PD-1 Pathway Inhibitors: Changing the Landscape of Cancer Immunotherapy

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1 Anti PD-/PD-L agents have a good safety profile and have resulted in durable responses in a variety of cancers. Toohey Lake Panorama_004K (detail). Photograph courtesy of Henry Domke, MD. PD- Pathway Inhibitors: Changing the Landscape of Cancer Immunotherapy Dawn E. Dolan, PharmD, and Shilpa Gupta, MD Background: Immunotherapeutic approaches to treating cancer have been evaluated during the last few decades with limited success. An understanding of the checkpoint signaling pathway involving the programmed death (PD-) receptor and its ligands (PD-L/) has clarified the role of these approaches in tumor-induced immune suppression and has been a critical advancement in immunotherapeutic drug development. Methods: A comprehensive literature review was performed to identify the available data on checkpoint inhibitors, with a focus on anti PD- and anti PD-L agents being tested in oncology. The search included Medline, PubMed, the ClinicalTrials.gov registry, and abstracts from the American Society of Clinical Oncology meetings through April 04. The effectiveness and safety of the available anti PD- and anti PD-L drugs are reviewed. Results: Tumors that express PD-L can often be aggressive and carry a poor prognosis. The anti PD- and anti PD-L agents have a good safety profile and have resulted in durable responses in a variety of cancers, including melanoma, kidney cancer, and lung cancer, even after stopping treatment. The scope of these agents is being evaluated in various other solid tumors and hematological malignancies, alone or in combination with other therapies, including other checkpoint inhibitors and targeted therapies, as well as cytotoxic chemotherapy. Conclusions: The PD-/PD-L pathway in cancer is implicated in tumors escaping immune destruction and is a promising therapeutic target. The development of anti PD- and anti PD-L agents marks a new era in the treatment of cancer with immunotherapies. Early clinical experience has shown encouraging activity of these agents in a variety of tumors, and further results are eagerly awaited from completed and ongoing studies. From the Pharmacy Service (DED) and the Genitourinary Oncology Program (SG) at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted February 6, 04; accepted April 9, 04. Address correspondence to Shilpa Gupta, MD, Genitourinary Oncology Program, 90 Magnolia Drive, Tampa, FL 6. Shilpa.Gupta@Moffitt.org No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. The authors have disclosed that this article discusses unlabeled/ unapproved uses of anti PD-/PD-L drugs. Introduction An intact immune system is capable of recognizing and eliminating tumor cells through immune checkpoints; however, tumors can adapt and circumvent these natural defense mechanisms. - Over the last several decades, significant efforts have targeted and activated the immune system to treat cancers; presently, increasing evidence exists that tumors can evade adaptive immunity and disrupt T-cell checkpoint pathways. The interaction between the programmed death (PD-) receptor and its ligand and (PD-L/) is a key pathway hijacked by tumors to July 04, Vol., No. Cancer Control

2 suppress immune control.,4-7 Reversing the inhibition of adaptive immunity can lead to active stimulation of a patient s immune systems; one such approach utilizes antagonistic antibodies to block checkpoint pathways, thus releasing tumor inhibition. These antagonistic antibodies target cytotoxic T-lymphocyte antigen 4 (CTLA-4), the PD- receptor and PD-L, block immune checkpoints, and facilitate antitumor activity. These agents are unique among antagonistic antibodies because they target lymphocyte receptors or their ligands. 8,9 In this review, we discuss the role of the PD-/ PD-L pathway and the drug development efforts to block this pathway in cancer, focusing on the currently available data from completed and ongoing clinical trials. The clinical development of several anti PD- and anti PDL- agents, their efficacy, toxicity, and scope in these cancers as single agents, or in combination with other therapies, will also be discussed. Role of PD-/PD-L Pathway PD- is an immunoinhibitory receptor that belongs to the CD8 family and is expressed on T cells, B cells, monocytes, natural killer cells, and many tumor-infiltrating lymphocytes (TILs) 0 ; it has ligands that have been described (PD-L [B7H] and PD-L [B7-DC]). Although PD-L is expressed on resting T cells, B cells, dendritic cells, macrophages, vascular endothelial cells, and pancreatic islet cells, PD-L expression is seen on macrophages and dendritic cells alone. 0 Certain tumors have a higher expression of PD-L. PD-L and L inhibit T-cell proliferation, cytokine production, and cell adhesion. PD-L controls immune T-cell activation in lymphoid organs, whereas PD-L appears to dampen T-cell function in peripheral tissues. 4 PD- induction on activated T cells occurs in response to PD-L or L engagement and limits effector T-cell activity in peripheral organs and tissues during inflammation, thus preventing autoimmunity. This is a crucial step to protect against tissue damage when the immune system is activated in response to infection. 5-7 Blocking this pathway in cancer can augment the antitumor immune response. 8 Like the CTLA-4, the PD- pathway down-modulates T- cell responses by regulating overlapping signaling proteins that are part of the immune checkpoint pathway; however, they function slightly differently. 4,6 Although the CTLA-4 focuses on regulating the activation of T cells, PD- regulates effector T-cell activity in peripheral tissues in response to infection or tumor progression. 6 High levels of CTLA-4 and PD- are expressed on regulatory T cells and these regulatory T cells and have been shown to have immune inhibitory activity; thus, they are important for maintaining self-tolerance. 6 The role of the PD- pathway in the interaction of tumor cells with the host immune response and the PD-L tumor cell expression may provide the basis for enhancing immune response through a blockade of this pathway. 6 Drugs targeting the PD- pathway may provide antitumor immunity, especially in PD-L positive tumors. Various cancers, such as melanoma, hepatocellular carcinoma, glioblastoma, lung, kidney, breast, ovarian, pancreatic, and esophageal cancers, as well as hematological malignancies, have positive PD-L expression, and this expression has been correlated with poor prognosis. 8,9 Melanoma and kidney cancer are prototypes of immunogenic tumors that have historically been known to respond to immunotherapeutic approaches with interferon alfa and interleukin. The CTLA-4 antibody ipilimumab is approved by the US Food and Drug Administration for use in melanoma. Clinical activity of drugs blocking the PD-/PD-L pathway has been demonstrated in melanoma and kidney cancer. 0-4 In patients with kidney cancer, tumor, TIL-associated PD-L expression, or both were associated with a 4.5-fold increased risk of mortality and lower cancer-specific survival rate, even after adjusting for stage, grade, and performance status. 8,9,5,6 A correlation between PD-L expression and tumor growth has been described in patients with melanoma, providing the rationale for using drugs that block the PD-/PD-L pathway. 9,7 Historically, immunotherapy has been ineffective in cases of non small-cell lung cancer (NSCLC), which has been thought to be a type of nonimmunogenic cancer; nevertheless, lung cancer can evade the immune system through various complex mechanisms. 8 In patients with advanced lung cancer, the peripheral and tumor lymphocyte counts are decreased, while levels of regulatory T cells (CD4 + ), which help suppress tumor immune surveillance, have been found at higher levels. 9- Immune checkpoint pathways involving the CTLA-4 or the PD-/PD-L are involved in regulating T-cell responses, providing the rationale for blocking this pathway in NSCLC with antibodies against CTLA-4 and the PD-/PD-L pathway. Triple negative breast cancer (TNBC) is an aggressive subset of breast cancer with limited treatment options. PD-L expression has been reported in patients with TNBC. When PD-L expression was evaluated in TILs, it correlated with higher grade and larger-sized tumors. Tumor PD-L expression also correlates with the infiltration of T-regulatory cells in TNBC, findings that suggest the role of PD-L expressing tumors and the PD-/PD-L expressing TILs in regulating immune response in TNBC. 4 The PD-/PD-L interaction may create an initial site for viral infection followed by an adaptive immune resistance, and PD- levels may positively correlate with a favorable outcome. 5,6 It is hypothesized that human papilloma virus (HPV) associated oropharyn- Cancer Control July 04, Vol., No.

3 geal cancers express PD-L as an immune evasion mode and PD-L expressing tumors were more likely to be HPV positive, thus pointing to the potential role of this pathway as a therapeutic target in HPV-associated head and neck cancer. No correlation existed between PD-L expression and disease recurrence, but a correlation was seen between PD-L expression and the development of distant metastases. 7 Drugs Targeting the PD- vs PD-L Pathway The anti PD- antibody blocks interactions between PD- and its ligands, PD-L and PD-L, while the anti PD-L antibody blocks interactions between PD-L and both PD- and B7- (CD80), which is implicated in the down-modulation of T-cell responses. Several PD- and PD-L inhibitors are in clinical development in early- and late-stage clinical trials across a wide variety of cancers (Tables and ). Patterns and Evaluation of Response A finding related to response to the anti PD-/PD-L drugs is that a flare response can be seen, with transient worsening of disease or its progression before stabilization or tumor regression occurs. Patients may exhibit durable responses, and, after discontinuing therapy, they may respond to re-treatment with these therapies in cases of progression. From early clinical experience, both the anti PD- and the anti PD-L drugs appear to have activity in various cancers, but no definitive conclusions can be drawn regarding the differences in their effectiveness. 0-4,8-4 However, looking at available results from several studies, it appears that objective responses for anti PD-L antibodies may be somewhat lower than those with anti PD- antibodies, because the latter blocks signaling via both the PD-L and PD-L. 0-4,8-4 Safety The anti PD-/PD-L agents are relatively well tolerated. However, drug-related adverse events with potential immune-related causes, such as pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis, can occur. The incidence of immune-related adverse events with anti PD-/PD-L agents is similar to that seen with ipilimumab but is less severe. 0-4,8-4 A comparison of immune-related adverse events with anti PD-/PD-L drugs, including ipilimumab, is shown in Table. 0,,,9,4 An often severe adverse event that has emerged with these agents is pneumonitis; high levels of PD-L expressing antigen-presenting cells seen in the lung may give relevance not only to the toxicity across cancers but also the observed responses in NSCLC. 4 Pneumonitis may be associated with anti PD- drugs, not with anti PD-L drugs, making the latter potentially safer. 0-4,8-4 PD-L Inhibitors BMS-96559/MDX-05 is a fully human, high affinity, immunoglobulin (Ig) G4 monoclonal antibody to PD-L. Initial results from a phase trial of 07 patients Table. Selected Ongoing Clinical Trials of Anti PD-L Drugs Indication Compound Clinical Trials No. Phase Advanced solid tumors BMS NCT MEDI476 NCT06956 Melanoma MPDL80A + vemurafenib NCT b MEDI476 + dabrafenib + trametinib or trametinib alone NCT00796 / NSCLC MPDL80A + erlotinib NCT009 b MPDL80A NCT MPDL80A NCT00458 MPDL80A vs docetaxel NCT09099 MPDL80A vs docetaxel NCT00087 MEDI476 + tremelimumab NCT b RCC MPDL80A ± bevacizumab vs sunitinib NCT09844 Solid or hematological malignancies MPDL80A NCT07584 Solid tumors MPDL80A + bevacizumab and/or chemotherapy NCT06970 MPDL80A + cobimetinib NCT MEDI476 NCT0986 MEDI476 + tremelimumab NCT09758 MSB00078C NCT09446 MSB00078C NCT PD-L = programmed death ligand, NSCLC = non small-cell lung cancer, RCC = renal cell carcinoma. July 04, Vol., No. Cancer Control

4 Table. Ongoing Clinical Trials of Anti PD- Drugs for Solid Tumors Indication Compound Clinical Trials No. Phase Advanced cancer AMP-4 NCT05884 Advanced solid tumors + iliolumbar (anti-kir) NCT07479 Castration-resistant prostate cancer, melanoma, NSCLC, RCC NCT b Colon Pembrolizumab NCT08765 Gastric, head and neck, TNBC, urothelial Pembrolizumab NCT Gastric, pancreatic, small-cell lung cancer, TNBC ± ipilimumab NCT09894 / Glioblastoma ± ipilimumab vs bevacizumab NCT00777 Hepatocellular NCT Hodgkin lymphoma, myeloma, myelodysplastic syndrome, non-hodgkin lymphoma Pembrolizumab NCT09569 Malignant gliomas Pidilizumab NCT / Melanoma ± ipilimumab vs ipilimumab + ipilimumab vs ipilimumab + ipilimumab sequentially with ipilimumab vs DTIC or carboplatin/paclitaxel after ipilumumab vs DTIC + multiple class peptides and montanide ISA 5 VG + multiple class peptides and montanide ISA 5 VG Pembrolizumab vs chemotherapy Pembrolizumab vs ipilimumab NCT NCT09749 NCT004 NCT07898 NCT07746 NCT0777 NCT07646 NCT NCT06490 NCT NCT08669 Melanoma, NSCLC Pembrolizumab NCT09587 NSCLC ± gemcitabine/cisplatin, pemetrexed/cisplatin, carboplatin/paclitaxel, bevacizumab, erlotinib, ipilimumab vs docetaxel vs docetaxel Pembrolizumab vs docetaxel Pembrolizumab NCT04540 NCT NCT NCT07759 NCT NCT NCT / Pancreatic Pidilizumab + gemcitabine NCT046 Prostate Pidilizumab + sipuleucel-t + cyclophosphamide NCT RCC + sunitinib, pazopanib, or ipilimumab vs everolimus Pembrolizumab + pazopanib Pidilizumab ± dendritic cell/rcc fusion cell vaccine NCT04708 NCT0544 NCT NCT0587 NCT00466 NCT Solid tumors Anti-LAG (BMS-98606) ± nivolumab + interleukin- AMP-554 NCT NCT NCT NCT00804 Solid tumors, NSCLC Pembrolizumab NCT PD- = programmed death, NSCLC = non small-cell lung cancer, RCC = renal cell carcinoma, TNBC = triple negative breast cancer. 4 Cancer Control July 04, Vol., No.

5 showed durable tumor regression (objective response rate of 6% 7%) and prolonged stabilization of disease (% 4% at 4 weeks) in patients with advanced cancers, including NSCLC, melanoma, and kidney cancer. 0 MPDL80A is an engineered human monoclonal antibody targeting PD-L. In a phase study of 7 patients with advanced solid tumors, an overall response rate of % was observed in nonselected solid tumors among several patients exhibiting delayed responses following initial radiological progression. 9 The 4-week progression free survival rate was 44%. Patients with PD-L expressing tumors had an overall response rate of 9% and % had progressive disease. Those with PD-L tumors had an overall response rate of % and 59% had progressive disease. 9 Additional anti PD-L agents, including MSB00078C and MEDI47, are being tested in early-phase trials (see Table ). PD- Inhibitors CT-0/pidilizumab is a humanized IgG monoclonal antibody that binds to PD-. A phase study in 7 patients with advanced stage hematologic malignancies (acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, multiple myeloma, non-hodgkin lymphoma) showed a clinical benefit in % patients and a prolonged complete response of longer than 68 weeks in patient. 8 Several phase and trials are ongoing to study the use of this agent in various solid tumors, including prostate and renal cell cancers (see Table ). BMS-96558/MDX-06/nivolumab is a fully human IgG4 monoclonal antibody against PD-. The first human study evaluated its safety and tolerability in 9 patients with advanced refractory solid tumors. Results of a larger phase study in 96 patients have also been reported.,4,40 Objective responses were seen in % of patients with melanoma, 7% in patients with NSCLC, and 9% in patients with RCC. 40 A total of 65% of responders had durable responses lasting for more than year. Stable disease lasting 4 weeks was seen in patients with melanoma (7%), NSCLC (0%), and RCC (7%). The median overall survival rate for patients with melanoma was 6.8 months. PD-L expression was tested in 4 patients; 9 out of 5 (6%) patients had PD-L expressing tumors and experienced an objective response to PD- blockade, while the remaining 7 patients had PD-L negative tumors that were nonresponsive. Pembrolizumab is a highly selective, humanized IgG4-kappa monoclonal antibody with activity against PD-. Its safety and efficacy were evaluated in a phase trial in solid tumors. 4 The rate of median progression-free survival was more than 7 months; however, the median overall survival rate was not been reached. Rationale for Combination Therapies Thus far, anti PD and anti PD-L antibodies have yielded promising results with durable responses in several tumors and a reasonable safety profile. Given that these agents produce durable responses despite treatment discontinuation, it is thought that the Table. Comparison of Immune-Related Adverse Events Between Anti PD-/PD-L Drugs and Ipilimumab Ipilimumab (%) 4 / BMS (%) Pembrolizumab/ MK-475 (%) Pidilizumab/ CT-0 (%) 5 BMS MPDL80A (%) 0 (%) 9 Colitis 7.6/ Dermatological 4/.5 / Diarrhea /5 8 0/ Fatigue 4/7 0/ Hepatic / Hypothyroid 8/ Hypophysitis.5/.5 Infusion reactions 0 Pneumonitis / 4/0 0/0 Pruritus Total grade / Total immune-related PD = programmed death, PD-L = programmed death ligand, NSCLC = non small-cell lung cancer, RCC = renal cell carcinoma. July 04, Vol., No. Cancer Control 5

6 re-education of the immune system helps it adapt to tumor manipulation to develop resistance. 6 Preclinical evidence exists for the complementary roles of CTLA-4 and PD- in regulating adaptive immunity, and this provides rationale for combining drugs targeting these pathways Paradoxically and originally believed to be immunosuppressive, new data allow us to recognize that cytotoxic agents can antagonize immunosuppression in the tumor microenvironment, thus promoting immunity based on the concept that tumor cells die in multiple ways and that some forms of apoptosis may lead to an enhanced immune response. 8,5 For example, nivolumab was combined with ipilimumab in a phase trial of patients with advanced melanoma. 46 The combination had a manageable safety profile and produced clinical activity in the majority of patients, with rapid and deep tumor regression seen in a large proportion of patients. Based on the results of this study, a phase study is being undertaken to evaluate whether this combination is better than nivolumab alone in melanoma (NCT ). Several other early-phase studies are underway to explore combinations of various anti PD-/PD-L drugs with other therapies across a variety of tumor types (see Tables and ), possibly paving the way for future combination studies. PD-L as a Predictive Biomarker Tumor PD-L expression has been shown to correlate with poor prognosis in many cancers. 47 Available early data allude to PD-L expression in tumors as a possible predictive biomarker of response to anti PD-/ PD-L drugs; however, these data must be confirmed, and the role of tumor expression of PD-L must be further elucidated. Conclusions The discovery of agents targeted at the anti programmed death and anti programmed death ligand pathway, as well as their remarkable activity in several cancers, has launched an era of effective immunotherapeutic drugs that will change the landscape of cancer treatment. These agents also produce responses in nonimmunogenic cancers such as non small-cell lung and colon cancers, broadening their scope beyond classic immunogenic tumors like melanoma and renal cell cancer. 0 The activity of these agents has been suggested in early-phase studies of melanoma, renal cell, and non small-cell lung cancers, and the results from completed and ongoing phase studies are eagerly awaited. In addition, these agents are being explored alone or in combination across other difficult-to-treat tumor types. 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