanoma, NSCLC, squamous cell carcinoma of head and neck (HNSCC), bladder cancer, renal cancer, triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC).
This isn’t an exhaustive list and there have been several others during the last 4–5 years.
The recent FDA approval of anti-PD-1 in microsatellite high (MSI–H) solid tumours also represents the first tissue-agnostic approval of an oncology drug based on a tumour biomarker. Benefits with checkpoint blockers have also been observed in high unmet need segments including patients with poor prognostic characteristics.
Their relative safety, lack of impairment of quality of life, combinability with diverse modalities and potential for cure opened the way for use of these agents in treatment naïve and early stage settings. This resulted in their use as backbone therapies across the patient continuum.
Dr Nidhi Dhingra
CAR-Ts and T cell engaging approaches further continued the success story and reinforced IO as fifth pillar of cancer treatment (after surgery, radiation, chemotherapy and other targeted agents).
KSR: Are there any overarching themes emerging from the current MoAs being targeted?
SA: Anti-PD-1/L1 redefined treatment in many indications; however, only a limited set of patients respond to these agents. This has led to a revolution in exploring other novel IO approaches that can raise the bar. Several new classes of agents targeting diverse novel immune mechanisms are being assessed, including the following:
- costimulatory or coinhibitory agents
- cytokines
- chemokines
- oncolytic viruses
- neoantigen vaccines
- metabolic signalling inhibitors
- bifunctional mAbs
- fusion proteins
- adoptive cell transfer therapies such as CAR-Ts and several others.
The immune mechanisms that have so far been examined include the stimulation of innate immunity, adaptive antitumour immunity, the enhancement of T cell priming, antigen presentation and epigenetic modulation to overcome TME resistance and improve immune cell infiltration.
Clinical experience suggests that the single-agent efficacy of these therapies will not only be important for their success as monotherapies … but also as combinations.
Only a few IO agents have been able to pass this benchmark so far. Several novel IO agents and non-IO drugs are being combined with checkpoint inhibitors to improve the rates, depth and durability of responses in low immuno-responsive tumours (such as microsatellite-stable cancers, PD-L1 low expressors and tumours with low mutational burden).
Furthermore, combinations are also being evaluated with the hope that they will enhance the infiltration of immune effector cells into tumour types generally considered to be “immune excluded” or “immune deserts” and turn them into “hot” tumours. Moreover, combinations are also being tried with the goal of restoring responsiveness in tumours that have previously experienced checkpoint inhibitors and have since become refractory or resistant.
Although optimal combinations are yet to be identified, a few have been approved — including the combined IO/IO regimen of PD-1 and CTLA-4 blockade mentioned previously. Although other novel IO/IO combinations are still exploratory, promising early results have been seen in trials of checkpoint inhibitors combined with TLR agonists, stimulatory cytokines and oncolytic viruses. This still needs to be validated in a broader spectrum of indications.
By contrast, combinations of checkpoint inhibitors with conventional chemotherapies and radiation have shown some benefit and also resulted in some approvals; however, the benefits of chemotherapy combinations are inconsistent across tumours and is not evident in some low immune-responsive tumours such as gastric cancer.
Anti-PD-1/L1 agents with tyrosine kinase inhibitors (TKIs) have also recently demonstrated meaningful efficacy in low immune-responsive tumours and should be investigated further. One major challenge is the virtual explosion of IO combination trials, which has put severe constraints on resources. A recent analysis showed that there are 1716 open trials of anti-PD-1/L1 antibodies attempting to enrol 380,900 patients.
Dr Jaideep V. Thottassery
KSR: Can the applicability of CAR-Ts be expanded to solid tumours?
SA: A new IO modality called CAR-T — for chimeric antigen receptor T cell therapy — has been generating a lot of noise since the approval of two agents in this class in 2017 for blood cancers. Although their utility in inducing life-saving remissions in refractory and relapsed lymphomas and leukaemias is a true breakthrough, one must acknowledge that they come with severe side-effects and a heavy price tag.
A number of trials are, however, now evaluating CAR-Ts against various targets in solid tumours as well. The successful application of CAR-Ts in solid tumours hinges on improving CAR-T persistence, overcoming barriers in the microenvironment and manufacturing challenges.
KSR: What will the IO market look like in five years? What will the key developments be and how will they come about?
SA: The global cancer immunotherapy market is set to reach about US$30 billion in 2019 and will steadily rise to about $100 billion by 2022. This is expected to be driven largely by use of these agents in nine key tumour types (melanoma, NSCLC, urothelial, RCC, HNSCC, TNBC, gastric, oesophageal and HCC).
The four key players will include BMS, Roche, Merck and AstraZeneca. These players are investing heavily in both basic research and clinical trials, which will contribute to market growth. Increasing innovation and the approval of novel treatments in the Asia-Pacific region will also contribute to market growth.
A large share of this growth will be the result of key IO approvals in early disease such as adjuvant and neoadjuvant settings. It is likely, therefore, that these advances could result in the cannibalisation of market share from advanced disease settings. Another constraint on market growth will be the high cost of these therapies.
KSR: And, IO biomarkers: where do we stand?
SA: The limited efficacy of IOs demonstrated in unselected populations thus far, coupled with several failures, indicates that appropriate predictive biomarkers will be crucial in enhancing benefit rates and for developing tailored therapies. This recognition has led to the exploration of a range of immune markers that are predictive of IO monotherapy and combination response in pivotal and early phase studies.
Consequently, there has been a rapid rise in the market for various IO assay reagents and technologies. According to some recent reports, the global IO assays market was approximately $2.9 billion in 2018 and is expected to exceed $6 billion by 2025, growing at a CAGR of around 12.9% between 2019 and 2025.
There is also substantial interest in developing predictive biomarkers from liquid biopsies and other non-invasive methods, although the identification of appropriate biomarkers is severely limited by
- tumour complexity, microenvironment and immune system interactions
- variability in assay development and interpretation
- a lack of validation in large prospective trials.
The high cost of new technology and the diagnostics required for many of these unique biomarkers will also be a challenge.
KSR: What other key areas are clinical immuno-oncologists currently exploring?
SA: Despite several successes, IOs still remain a difficult area to tackle. Clinical immuno-oncologists are challenged with several key questions on multiple fronts. Besides identifying promising next-gen drug candidates, predictive biomarkers of response, combinations that can improve the efficacy and/or immune sensitivity of the low responsive tumours, other areas of focus in IO are as follows:
Trial design, endpoints and regulatory considerations: FDA’s commitment to bring new lifesaving treatments into the market has contrasted with the recent failure of many such drugs that were conditionally approved on the basis of endpoints other than survival, which has raised several questions regarding appropriate trial designs.
One issue being hotly debated is whether such failed IO drugs should be withdrawn or continued to be given to patients considering their benefit in some indications. The guidelines for innovative therapies such as bispecific/multispecific molecules, fusion proteins and cellular therapy products are also rudimentary and will need to be clearly defined.
Potential in early stage disease, treatment sequencing, duration and impact on later line therapy: Immunotherapies are shifting to early stage disease settings in many indications. Early disease positioning has several implications; treatment in naive settings and/or as maintenance will delay disease progression but will also modulate patient immune profiles, which will impact initiation and choice of next line therapy.
Tumour immune characteristics not only influence the response to IOs, but also the efficacy of conventional therapies and targeted agents given post-IO, which will complicate treatment sequencing decisions. Other challenging questions are the optimal duration of IO treatment, continuation beyond progression and when to discontinue the treatment. Many trials are trying to address these issues.
Value based frameworks for immuno-oncology: Given the unique pattern of responses with immunotherapies, current value frameworks are inadequate to measure the magnitude of clinical benefit. It has also become essential to address the cost-effectiveness of these new and expensive therapies.