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IntroductionPrior studies suggest lymphopenia following radiation therapy may impact toxicity and cancer control. Chronic radiation-related lymphopenia (RRL) has been noted in prostate cancer patients treated with conventionally fractionated pelvic radiation therapy. The impact of utilizing hypofractionated high integral dose therapies such as stereotactic body radiation therapy (SBRT) on RRL is less well characterized. This prospective study sought to evaluate the impact of prostate SBRT plus or minus supplemental pelvic nodal radiation (PNI) on RRL.MethodsBetween 2012 and 2023, serial serum absolute lymphocyte counts (ALCs) were measured in 226 men treated at MedStar Georgetown with robotic SBRT using the CyberKnife® (CK) (36.25 Gy in 5 fractions) alone or CK (19.5 Gy in 3 fractions) followed by supplemental PNI using VMAT (37.5–45.0 Gy in 15–25 fractions) per an institutional protocol (IRB#: 2012-1175). Baseline ALC (k/μL) was measured 1–2 hours prior to robotic SBRT and at each follow-up appointment (1, 3, 6, 9, 12, 18, and 24 months post-treatment). Lymphopenia was graded using the CTCAEv.4: Grade 1 (0.8-1.0 k/μL), Grade 2 (0.5-0.8 k/μL), Grade 3 (0.2-0.5 k/μL) and Grade 4 (

Background Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures.Methods Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method.Results At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs.Conclusions Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN.Trial registration number NCT02231749.

Abstract Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset.

Background As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration.Methods Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured.Results At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free.Conclusions Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Abstract Introduction COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy. Methods Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors. Results Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 – 1.39; targeted therapy OR 1.89, 95% CI 0.64 – 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 – 2.35). Conclusions Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.

Advanced renal cell carcinoma is a biologically heterogeneous disease with multiple treatment options that largely involve immunotherapy and/or anti-angiogenic therapies. The choice of initial and subsequent therapy depends on both clinical and biological considerations. Here, we describe the application of recent data to clinical practice.

Background To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.Methods Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies.Results 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary—1/19 (5%); chromophobe—1/6 (17%); and unclassified—3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of 3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death.Conclusions Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity.Trial registration number NCT03117309.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy may vary substantially in their clinical presentation, including natural history, outcomes to treatment, and patterns. The application of clinical guidelines for irAE management can be challenging for practitioners due to a lack of common or consistently applied terminology. Furthermore, given the growing body of clinical experience and published data on irAEs, there is a greater appreciation for the heterogeneous natural histories, responses to treatment, and patterns of these toxicities, which is not currently reflected in irAE guidelines. Furthermore, there are no prospective trial data to inform the management of the distinct presentations of irAEs. Recognizing a need for uniform terminology for the natural history, response to treatment, and patterns of irAEs, the Society for Immunotherapy of Cancer (SITC) convened a consensus panel composed of leading international experts from academic medicine, industry, and regulatory agencies. Using a modified Delphi consensus process, the expert panel developed clinical definitions for irAE terminology used in the literature, encompassing terms related to irAE natural history (ie, re-emergent, chronic active, chronic inactive, delayed/late onset), response to treatment (ie, steroid unresponsive, steroid dependent), and patterns (ie, multisystem irAEs). SITC developed these definitions to support the adoption of a standardized vocabulary for irAEs, which will have implications for the uniform application of irAE clinical practice guidelines and to enable future irAE clinical trials.

Immunotherapy offers deep and durable disease control to some patients, but many tumors do not respond to treatment with single-agent immune checkpoint inhibitors (ICIs). One strategy to enhance responses to immunotherapy is via combinations with signal transduction inhibitors, such as antiangiogenic therapies, which not only directly target cancer cells but also could potentially favorably modulate the tumor immune microenvironment. Combination strategies with ICIs have demonstrated enhanced antitumor activity compared with tumor-targeted or antiangiogenic therapy alone in randomized trials in a variety of solid tumor settings, leading to regulatory approval from the US Food and Drug Administration and agencies in other countries for the treatment of endometrial cancer, kidney cancer, melanoma, and hepatocellular carcinoma. Despite improved survival and response rates for some patients when antiangiogenic or targeted therapies are administered with ICIs, many patients continue to progress after combination treatment and urgently need new strategies to address this manifestation of resistance to immunotherapy. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-PD-(L)1. To provide guidance for clinical trial design and to support analyses of emerging molecular and immune profiling data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of anti-PD-(L)1 ICIs and targeted therapies. Definitions for resistance to ICIs in combination with chemotherapy and with other ICIs will be published in companion volumes to this paper.

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity—for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect.

Abstract The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd–5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Purpose/ObjectivesClinical trials of anti-Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) therapies have demonstrated a clinical benefit with low rates of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (ITs) and stereotactic radiosurgery (SRS) has yielded impressive results with regard to local control (LC) and overall survival (OS), it has also been associated with increased rates of radiation necrosis (RN) compared to historical series of SRS alone. We retrospectively reviewed patients treated with IT in combination with SRS to report on predictors of clinical outcomes.Materials and MethodsPatients were included if they had MBMs treated with SRS within 1 year of receiving anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes including OS, LC, intracranial death (ID), and RN were correlated with type and timing of IT with SRS, radiation dose, total volume, and size and number of lesions treated.ResultsTwenty-nine patients with 171 MBMs were treated between May 2012 and May 2018. Patients had a median of 5 lesions treated (median volume of 6.5 cm3) over a median of 2 courses of SRS. The median dose was 21 Gy. Most patients were treated with ipilimumab (n = 13) or nivolumab-ipilimumab (n = 10). Most patients underwent SRS concurrently or within 3 months of receiving immunotherapy (n = 21). Two-year OS and LC were 54.4% and 85.5%, respectively. In addition, 14% of patients developed RN; however, only 4.7% of the total treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID (p = 0.05) and RN (p = 0.03). There was no difference in OS, ID, or RN with regard to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of cumulative lesions treated.ConclusionsIn our series, patients treated with SRS and IT for MBMs had excellent rates of OS and LC; however, patients with an aggregate tumor volume >6.5 cm3 were found to be at increased risk of ID and RN. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.

Abstract The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Abstracts Background Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations. Methods We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018. Results We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. Conclusions Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

Abstract Background Immune checkpoint inhibitors (ICIs) have now become standard of care treatment for many malignancies. ICIs are associated with unique immune mediated adverse events (irAEs) due to dysregulation of immune activation. As treatment with ICIs is becoming more common, rare irAEs are also being recognized. Here we report a case of ICI-induced celiac disease. Case A 74-year-old Caucasian female with metastatic renal carcinoma received second line nivolumab (anti-PD1 antibody) after initial disease progression on sunitinib. Ipilimumab was added after she failed to respond to six cycles of nivolumab monotherapy. One week after her first cycle of combination treatment, she presented with nausea, vomiting, grade 1 diarrhea, and weight loss. She underwent endoscopy, which showed bile stasis in the stomach, normal appearing stomach mucosa, and nonbleeding erythematous mucosa in the duodenal bulb. Stomach biopsy showed moderate active chronic gastritis. Duodenal biopsy showed moderate chronic active duodenitis with focal neutrophilic cryptitis, mucosal erosions, villous atrophy, mildly increased intraepithelial lymphocytes, and moderate chronic inflammation in the lamina propria pathognomonic of celiac disease. Symptoms improved with gluten-free diet, twice-daily omeprazole and anti-emetics and she was able to continue on treatment. Conclusions There has been only one published case reporting ICI-induced celiac disease. Our case report highlights a rare irAE (celiac disease) associated with ICI treatment. It is unclear whether the patient had previously undiagnosed celiac disease or whether ICIs triggered her enteritis. Our patient was able to continue treatment with ICIs with dietary modifications, suggesting correct diagnosis is critical for optimal patient outcome.

Abstract The rapid development of immuno-oncology (I-O) therapies for multiple types of cancer has transformed the cancer treatment landscape and brightened the long-term outlook for many patients with advanced cancer. Responding to ongoing efforts to generate value assessments for novel therapies, multiple stakeholders have been considering the question of “What makes I-O transformative?” Evaluating the distinct features and attributes of these therapies, and better characterizing how patients experience them, will inform such assessments. This paper defines ways in which treatment with I-O is different from other therapies. It also proposes key aspects and attributes of I-O therapies that should be considered in any assessment of their value and seeks to address evidence gaps in existing value frameworks given the unique properties of patient outcomes with I-O therapy. The paper concludes with a “data needs catalogue” (DNC) predicated on the belief that multiple key, unique elements that are necessary to fully characterize the value of I-O therapies are not routinely or robustly measured in current clinical practice or reimbursement databases and are infrequently captured in existing research studies. A better characterization of the benefit of I-O treatment will allow a more thorough assessment of its benefits and provide a template for the design and prioritization of future clinical trials and a roadmap for healthcare insurers to optimize coverage for patients with cancers eligible for I-O therapy.

Abstract Balancing the potential for durable remissions with autoimmune-like toxicities is a key clinical challenge in the use of immune checkpoint inhibitors (ICI). Certain toxicities are associated with an increased response rate; however, the molecular underpinnings of this association are poorly understood. Here, we report a patient with wide spread uveal melanoma who had an exceptional response to treatment with ipilimumab and nivolumab, but suffered severe immune-related sequelae, including central serous retinopathy with retinal detachment, tinnitus, and vitiligo resembling Vogt-Koyanagi-Harada disease, and refractory enteritis. TCR-sequencing of the primary tumor, a hepatic metastasis, duodenal biopsy and peripheral blood mononuclear cells, identified the identical T cell clone in all four tissues. This case provides preliminary evidence for cross-reactivity as a mechanism for the association between effect and toxicity of ICIs.

Immuno-oncologics (IOs) differ from chemotherapies as they prime the patient’s immune system to attack the tumor, rather than directly destroying cancer cells. The IO mechanism of action leads to durable responses and prolonged survival in some patients. However, providing robust evidence of the long-term benefits of IOs at health technology assessment (HTA) submission presents several challenges for manufacturers. The aim of this article was to identify, analyze, categorize, and further explore the key challenges that regulators, HTA agencies, and payers commonly encounter when assessing the long-term benefits of IO therapies. Insights were obtained from an international, multi-stakeholder steering committee (SC) and expert panels comprising of payers, economists, and clinicians. The selected individuals were tasked with developing a summary of challenges specific to IOs in demonstrating their long-term benefits at HTA submission. The SC and expert panels agreed that standard methods used to assess the long-term benefit of anticancer drugs may have limitations for IO therapies. Three key areas of challenges were identified: (1) lack of a disease model that fully captures the mechanism of action and subsequent patient responses; (2) estimation of longer-term outcomes, including a lack of agreement on ideal methods of survival analyses and extrapolation of survival curves; and (3) data limitations at the time of HTA submission, for which surrogate survival end points and real-world evidence could prove useful. A summary of the key challenges facing manufacturers when submitting evidence at HTA submission was developed, along with further recommendations for manufacturers in what evidence to produce. Despite almost a decade of use, there remain significant challenges around how best to demonstrate the long-term benefit of checkpoint inhibitor-based IOs to HTA agencies, clinicians, and payers. Manufacturers can potentially meet or mitigate these challenges with a focus on strengthening survival analysis methodology. Approaches to doing this include identifying reliable biomarkers, intermediate and surrogate end points, and the use of real-world data to inform and validate long-term survival projections. Wider education across all stakeholders—manufacturers, payers, and clinicians—in considering the long-term survival benefit with IOs is also important.

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient’s voice, and sharing evolving data to improve the management of irAEs.