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WHITE PAPER IMMUNO-ONCOLOGY: PAST, PRESENT AND FUTURE

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PAREXEL International IMMUNO-ONCOLOGY: PAST, PRESENT AND FUTURE WHITE PAPER
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PAREXEL International

IMMUNO-ONCOLOGY: PAST, PRESENT AND FUTURE

WHITE PAPER

Although the concept of harnessing the body’s immune system to fight cancer emerged over a century ago, the early days of developing cancer immunotherapies often proved disappointing. One of the first anticancer vaccines that reached approval stage was the anti-prostate-specific antigen (PSA) vaccine, Provenge®, for prostate cancer. A large amount of work was also invested in creating vaccines against HER2 in breast cancer, melanoma-associated antigen 3 in melanoma and mucin-1 in non-small cell lung cancer (NSCLC). Unfortunately, none of these have provided the level of efficacy that the oncology community dreams about.

Obstacles to the success of such cancer vaccines include the large residual tumor burden challenging even the most effective anticancer therapy, the host’s physiological state of immunosuppression related to age and the immunosuppressive effects of prior multimodality anticancer therapy (eg, surgery, radiation therapy and chemotherapy), poor nutritional status, environmental factors, or inherited aspects of immune function, eg, HLA type. In the face of high disease burden and a suppressed immune system, vaccine therapy was almost destined to fail. On top of these challenges, our understanding of the full spectrum of suppressors of the anticancer immune response was incomplete.

UNLOCKING THE SECRETS OF ANTITUMOR IMMUNITY

Clearly, a better understanding of the mechanisms of immune suppression in cancer was needed. Extensive research was conducted to describe the integral components of the adaptive immune response and define its regulation in the context of cancer. Figure 1 Illustrates, in brief, what has been learned about antitumor immunity.1 Host cytotoxic T cells can successfully kill cancer cells but only after a multistep process of cancer cell antigen presentation, T cell

priming and activation, T cell migration, and cancer cell recognition and lysis. However, this pathway is overlaid by a variety of immune regulatory checkpoints that interact with the major components of the immune response to maintain homeostasis and prevent autoimmunity. These suppressors must be ‘switched off’ or counteracted before an effective therapeutic immune response can be triggered against tumor cell antigens.

YOUR JOURNEY. OUR MISSION.® | 1

EARLY DISAPPOINTMENTS

IMMUNE CHECKPOINT INHIBITOR THERAPY: WHERE WE ARE TODAY

Figure 1. Schematic of the pathway to generation of antitumor immunity1

Three inhibitory immune checkpoint molecules that are fundamental to the recent revolution in immune-oncology are cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and its ligand,

PD-L1. These are the first checkpoints to be targeted in the development of therapeutic immune checkpoint inhibitors (ICIs). However, the list of other ICIs, both stimulatory and inhibitory, is illustrated in Figure 2.2

YOUR JOURNEY. OUR MISSION.® | 2

APCs, antigen-presenting cells; CTLs, cytotoxic T lymphocytes

From Sznol M, Chen L. Clin Cancer Res 2013;19:1021-1034.

⑦Release of

cancer cell antigens(cancer cell death)

Cancer antigen presentaion

(dendritic cells/APCs)

Priming and activation(APCs & T cells)

Trafficking of T cells to tumors

(CTLs)

Infiltration of T cells into tumors

(CTLs,endthelial cells)

Recognition of cancer cells by T cells

(CTLs,cancer cells)

killing of cancer cells(immune and cancer cells)

Full T cell activation by antigen-presenting cells (APCs) requires presentation of the cancer antigen to the T cell receptor (TCR) via the major histocompatibility complex (MHC) proteins, as well as binding of B7 on the APC to CD28 on the T cell (Figure 3). CTLA-4 expressed on the

surface of T cells can preferentially bind B7 on APCs, thus preventing T cell activation; conversely, blocking CTLA-4 masks its suppressive action, permitting B7–CD28 binding and T cell activation, with resultant antitumor immunity (Figure 3).

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Figure 2. Therapeutic targets in the regulation of T cell antitumor response2

Anti-CTLA-4 ICIs

Activating receptors

Agonistic antibodies Blocking antibodies

Inhibitory receptors

CD40L

OX40

4-1BB(CD137)

CD27

CD28TCR

T cell

LAG3

TIM3

PD-1

CTLA-4 • lpilimumab

• Tremelimumab

aPD-1

• Nivolumab

• Pembrolizumab

• Pidilizumab

• AMP-224

aPD-L1

Agonist

• Dacetuzumab

• Chi Lob 7/4

• CP-870893

• LucatumumabAutagonist

• Avelumab (MSB0010718C)

• MED14736

• Urelumab (BMS-663513)

• Varlilumab (CDX-1127)

• PF-05082566

• MED16469

• MEDL3280A

• BMS-936559

YOUR JOURNEY. OUR MISSION.® | 4

Figure 3. Two mechanisms of action of immune checkpoint inhibitors

Anti-PD-1 ICIs

Although a 1996 preclinical study showed that blocking CTLA-4 could cause tumor regression in mice,3 the major clinical breakthrough came in 2010 when Hodi and coworkers demonstrated that ipilimumab, a monoclonal antibody to CTLA-4, improved overall survival (OS) in patients with metastatic melanoma who had failed prior treatments.4 Ipilimumab was approved for recurrent and then first-line therapy of metastatic melanoma. A prominent feature was the durability of responses in treated patients, lasting upwards of 2 to3 years in 20-25% of responding patients.4,5 The downside was severe gastrointestinal, dermatologic and endocrine toxicities that limited efficacy because of the need to interrupt therapy or introduce glucocorticosteroid therapy to ameliorate some of the adverse effects and improve the tolerability of ipilimumab. The major media in the USA (NY Times, December 4, 2016) alerted the public to some of these

A second mechanism exploited by ICIs involves the interaction between activated T cells and tumor cells (Figure 3). Binding of PD-1 on activated T cells to its ligands PD-L1 and/or PD-L2 expressed by some tumorcells inhibits T cell function and allows the tumor to evade attack. By blocking the PD-1 binding site with an anti-PD-1 ICI, the T cell remains activated, with resultant cytotoxic T cell-mediated antitumor activity.

major life-threatening toxicities, taking some of the glimmer and glamor of ICI therapy.

Nivolumab is a humanized monoclonal antibody against PD-1 with approved indications in advanced melanoma, metastatic NSCLC and renal cell carcinoma. Overallresponse rates with nivolumab in these conditions range

Tumor Microenvironment

Activation

(cytokines,lysis,proliferation

migration to tumor)

Dendriticcell

anti-CTLA-4

CTLA-4B7

B7 CD28

anti-PD-1

PD-1 PD-L1

PD-L2PD-1

anti-PD-1

T cell T cell Tumorcell

TCRMHC MHC

TCR

YOUR JOURNEY. OUR MISSION.® | 5

from 17–32%, with 1-year survival rates of 42–70%6-9 – considerably better outcomes than have been obtained with conventional therapies. Also, immensely encouraging is the considerable proportion of patients who show a durable response to nivolumab that is sustained after treatment completion.6-9 Durable responses have also been observed in patients with metastatic melanoma treated with the PD-1 inhibitor pembrolizumab.10 Dr. Miller remarked, “the durability of response observed with ICIs is tremendously exciting as it doesn’t usually happen; patients on conventional cancer therapy invariably develop recurrent disease sometime after therapy is completed”.

Hematologic malignancies were a delayed target of ICI therapy, but the remarkable results with pembrolizumab in heavily pretreated patients with Hodgkin lymphoma11 opened the assault on other hematologic malignancies including acute myeloid leukemia, non-Hodgkin lymphoma and multiple myeloma.

Two anti-PD-L1 monoclonal antibodies received breakthrough designation by the US FDA in 2016. Atezolizumab and durvalumab are approved for the treatment of recurrent urothelial cancer.

Other novel ICIs

Combination therapy with ICIsPD-L1 inhibitors

immunosuppression is mediated by LAG3 and PD-1 supporting a role for combination therapy.

Following the initial success of anti-CTLA4s, anti-PD1s and anti-PD-L1s, a rapidly expanding group of other ICIs have been discovered and are in early phases of development, many of which are in combination with anti-PD1s or anti-PD-L1s. The most promising of these include:

• LAG3 or lymphocyte activating gene 3 which is expressed on activated T-cells, NK cells, B-cells and plasmacytoid dendritic cells. Of note is that synergistic

Not surprisingly, combinations of ICIs have been evaluated in malignant melanoma and NSCLC and have shown superiority over ICI monotherapy. The most notable success stories are nivolumab plus ipilimumab in malignant melanoma and pembrolizumab and ipilimumab in NSCLC.12,13 The safety profile of the combination was favorable and the efficacy was clearly better than that achieved with monotherapy alone.12,13

Combination therapy of ICI with small molecule TKIs, chemotherapy, radiation therapy, and peptide vaccines are all undergoing clinical trials. Thus, the permutations and combinations may be limitless. These investigations continue and even more immune regulators — both stimulatory and inhibitory — are being identified and evaluated clinically (Figure 3).2

• TIM3, or T-cell immunoglobulin and mucin 3, is expressed on activated T-cells, NK cells and monocytes and is co-expressed with PD-1 on tumor infiltrating lymphocytes (TILs), again suggesting a role for combination therapy.

• B7H3 or CD273 is widely expressed in a wide variety of malignancies and behaves more like a co-stimulatory molecule than a classical ICI.

• TIGIT or T-cell ITIM domain downregulates the proliferation of T cells. Co-administration with an anti-PD-L1 or anti-PD1 is being explored.

• Other costimulatory or coinhibitor molecules currently in early phases of development include OX40, adenosine 2A receptor, indoleamine 2,3 dioxygenase or IDO, and V domain Ig-containing suppressor of T-cell activation or VISTA.

MAXIMIZING THE BENEFITS OF THE ICI ERA

YOUR JOURNEY. OUR MISSION.® | 6

It is essential that companion diagnostics are developed and validated in concert with immunotherapies, starting at the earliest stages of drug development. Identifying reliable predictive biomarkers will facilitate selection of appropriate candidates for the treatment in question, ie, those patients, and cancers, with an increased probability of response to the particular immunotherapy.

Attendant to the rapid advances in immune-oncology are a number of related issues that must be considered and addressed if the full benefits of ICIs are to be realized.

A number of studies have shown that PD-L1 is overexpressed in many cancers and that PD-L1 positivity is associated with a better response to monotherapy with PD-L1 inhibitors in selected malignancies. However, a number of interacting factors have an impact on the predictive and prognostic influence of PD-L1 expression. These include:

Issues surrounding PD-L1 expression

Identify and validate biomarkers of responsiveness

• The tissue itself assayed (archival versus fresh tissue, original sample versus sample after one or more lines of therapy or multiple modalities of therapy), raising questions about the stability of PD-L1 expression

Given the research and development costs of bringing a monoclonal antibody to clinical use, the treatment costs of ICIs for patients and healthcare systems are substantial – placing these therapies beyond the reach of many of the world’s cancer patients. “Financial toxicity is something we must find a way to address or we will have effective therapies at hand that many cancer patients will not be able to access,” warned Dr. Miller.

Improved affordability

The patterns of response to immunotherapies like ICIs differ markedly from those to conventional chemotherapy. The response evaluation criteria in solid tumors (RECIST) are well suited to evaluating tumor response to cytotoxic drugs, but do not account for the unique characteristics of immunologic agents, such as the weeks or months before evidence of clinical response, often after an apparent episode of progressive disease. The immune-related response criteria (irRC) were developed

Employ response assessment criteria specific to immunotherapies

• Variability of expression of PD-L1 within the tumor itself and on different cells in the tumor microenvironment

• The assay used and if the assay is done in a central reference laboratory or at participating institutions

• The definition of “positivity”. An important lesson was learned from two somewhat similar studies evaluating

two different anti-PD-L1s as monotherapy for the first-line therapy of NSCLC.14,15 PD-L1 positivity defined as an expression of ≥50% was associated with a significantly better OS in Merck’s study of pembrolizumab. 14 In a somewhat similar study of nivolumab in the same indication and line of therapy, PD-L1 positivity was defined as ≥1%, but a better survival was not observed in these “PD-L1 positive” patients.15

FUTURE PERSPECTIVES FOR ICIs IN CANCER

YOUR JOURNEY. OUR MISSION.® | 7

to better recognize patterns of tumor response seen with immuno-oncologic agents. 16 Clinical studies conducted using irRC and RECIST criteria in parallel suggest that the conventional criteria may underestimate the clinical benefit of ICI therapy in some patients. New response criteria tailored for immunotherapeutics will require appropriate validation and regulatory approval, but are clearly a necessity in this new era of immune-oncology.

The complexity of the immunostimulatory pathway provides multiple points at which immunotherapies can promote antitumor activity.1 It is increasingly clear that combinations of immunologic agents with different mechanisms of action may be needed for optimal effectiveness. A great deal more research will be needed – decades worth – to define which drugs to combine and in which patients. The ideal combination therapy appears likely to vary between different patients,

2016 saw the first regulatory approval of a PD-L1 inhibitor (atezolizumab for bladder cancer18), and approvals for other indications, as well as expansion of the approved indications for PD-1 inhibitors, are anticipated in the near future. Looking slightly further ahead, PD-1/PD-L1 inhibitors may move into first-line therapy and additional companion diagnostics will be approved. Dr. Miller also noted the burgeoning scope for combination therapy – immunotherapies with other immunotherapies and with conventional modes of treatment – and the

Continuing clinical success with ICI therapy will also require more data on toxicity profiles, toxicity management and long-term safety outcomes, as well as the creation of accurate companion diagnostics for each agent to identify the patients likely to respond. Validation and broader use of immune-related RECIST that are compatible with the response patterns of immunotherapies will also be fundamental to treatment management.

continued endeavors to define further immune pathways regulating antitumor activity.

Individualize treatment according to the tumor microenvironment genotype

therapy appears likely to vary between different patients, with one recent review describing four distinct genotypic subtypes or ‘nodes’ of tumor microenvironment based on tumor-infiltrating lymphocytes and PD-L1 expression in the tumor. 17 This finding is illustrative of the potential for marked heterogeneity in tumor microenvironments, and the essential role genotyping may play in defining, and refining, the best combination of therapies for individual patients.

Maintain caution regarding the late effects of overstimulation of the immune response with the development of autoimmune disorders

[CALLOUT] “We have reached a renaissance of cancer drug development – now that we understand some of the immune system suppressors and how to counteract them, or how to activate promoters, we can finally mount an effective response for treating cancer.” – Dr. Deny Miller

References

YOUR JOURNEY. OUR MISSION.® | 8

Dr. Miller also recommended great care be taken with future trial design to ensure that the investment generates clinically relevant data. The potential for resistance development should be anticipated, and second-line strategies to address resistance mutations developed. As inhibition of single regulatory pathways is invariably inadequate, combinations targeting multiple

1. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res 2013;19:1021-1034.

2. Batlevi CL, et al. Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 2016;13:25-40.

3. Leach DR, et al. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736.

4. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723.

5. Wolchok JD, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155-164.

6. Gettinger SN, et al. Long-term survival, clinical activity and safety of nivolumab (anti-PD-1; BMS-936558, ONO-4538) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 2014;90:S34.

7. Topalian SL, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 2014;32:1020-1030.

8. Hodi FS, et al. Long-term survival of ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with nivolumab (anti-PD-1; BMS- 936558; ONO-4538) in a Phase I trial. J Clin Oncol 2014;32(15 Suppl):Abstract 9002.

9. McDermott DF, et al. Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol 2015;33:2013-2020.

10. Ribas A, et al. Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma. J Clin Oncol 2013;31(suppl):Abstract 9009.

11. Armand P, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016;34:3733-3739.

12. Wolchok JD, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-133.

13. Hellmann MD, et al. CheckMate 012: Safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. J Clin Oncol 2016;34(suppl): Abstract 3001.

14. Reck M, et al; for the KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016;375:1823-1833.

16. Wolchok JD, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-7420.

17. Smyth MJ, et al. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol 2016;13:143-158.

18. FDA News Release. FDA approves new, targeted treatment for bladder cancer. Available at: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm. Accessed 23 September 2016.

15. Socinski M, et al. CheckMate 026: A phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC. Ann Oncol 2016;27(suppl_6): LBA7_PR.

pathways are the future of immune-oncology. Finally, Dr. Miller concluded by reiterating the importance of cost control. “By controlling costs, new, effective, safe therapies can be made available to greater numbers of patients around the world; without that, our achievements will fail to deliver the benefits that clinicians and patients hope for.”

WHEREVER YOUR JOURNEY TAKES YOU, WE’RE CLOSE BY.

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