Those were heady times. We saw ourselves on the verge of mastering the immune system and, with such mastery, conquering cancer’s most elusive trait. Initial clinical trials were not only demonstrating broad antitumor activity, but complete remissions in melanoma, as well as significant responses in other solid tumors and hematologic malignancies. We were witnessing the dawn of a new therapeutic era with a much anticipated arsenal of weapons that would exploit the human immune system and overcome cancer’s cloaking device.
My original research in the field was rewarded with manuscripts accepted by the Journal of Clinical Oncology and The Journal of the American Medical Association, as well as an abstract selected for oral presentation at the American Society of Clinical Oncology’s Annual Meeting. The year was not 2013, it was 1986. I was a fellow at MD Anderson Cancer Center in Houston, Texas, in the Developmental Therapeutics Department. Interleukins, interferons, tumor necrosis factor, cytokines, and lymphokines comprised a new language of biologic therapies that would eclipse and replace the cytotoxic and cytostatic traditional chemotherapies of the past. The enthusiasm over this first generation of immuno-oncology agents was eventually tempered by toxicity and limited efficacy, leading to the commercialization of only a handful of agents that would have an impact on relatively small disease populations of hairy cell leukemia, chronic myeloid leukemia, HIV-related lymphoma, localized recurrent bladder cancer, melanoma, and renal cell cancer. Over the subsequent 2 decades, a second generation of development, pioneered by Steven A. Rosenberg, MD, PhD, at the National Cancer Institute (NCI), heralded a future for vaccine-based therapy, which failed to materialize. Eventually, researchers explained the failure of these first 2 forays into immuno-oncology by elucidating the mechanisms by which tumors evaded the activated and enriched T-cells: the tumors subverted immune checkpoint pathways and other immuneregulatory mechanisms.
Now, nearly 30 years later, we find ourselves at a similar junction in the history of cancer and drug discovery, filled with promise and triumph as science conquers another frontier. How is this third generation of immuno-oncology different? Why is this scientific breakthrough more transcendent? What will be the response of stakeholders—patients, providers, and payers—to the emergence of this new class of therapeutics? Are these times and circumstances really so different? Such are the questions before us.
Stakeholder adoption of new therapeutics classically hinges on the quality valuation triad of efficacy, toxicity, and cost. But as we have learned from experience and the discipline of behavioral economics, our choices of treatment are often more complex. We are immersed in an era of precision medicine and targeted drug development, being convinced that each cancer has its unique gene signature and thereby represents an N of 1. Tumors that appear phenotypically identical are genetically distinct, owing to the differential expression of multiple mutated genes (from 10 to >100), without a clear distinction of the most critical gene(s). Targeted treatment of such patients has produced some dramatic responses, albeit transient and without cures.1 Thus, the allure of precision medicine combined with targeted therapy is becoming tarnished by tumor adaption to pathway interference, resulting in the lack of a durable response—reminiscent of the limitations of traditional chemotherapy. What makes immuno-oncology seem so transformative and, thereby, so appealing is the gestalt of panacea, therapies that are histology agnostic unleashing an immune system to recognize self from abnormal self regardless of cell origin. Even more so today than in the 1980s, we are rightly captivated by the promise of an arsenal of broadly active antitumor drugs that demonstrate rapid and durable responses with limited grade 3-4 toxicity.
A corollary to the perception of immuno- oncology as the anticipated evolution of cancer treatment is its equally compelling mechanism of action. Stakeholders are much more likely to embrace treatments that intellectually and emotionally appeal to them. Many complex multicellular regulatory events keep the immune system from overreacting to a stimulus or mistaking a component of itself for a dangerous invader. Most notable among the “antigen presenting cell-T-cell—microenvironment” that regulates inflammatory responses in the tissues is the programmed cell death protein 1 (PD-1) pathway. One or both of the PD-1 ligands, PD-L1 and PD-L2, which are expressed on cells in the tissues, bind to PD-1 receptors on T-cells and inhibit their function. Blocking this interaction between PD-1 and its ligands can result in T-cell activation and a more florid tissue inflammatory response.2 Although this third generation of immuno-oncology truly began with the FDA’s approval of the vaccine sipuleucel-T (Provenge) in 2010 and the immunostimulatory cytotoxic T-lymphocyte—associated protein 4 (CTLA-4) monoclonal antibody ipilimumab (Yervoy) in 2011, the PD-1 pathway drugs are driving our current interest in immuno-oncology, as response rates with ipilimumab and sipuleucel-T have been modest at best.3,4
Despite the increasing impact of cost on treatment considerations and toxicity on prescribing patterns, efficacy remains the most critical driver of new therapeutic adoption. Recently published reports provided additional data on the efficacy of immune therapy; specifically, on the role of antibodies blocking the PD-1 receptor pathway in the treatment of metastatic cancer. Robert et al described an improved objective response rate (ORR) (40%) and 1-year survival rates (72.9%) among patients with untreated metastatic melanoma that received the anti—PD-1 drug nivolumab compared with dacarbazine.5 Ansell et al reported a remarkably high ORR of 87% among heavily pretreated patients with Hodgkin’s lymphoma receiving nivolumab.6 In September 2014, another anti—PD-1 drug, pembrolizumab (Keytruda), was granted accelerated approval in the United States, but only for the treatment of metastatic melanoma in patients with progressive disease after treatment with the current standard of care, ipilimumab (an anti–CTLA-4 antibody) and a BRAF-targeted agent (for tumors with a V600 mutation).7 Breakthrough Therapy designation for pembrolizumab in advanced non-small cell lung cancer was supported by response data from the ongoing phase 1b KEYNOTE-001 study.8 Pembrolizumab, like other drugs in the PD-1 pathway, is actively being studied as monotherapy and in combination across more than 30 types of cancers. But such robust responses, as has been published by Roberts and Ansell et al, is not the case in all tumors studied.5,6 In the KEYNOTE-012 trial, pembrolizumab resulted in a meager 18.5% response rate in women with triple-negative breast cancer.9 Similar response rates with PD-1 inhibitors in other solid tumors may diminish their current popularity.
Efficacy, in and of itself, may be seen as a complex triad of factors including time, depth, and duration of response. One of the most striking observations from the checkpoint-inhibitor clinical trials is the early objective responses and durable tumor control and survival. The vast majority of responders do so rapidly with upwards of 80% maximum tumor shrinkage, including complete response, within 12 weeks of initiation.10 Unleashing a memory immune response may also result in long-term disease stabilization as T-cells are stimulated by peptide ligands, resulting in memory that may be lifelong. Maturing data in more than 4800 patients have shown that approximately 1 in 5 patients treated with ipilimumab has the potential to survive for at least 3 years, and up to 10 years, from treatment initiation, which more than doubles results with conventional drugs.11 Although the PD pathway may be the poster child for this third generation of immuno-oncology due to its compelling mechanism of action and impressive clinical trial survival data, the field of immuno-oncology is becoming incredibly crowded and competitive, especially for the first generation of targets (eg, CTLA-4, PD-1/PD-L1, TIM3, LAG3, OX40, etc).
When treatment is not curative, toxicity becomes a significant factor in stakeholder adoption. There was early recognition that stimulating the immune system might result in autoimmune events: as expected, enterocolitis, hepatitis, dermatitis, pneumonitis, endocrinopathy, and neuropathy have been the most common autoimmune-related adverse events (AEs) observed. Rate of AEs with single agent immuno-oncology regimens have ranged from 46% to 64% for any grade event and 6% to 18% for grade 3-4 events.10 In the KEYNOTE-012 trial, 18 of the 32 treated patients experienced a treatment-related AE.9 Four patients had grade 3 events, which included anemia, headache, aseptic meningitis, and pyrexia; 1 patient had a grade 4 event. A concern for increased toxicity with combination therapy was corroborated when grade 3-4 toxicities were observed in 62% of patients treated with the combination of ipilimumab and nivolumab.12 The unusual constellation of autoimmune AEs may pose a dilemma for oncologists not accustomed to identifying and managing such conditions. Despite low levels of serious AEs with single-agent PD-1 treatment, the toxicity profile and early safety signals with combination therapies may limit stakeholder adoption.
The impact of a cultural shift to precision medicine may also be a factor in the breadth of immuno-oncology adoption. Immunohistochemical analysis following anti—PD-1 therapy in metastatic melanoma has shown higher response rates and improved progression-free survival in patients with at least 5% of tumor cells from a pretreatment metastatic lesion staining for membrane PD-L1 expression. In the study by Robert et al, melanoma patients were stratified according to tumor PD-L1 expression status. However, nivolumab showed substantial benefit even in patients with negative or indeterminate biomarkers.5 Will clinical pathways depend on biomarkers to select between anti-BRAF and anti—PD-1 therapy in patients with BRAF-mutated metastatic melanoma or to determine which patients might be better responders following anti-PD-1 therapy alone? Perhaps to choose the best combination therapy among the many potentially active ones that will be developed over the coming years? Due to the complex tumor-host relationship and multitude of variables that may influence outcome with respect to pharmacologic intervention, development of reliable and affordable predictive biomarkers will be difficult and require a substantial investment in resources. Findings of Robert et al have underscored the need to validate a prospective predictive biomarker in a randomized, controlled clinical trial.
The unsustainable cost trend in healthcare in general, and cancer care in particular, has often been blamed on the rising cost of drug treatment. The last 10 oncology drugs that have come to market, including the immuno-oncology agents discussed herein, have price tags that exceed $10,000 per month. Although the cost versus value can be debated, cost has increasingly become a factor in stakeholder adoption. Even when novel therapeutics are awarded Breakthrough Therapy designation or demonstrate cure (as in the case of the new class of hepatitis C drugs), cost has been at the forefront of stakeholder discussions. The potential scope of application, coupled with continued use as maintenance therapy in responders, likelihood of combination therapy, and effectiveness in transforming life-threatening diagnoses to chronic diseases magnify the price scrutiny of immuno-oncology agents. I believe that the parallels to hepatitis C agents cannot be overstated and that the recent market response should be viewed seriously, as 3 to 6 PD-1 pathway drugs will likely enter the market with similar indications and labeling in the next 2 years.
The foundation for immuno-oncology as an anticancer treatment was built upon the knowledge that tumor cells can use complex and overlapping mechanisms to avoid immune detection. As the evidence builds around the impressive clinical activity of PD-1 and PD-L1 antagonists in patients with a variety of cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable. The success achieved to date was accomplished with agents directed against only 2 of the many potentially important immune targets. Rapid responses, durable tumor control, and long-term survival through harnessing the power of the immune system are now realities. Data with agents that block CTLA-4, PD-1, and other checkpoint proteins are affording a benchmark to measure the efficacy of future therapies while stimulating interest in alternative sequencing or smart combination approaches to further improve outcomes. The potential for broad antitumor activity agnostic to histology or complex genotype, rapid onset of response, the relatively low toxicity profile of PD-1 and PD-L1 antagonists, and possibility of T-cell memory resulting in durable responses differentiate this third generation of immuno-oncology agents from the preceding ones. We must remember, however, that these agents have toxicities, are enormously expensive, and are not currently curative. Informed stakeholders are likely to weigh all these factors carefully in their decision to adopt immuno-oncology drugs.
Bruce Feinberg, DO, is vice president and chief medical officer, Cardinal Health Specialty Solutions.
1. Lynch TJ, Bell DW, Sordella RN, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139.
2. Robert C, Soria JC, Eggermont AM. Drug of the year: programmed death-1 receptor/programmed death-1 ligand-1 receptor monoclonal antibodies. Eur J Cancer. 2013;49(14):2968-2971.
3. Provenge (sipuleucel-T) [prescribing information]. Seattle, WA: Dendreon Corporation, 2014. Provenge website. http://www.provenge.com/pdf/prescribing-information.pdf.
4. Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2013. Bristol-Myers Squibb website. http://packageinserts.bms.com/pi/pi_yervoy.pdf.
5. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation [published online November 16, 2014]. N Engl J Med. doi:10.1056/NEJMoa1412082.
6. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma [published online December 6, 2014]. N Engl J Med. doi:10.1056/NEJMoa1411087.
7. Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck and Co; 2014. Merck website. http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
8. Garon EB, Gandhi L, Rizvi N, et al. Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non—small cell lung carcinoma (NSCLC). Presented at: ESMO 2014 Congress; September 28, 2014; Madrid, Spain. Abstract LBA43.
9. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09.
10. Berman K, Korman A, Peck R, Feltquate D, Lonberg N, Canetta R. The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience [published online December 1, 2014]. Pharmacol Ther. doi:10.1016/j.pharmthera.2014.11.017.
11. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Eur J Cancer. 2013;49(suppl 3). Abstract LBA24.
12. Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl):5s. Abstract LBA9003.