Across Cancer Settings, ICIs Continue to Make Deep Inroads

Mario Sznol, MD

With immune checkpoint inhibitors (ICIs) gaining widespread adoption, their optimal use hinges on a greater understanding of biomarkers, practical applications, and their potential in combination with cellular therapies.

The 5th Annual International Congress on Immunotherapies in Cancer®, hosted by Physicians’ Education Resource®, LLC (PER®) to be held virtually on December 12, 2020, will focus on practice-changing applications of these ubiquitous cancer agents.

Mario Sznol, MD, cochair of the 1-day conference, discussed biomarkers, practical applications in the clinic, and the emerging role of adoptive T-cell therapies in solid tumors. “Keeping up with all the clinical applications of the immune checkpoint inhibitors can be difficult,” Sznol, professor of medicine (medical oncology) at Yale School of Medicine, co-director of Yale SPORE in Skin Cancer, and co-leader of Cancer Immunology at Yale Cancer Center in New Haven, Connecticut, said in an interview with Targeted Therapies in Oncology. “Even though these agents have been approved for some time, I think oncologists still have a relative level of discomfort with managing all of the [associated] adverse effects [AEs].”

The conference will provide information about the science behind ICIs and also examine recent advances in the use of these agents in a number of disease settings.

Early Research

The early research by William B. Coley, MD, in the late 19th century laid the groundwork for the role of immunotherapy in treating cancer.¹ Coley and others had noticed that when patients with cancer were injected with a mixture of heat-killed Streptococcus pyogenes and Serratia marcescens, they would enter remission. This combination of gram-positive and gram- negative bacteria was particularly effective in sarcoma, resulting in long-term cure rates.²

The advancements since Coley’s time could be characterized as modest success, that is, until the emergence of ICIs.

Practical Applications

The meeting will examine practical applications in solid tumor and hematologic settings including genitourinary, gastrointestinal, breast and ovarian, hematologic malignancies, and lung, head, and neck. Esteemed faculty will share their expertise with attendees and demonstrate the complexity and nuance required when treating patients with ICIs through case studies and lively interactive discussion sessions.

Small cell and non–small cell lung cancer will be addressed by Naiyer A Rizvi, MD, the Price Family Professor of Medicine and director of Thoracic Oncology at Columbia University Irving Medical Center and research director of the Price Family Comprehensive Center for Chest Care at NewYork-Presbyterian Hospital in New York, New York, and Julie R. Brahmer, MD, professor of oncology and co-director of the Upper Aero digestive Department at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland

In head and neck cancers, Tanguy Y. Seiwert, MD, director of the Head and Neck Cancer Oncology Disease Group at Bloomberg-Kimmel Institute for Immunotherapy at the Head and Neck Cancer Program, co-director of the Bloomberg-Kimmel Institute for Immunotherapy at the Head and Neck Cancer Program at the Johns Hopkins School of Medicine, and assistant professor of oncology at the Johns Hopkins School of Medicine in Baltimore, Maryland, will lead the discussion. In breast cancer, Leisha A. Emens, MD, PhD, professor of medicine and director of Translational Immunotherapy for the Women’s Cancer Research Center at the University of Pittsburgh in Pennsylvania, will offer her insights. In the genitourinary arena, Targeted Therapies in Oncology’s own physician coeditor in chief, Arjun V. Balar, MD, will offer practical insights in bladder cancer.

The advancements made with anti–PD-1 and anti–PD-L1 agents in multiple disease settings and in combinations with other immunotherapies and targeted therapies have led to exciting developments, said Sznol.

“Expanding the indications for anti–PD-1 [agents] to many tumor types has broadened the reach of immunotherapies,” Sznol said. “It’s hard to think of a malignancy in which immune checkpoint inhibitors don’t enter into the treatment discussion. In the vast majority of malignancies, anti–PD-1 plays a role.”

Exploring Biomarkers

Sznol is especially interested in the biomarker portion of the conference with its focus on tumor mutational burden (TMB) and microsatellite instability-high (MSI-H) cancers. “I think people will want to know how to correctly measure tumor mutational burden and how to apply this biomarker in the clinic,” he said.

Sznol explained that the complexity of using these agents presents challenges, especially in community oncology. “Community oncologists have to think about what line of disease and in which disease to use these agents,” Sznol said. “Further, there could be diseases, such as cholangiocarcinoma, for which there is no indication and yet [evidence] suggests a subset of patients with cholangiocarcinoma could be good candidates for these drugs. The key is finding the right biomarkers to aid in selection.”

Further, “these are the practical questions [concerning the use of ICIs], and because advancements occur very quickly, I think it’s important to continue to educate people about these developments,” continued Sznol.

As an example, Sznol mentioned the recent approval of pembrolizumab (Keytruda) in June 2020. The FDA granted accelerated approval to the PD-1 inhibitor for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high (≥ 10 mutations/megabase) solid tumors.3 The FDA also expanded the approval for the FoundationOne CDx assay (Foundation Medicine, Inc) alongside the agent as a companion diagnostic.

Efficacy was determined based on results from the phase 2 basket study KEYNOTE-158 (NCT02628067), in patients with various unresectable or metastatic TMB-high solid tumors. Ten cohorts of patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity or documented disease progression. Differences in objective response rates according to cancer type were observed.

Overall response rate (ORR) and duration of response (DOR) were determined by blinded independent central review, according to RECIST 1.1, in patients who had received at least 1 dose of pembrolizumab.

Thirteen percent of patients had tumors identified as high TMB. The ORR for these patients was 29% (95% CI, 21%-39%). The complete response rate was 4% and the partial response rate was 25%. The median DOR was not reached, according to the investigators, and the rate of responses lasting at least 12 months was 57%. The percentage of patients with a duration of response at least 24 months was 50%.

Treatment-related AEs occurred in 64.8% of patients, with the most common being fatigue (14.6%), pruritus (12.9%), diarrhea (12.0%), and asthenia (10.7%). Grade 3 or greater treatment-related AEs occurred in 14.6% of patients.

Immune-Related Adverse Effects

Further complicating the clinical picture is the emergence of immune-related AEs (irAEs), the onset of which are variable and differ by organ system and type of therapy.⁴ Differentiating between these AEs compared with those observed with other systemic cancer therapies is critical because prompt recognition with appropriate management results in resolution, allowing patients to continue on therapy.

“The best way to learn about managing immune[-related] AEs is to go through patient cases [with attendees],” Sznol said. Jeffrey Weber, MD, PhD, deputy director of NYU Langone Health’s Perlmutter Cancer Center in New York, New York, will be leading this session of the conference.

Sznol noted that although these agents have been approved for more than 6 or 7 years, there is still a level of uncertainty about how to treat the resulting AEs in clinic. As an example, he said that for patients who experience a severe irAE and who are on steroids, the tendency is to begin tapering the dose of steroids. Restarting treatment with ICIs before the irAE fully subsides, however, is a common practice.

“The better way [to manage these patients] is to complete the steroid treatment and make sure the immune[-related] AEs are gone before giving patients additional treatments. We [tend to] undertreat with steroids,” Sznol emphasized. When patients don’t respond to steroid therapy, giving patients a second or third agent—such as the tumor necrosis factor blocker infliximab (Remicade) or a monoclonal antibody indicated for colitis such as vedolizumab (Entyvio)—to relieve irAEs can be daunting. “We try to go through some of these more complicated cases so that attendees get a feel for how to treat these patients if they show up in clinic,” he said.

It’s not uncommon for Sznol to receive 5 or 6 emails from colleagues asking the best way to manage patients who develop autoimmune AEs from ICI therapy. “I will see this [practice] even at cancer centers that have a lot of experience treating patients with immune-related AEs,” Sznol said. “We want to give people confidence in managing these drugs because the overall benefit-to-risk ratio is favorable. We don’t want patients to not get these drugs because the oncologist feels uncomfortable with AEs,” he said.

Adoptive T-Cell Session

Sznol said Amod Sarnaik, MD, a surgical oncologist in the Department of Cutaneous Oncology, the Immunology Program, and the Melanoma Center of Excellence at Moffitt Cancer Center in Tampa, Florida, will be presenting a special session on adoptive T-cell therapies in solid tumors. T-cell therapies are usually associated with treating melanoma, but activity has been demonstrated in lung cancer and in cervical cancer, according to Sznol.

Data on the safety and efficacy of lifileucel (LN-144; NCT02360579) in 66 patients with advanced metastatic melanoma who progressed on multiple prior therapies including anti–PD-1 therapy was presented at this year’s American Society of Clinical Oncology Virtual Scientific Program.⁵ In this heavily pretreated and PD-1 inhibitor–resistant group, the response rate was 38%, with a 3% complete response and 80% disease control rate. Durable responses were observed, and some responses were observed in patients with PD-1–negative tumors, suggesting that tumor infiltrating lymphocytes may be an effective option for patients with PD-1–resistant cancers or cancers with lower immunogenicity.

With the emergence of ICIs, another layer of complexity has been added to the management of patients with cancer. But their benefit outweighs the associated risks of AEs. “It’s a different world from just a few years ago,” Sznol said. “But it’s important for oncologists to learn how to use these agents and also how to manage their toxicities.”

_References:

_{1. Burdick CG. William Bradley Coley 1862-1936. Ann Surg. 1937;105(1):152-155. doi:10.1097/00000658-193701000-00015}

_{2. Decker WK, Safdar A. Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley’s legacy revisited. Cytokine Growth Factor Rev. 2009;20(4):271-281. doi:10.1016/j.cytogfr.2009.07.004}

_{3. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed September 28, 2020. https://bit. ly/3kQZWR5}

_{4. Daniels GA, Guerrera AD, Katz D, Viets-Upchurch J. Challenge of immune-mediated adverse reactions in the emergency department. Emerg Med J. 2019;36(6):369-377. doi:10.1136/emermed-2018-208206}

_{5. Sarnaik A, Kushalani NI, Chesney JA, et al. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lif ileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol. 2019;37(suppl 15):2518. doi:10.1200/JCO.2019.37.15_suppl.2518}