In 2001, the approval of Imatinibmesylate (Gleevec– Novartis) to treat chronic myeloid leukemia (CML) launched the modern era of targeted therapies against cancer. The phenomenal success of Gleevec spawned an explosion of anti-cancer drugs, small molecules and biologics, validating the clinical significance of oncogene targets and their role in tumor pathogenesis.

A decade later, Dendreon launched Provenge® (Sipuleucel-T), a cancer vaccine derived from the patient’s own immune cells, to treat prostate cancer, and Bristol-Myers Squibb (BMS) launched Yervoy® (Ipilimumab), a monoclonal antibody to treat melanoma. With that, began the modern era of cancer immunotherapy. Here, the target is the host immune system, which has been suppressed by the tumor. Immuno-oncology (IO) drugs help overcome this immune suppression and activate the patient’s immune system against the tumor.

The results of IO drug treatment have been nothing short of spectacular.

  • Broad tumor range: Since IO drugs act on the immune system and not directly on the specific oncogene or oncogenic pathway itself, there is the potential to impact a broad variety of tumors. This has given renewed hope to patients with melanoma, lung cancer, bladder cancer, and head & neck cancer, which currently have no alternative treatments
  • Durable response: Unlike conventional chemotherapy or targeted cancer therapies, IO drugs appear to confer a remarkably stable response extending up to 10 years
  • However, activity benefits only a small subset of patients, ranging from 10-40 percent

The Market for Immuno-Oncology Drugs

The unique mode of action of IO drugs characterized by their indirect activity on the immune system, and their clinical impact extending long-term survival, makes them eminently suitable for combination cancer therapy.

All modes of cancer therapies ranging from classical cytotoxic chemotherapy through cytokines, and vaccines through current targeted agents that earlier showed marginal or no benefit, are now back in consideration for potential synergies in combination with IO drugs. In a sense, IO drugs have created renewed optimism for all oncology stakeholders, vastly expanding the therapeutic options available for patients.

The market for IO drugs, estimated at $7 Billion in 2016, is expected to hit $28 Billion in 2025, growing at a CAGR (compound annual growth rate) of 16.5 percent. The opportunistic combination of market potential and medical challenges has spawned an onslaught of scientific and industrial endeavor, with over 1,000 single agent or combination therapies in development, and tens of biotech start-ups jumping into the fray.

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Immunotherapy: A Brief History

As a concept, immunotherapy dates back 120 years ago to “Coley’s toxins,” Erysipelas germs used by Dr. William Coley to treat sarcoma by stimulating the body’s own immune system. See Figure 1 for a chronology of milestones in immunotherapy leading up to the present-day launch of several IO drugs.

Figure 1: A Century of Scientific & Medical Advances in Immunotherapy

Immunotherapy focuses on the body’s immune system, which comprise T cells, B cells, antigen presenting cells (APCs), such as macrophages and dendritic cells, and a host of stimulatory or inhibitory factors. These defend the body against invasion by “foreign” pathogens and antigens. Immunotherapy or Immuno-oncology (IO), therefore, encompasses a wide variety of approaches aimed at stimulating the body’s immune system to attack and destroy cancer cells by targeting pathways in the cancer-immunity cycle.

IO Drugs Launched or In Development

Table 1 lists IO drugs that have either been launched or are in development as single agents or in combination, targeting various stages of the cancer-immunity cycle:

Table 1

Special Toxicity Issues

A consistent feature of IO drugs, particularly checkpoint inhibitors, is the finding of increased and unexpected toxicity liabilities compared to conventional targeted therapies. They include dermatologic, gastrointestinal, hepatic, endocrine, and other inflammatory events, most likely due to increased immunologic activity. Clinically, these so-called immune-related adverse events (irAEs), also called “Select Adverse Events,” can be managed with immune suppressors such as corticosteroids, TNF-alpha antagonists, etc., with appropriate caution towards the potential for opportunistic infections and other risks of immune suppression.

Immunotherapy Failures

While immunotherapy has had spectacular successes, there have also been some dazzling failures along the way. Even though we may have expected that harnessing the power of the immune system should be broadly efficacious in a wide range of cancers, not all cancers are equally responsive under all settings.

In May 2017, Roche reported that its anti-PD-L1 inhibitor, Atezolizumab (Tecentriq®) failed to meet its primary endpoint of ‘overall survival’ in metastatic bladder cancer in a Phase III trial (IMvigor211). The trial was conducted to confirm the findings of an earlier Phase II study (IMvigor210), on the basis of which FDA approval for first-line treatment was obtained in April 2017. To say that this puts the agency (and the field) in a serious dilemma would be a gross understatement.

Also, in April 2017, BMS announced that its anti-PD-1 inhibitor Nivolumab (Opdivo®) failed to demonstrate survival benefit in a Phase III brain cancer trial (Checkmate-143). Earlier, in August 2016, Nivolumab (Opdivo®) failed in a Phase III trial (Checkmate-026) for first line therapy for non-small cell lung cancer (NSCLC).

In July 2017, following reports of patient deaths, the FDA put clinical holds on two Phase III trials of Merck’s IO drug Pembrolizumab (Keytruda®) that was being tested for multiple myeloma in combination with Celgene’s Pomalidomide (Pomalyst®) – KEYNOTE-185 and Lenalidomide (Revlimid®)–KEYNOTE-183. In addition, a partial clinical hold was placed on KEYNOTE-023, a Phase I trial of Pembrolizumab combined with Lenalidomide in multiple myeloma.

The causes of these costly failures could be attributed to anywhere from incomplete understanding of the underlying immune-pathology to ill-conceived trial design. Even more serious are the safety failures in Keytruda leading to patient deaths, particularly in light of expected immune-related toxicity findings on checkpoint inhibitor IO drugs. Stimulation of the immune system can be dangerous, harking back to the near-death Phase I experiences of six subjects in 2006 who were treated with TeGenero’s CD28 super-agonist antibody TGN1412, which resulted in a “cytokine storm” by activated T cells. These failures will no doubt be the subject of much active debate in the months and years to follow.

Clinical Rationale for IO Combination Therapies

Monotherapy with an IO drug shows a lower median survival compared to conventional targeted- or chemotherapy, but a more durable response as the tail of the survival curve extends out to a longer time. This suggests a rationale for combination therapy in which combining the IO drug with another treatment modality could yield a synergistic effect of improving both median survival times AND extended duration of response. The vast majority of the 1,000-odd IO drugs in development are combination therapies.

A reasonable strategy to determine the winning IO+ combination might be to start with one of the approved checkpoint inhibitor IO drug as the foundation, taking advantage of their ability to extend durable response times. Thereafter, bring in additional drugs to:

  • Improve upon efficacy, in terms of the proportion of responders, which currently is 10-40 percent with monotherapy
  • Improve safety, particularly immune-related toxicities, which are higher than in other targeted therapies and may prove to be fatal
  • Widen the range of cancer indications responsive to IO – from currently “responsive” tumors, such as melanoma, lung, renal, bladder, and head and neck cancers to “resistant” tumors, such as prostate and pancreatic cancers

New R&D Approaches for IO Drugs

The fact IO drugs do not act directly on a cancer target, but indirectly activate the immune system to attack the cancer, poses new challenges for investigators. Since mouse models do not accurately or comprehensively reflect the human immune system, the tumor micro-environment (TME) more often than not does not translate well in human clinical predictions.

Therefore, the traditional sequential approach of starting with pre-clinical in vivo mouse studies, followed by Phase I human clinical trials is being replaced with a more cyclical, iterative approach of concurrent clinical and preclinical studies. Potential pharmacodynamic (PD) markers identified in mouse preclinical models are validated in samples obtained from small-scale Phase I trials. Mechanistic hypotheses-based clinical insights are confirmed in mouse models. For that reason, PD markers, correlating with intervention points A, B or C, could potentially help in the selection of IO+ combinations.

Moving from preclinical studies to later stage clinical development, the strategy and process for optimal dose selection and scheduling of the component drugs in the combination therapy involves integrating data from multiple sources, and sophisticated modeling and simulation approaches. They include:

  • Conventional pharmacokinetics/pharmacodynamics (PKPD)
  • Physiologically-based pharmacokinetic (PBPK)
  • Quantitative systems pharmacology (QSP)
  • Modeling
  • Drug-drug interaction (DDI) studies

An example of a key consideration in scheduling and sequencing of a two-drug combination, is determining the optimal duration time for induction therapy as the first drug before bringing in an IO drug as the second therapy. Given the added risk of immune-related toxicity, there is a need to balance the longer time that might be required to generate sufficient activated T cells for enhancing immune activity versus shortening the induction time in order to avoid a toxic response, such as a potentially life-threatening cytokine release storm.

Implications for Immunotherapy Clinical Trial Sponsors and CROs

It is clear that combination therapies with IO drugs are here to stay. However, immunotherapy drug development has unique challenges compared to other types of cancer therapies developed to date. The sheer volume of IO+ drugs in development, coupled with integrated development strategies across the spectrum from preclinical studies through clinical trials and approval, will put tremendous pressure on this ecosystem. This will require an increased number of patients, trained investigators and laboratory scientists. Now more than ever, sponsors and CROs need to be prepared with better training, planning, communication, and operational systems in place, starting with preclinical development.

  • Early Research: The selection and validation of IO+ combinations requires close integration of teams conducting preclinical studies and multiple Phase I trials, either internally or through external alliances
  • Clinical Development: Innovative strategies and pathways to accelerated approval as seen with Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®) require rapid response to clinical protocol amendments and clinical operational readiness
  • Novel Endpoints: Likewise, investigators must be equipped to have a better understanding of non-conventional clinical endpoints, biomarker evaluation and, most importantly, immune-related toxicity signals
  • Patient Recruitment and Involvement: Through a combination of media reporting and DTC promotions, IO drugs have captured the imagination of the public, raising hopes and expectations of cancer patients. Clinical research professionals and patient advocacy groups will have an expanded role in managing and tempering these expectations

Ramani A. Aiyer, PhD, MBA


Shasta BioVentures