OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

During the past several decades, cancer research has produced revolutionary discoveries leading to dramatic results for many patients.Many of these advances, in areas such as precision medicine and immunotherapy, have been made possible in part by investigators’ ability to study patients’ tumor samples, obtained through clinical trials or other research protocols. 

To continue advancing our understanding of cancer, we must be able to study tumor samples and clinical information from patients on a greater scale. The next wave of advances in cancer care will require aggregating and linking huge amounts of genomic, molecular, clinical, patient-reported, and experimental data from a diverse set of patients. This will help us turn our cancer care system into a learning system, enabling investigators to find patterns in data that will help lead to new discoveries and treatment strategies.

The challenge in designing such large-scale studies is that most tumors, and the associated clinical information, have not been readily available for study. This is largely because most adult patients with cancer in the United States are cared for in community settings or smaller cancer centers where this type of research is not typically done. Because of logistical, systemic, and financial barriers, these data have not routinely been accessed or collected broadly—certainly not from diverse patient populations or remote corners of the country. Most patients with cancer have never been asked whether they want to contribute their tissue samples and medical information for biomedical research. 

That situation is changing. Factors such as social media, the internet, advocacy groups, and empowered patients have presented new opportunities for patients with cancer to participate in the research process regardless of where they receive care.

Several years ago, we began exploring new models for patient-partnered cancer research. We hypothesized that the challenges in aggregating data from patients with cancer could be addressed by engaging with them directly, empowering them to share medical records, tumor samples, and personal experiences with investigators everywhere. The idea was simple: Let knowledge about every patient’s experience benefit others. 

With this in mind, we launched Count Me In, a research initiative and nonprofit organization dedicated to accelerating progress against cancer through patient-partnered research. The mission of Count Me In is to transform cancer care, empowering patients to accelerate biomedical research by sharing their samples, clinical information, and voices. 

Count Me In aims to engage hundreds of thousands of patients with all major cancer types, including rare and pediatric cancers. The goal is to create a publicly available data set of linked genomic, molecular, clinical, and patient-reported data to facilitate research. In addition, we hope to bring about a cultural shift empowering patients, investigators, and clinicians to work in partnership and accelerate medical progress. 

The program engages patients with cancer through direct interactions (ie, via social media and advocacy groups) and asks them to visit JoinCountMeIn.org to learn more. The project’s outreach program—developed in collaboration with patients, advocates, and advocacy organizations—serves to connect thousands of patients with cancer from the United States and Canada, allowing them to participate regardless of where they live (FIGURE).

Once patients have signed up on the website, they are sent an online consent form asking for permission to obtain and analyze their medical records, tumor tissue, and saliva. Once they consent, the Count Me In team requests copies of patients’ medical records from doctors’ offices/hospitals and obtains portions of tumor tissue from pathology departments in which they are stored. Patients mail in a saliva sample using a kit sent to them. They also have the option of taking a blood sample kit to their next blood draw or a local lab to have a sample drawn and sent in. 

Tumor tissue, blood, and saliva samples undergo genomic analysis in our research laboratory at the Broad Institute of MIT and Harvard, in Boston, Massachusetts. The genomic information is analyzed in the context of the clinical data to help improve our understanding of cancer. Importantly, all deidentified clinical, molecular, and genomic data generated in the project are widely available for other investigators to use—as they are generated and before publication—so that tissue and data donated by patients can be used for many research projects, breaking down silos that typically exist in cancer research.

Studying Common Cancers, Rare Cancers, and Rare Clinical Cohorts

Count Me In has registered more than 10,000 adult and pediatric patients from all 50 states and US territories and Canada. More than 5200 patients from over 1800 institutions have fully enrolled in the study, providing consent to share medical records and tumor and saliva samples. They have also agreed to have comprehensive genomic analysis performed on their samples. More than 100 different cancer types are represented, including common and rare cancers. Patients, advocates, and advocacy groups have been involved in conceiving, designing, implementing, testing, and refining this study.

Major analyses in Count Me In projects focus on genomic biomarkers associated with specific patient subgroups. Other subjects of analysis include clinical behavior, mechanisms of response and resistance, exceptional responders and long-term survivors, rare subsets and outliers, genomic landscape, tumor evolution and heterogeneity, novel drivers and targets, cancer epidemiology, and real-world patterns. Patientreported data provide the opportunity to identify and study groups of patients with rare diseases that have been particularly challenging to study using traditional approaches.

Questions we would like to be able to answer include the following:

What are the genomic and molecular underpinnings of rare cancers and rare clinical subsets? 

What are the optimal second-line therapies after first-line standard of care is exhausted? 

What explains why some patients show extraordinary responses to a particular treatment? 

What are some factors that can lead to young-onset cancer?

What are the differences in cancers for patients from underrepresented or historically excluded communities?

Within Count Me In, there are several patient-partnered genomics research projects focusing on rare, common, and pediatric cancers. Active research cohorts under investigation include metastatic breast cancer, angiosarcoma, metastatic prostate cancer, esophageal and stomach cancers, pediatric and adult brain tumors, osteosarcoma, colorectal cancer, and leiomyosarcoma. 

Data have been published from 3 of these cohorts—metastatic breast cancer, angiosarcoma, and metastatic prostate cancer—on several platforms, including the National Cancer Institute Genomic Data Commons, the database of Genotypes and Phenotypes, cBioPortal for Cancer Genomics, and through our own data browsers.

 The publicly available deidentified data have also been used in more than 50 peer-reviewed publications by investigators independent of Count Me In, highlighting the value of the data to the research community.

The potential scientific impact of the patient-partnered approach is perhaps best illustrated in angiosarcoma—an exceedingly rare, aggressive sarcoma with an annual incidence of 300 cases in the United States and a median overall survival of less than 1 year for patients with metastatic disease. Like all rare cancers, angiosarcoma has been difficult to study because of the low incidence and geographically dispersed patient population, which has resulted in significant unmet clinical needs for patients. 

In recent years, more than 650 patients with this rare cancer registered for Count Me In and consented to share records and biospecimens. In the first 18 months of the project, we performed whole-exome sequencing on 47 angiosarcoma tumor samples—the largest cohort of angiosarcomas to undergo whole-exome sequencing at that time. 

The analysis identified new recurrent mutated genes and new patterns of mutational mutual exclusivity and alterations associated with distinct angiosarcoma disease subclassifications.

 Analyses of integrated genomic and clinical data in angiosarcoma enabled several novel observations with important biological and clinical implications.

 We found recurrent noncanonical activating PIK3CA mutations almost exclusively in primary breast angiosarcoma, suggesting these patients could be amenable to treatment with PI3K inhibitors.

We also found that a high tumor mutation burden (TMB) and concomitant dominant UV damage mutational signature occurs uniquely in angiosarcoma of the head, neck, face, and scalp (HNFS), which is the most common site of origin of angiosarcoma, highlighting a previously unrecognized etiology in this angiosarcoma subtype. Like melanoma, this suggested a potential therapy for patients with HNFS angiosarcoma using immune checkpoint inhibitors (ICIs). 

In our cohort, we identified 2 patients with refractory, metastatic HNFS angiosarcoma who had received off-label anti–PD-1 therapy, both of whom had complete responses to the therapy and who remain disease-free years later. Our subsequent analysis identified that both tumors had a high TMB and UV light exposure mutational signature. These results helped catalyze the development of a clinical trial of ICIs in patients with HNFS angiosarcoma. Collectively, these analyses of integrated genomic and clinical data in angiosarcoma generated new insights into testing etiologic and therapeutic hypotheses, which was only possible through deep partnerships with patients with angiosarcoma to rapidly catalyze research in this rare cancer. The study demonstrated that empowering patients to directly participate in research can overcome barriers in rare diseases and can enable discoveries.

Enthusiasm for Patient-Partnered Genomics Research 

As we have conducted this research, we have seen a parallel emerging social movement that emphasizes this partnership between patients and researchers. There has been an organic emergence of “Count Me In selfies” on social media, including pictures of patients proudly posing with their saliva kits and encouraging others to join them. 

The partnership extends beyond social media as well. Many of the saliva kits patients have sent in are stuffed with personal notes or drawings from children. Patients and team members also frequently interact in person, via visits to our laboratories, or at national conferences and patient-focused events. 

Most cancer research has concentrated on patients with European ancestry. However, it is well known that patients from underserved communities—including Black, Hispanic/Latino, and Indigenous/American Indian populations— experience worse outcomes compared with White patients. 

Count Me In continues to work to promote equity in research and our scientific discoveries, with a particular focus on enrolling underrepresented and historically excluded patient groups. Our strategy has focused on 4 areas: building trust, transparency, and relationships in underserved communities; utilizing digital marketing and social media to reach underserved and marginalized communities; leveraging opportunities for national partnerships with well-known organizations, including our recent campaign with Stand Up To Cancer and a new partnership with American Society of Clinical Oncology’s CancerLinQ; and partnering with patients and advocates who are leading outreach efforts in communities of color. 

To date, these have been mainly grassroots activities, and we have made particularly meaningful strides in building trust and relationships in underserved communities. We recently collaborated with a community of Spanish-speaking patient advocates to translate the website, enrollment portal, consent, surveys, and all informational materials into Spanish. 

We have also launched a new social media campaign, Amplifying Black Voices Across Cancer, focused on lifting Black voices, highlighting lived experiences, and providing insight into existing cancer disparities. The website serves as a platform for Black patients with cancer to share stories, make connections, and find resources.

Further prospective profiling of clinical data and biospecimens reflecting modern treatment regimens—coupled with open data sharing—is needed to improve our understanding of cancer, to identify biomarkers of therapeutic response and resistance, to develop new treatments and treatment strategies, and to help address disparities. Partnering with patients can accelerate inclusive cancer genomics and precision medicine research, particularly the study of questions that require large numbers, studies of rare subgroups, and studies that include underrepresented or historically excluded participants.

Wagle N, Painter C, Anastasio E, et al. The metastatic breast cancer (MBC) project: accelerating translational research through direct patient engagement. J Clin Oncol. 2017;35(suppl 15):1076. doi:10.1200/JCO.2017.35.15_suppl.1076 

Barroso-Sousa R, Jain E, Cohen O, et al. Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann Oncol. 2020;31(3):387-394. doi:10.1016/j.annonc.2019.11.010 

Painter CA, Jain E, Tomson BN, et al. The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research. Nat Med. 2020;26(2):181-187. doi:10.1038/s41591-019-0749-z 

Crowdis J, Balch S, Sterlin L, et al. A patient-driven clinicogenomic partnership through the Metastatic Prostate Cancer Project. bioRxiv. Preprint posted online July 11, 2021. doi:10.1101/2021.07.09.451849

What are the genomic and molecular underpinnings of rare cancers and rare clinical subsets?  What are the optimal second-line therapies after first-line standard of care is exhausted?  What explains why some patients show extraordinary responses to a particular treatment?  What explains why some tumors never respond to a particular treatment, or why some tumors initially respond but later develop resistance? Tissue samples are identified in medical records Tissue samples are requested and received Medical records are abstracted  What are some factors that can lead to young-onset cancer? Updates and insights are provided to patient Patient-reported data are cleaned and standardized. Genomic sequencing data is standardized for platforms. Tissue, blood, saliva samples are sequenced Data are linked, de-identified, and shared ■ Patient steps Sequencing data are analyzed ■ Study team steps  What are the differences in cancers for patients from underrepresented or historically excluded communities?

Articles

Oncology Live®

During the past several decades, cancer research has produced revolutionary discoveries leading to dramatic results for many patients.

Direct Partnership With Patients  May Accelerate Cancer Research  and Precision Oncology

After nearly a decade of PD-1/PD-L1–targeting antibodies dominating the immune checkpoint inhibitor (ICI) landscape, the cancer immunotherapy field is branching out.

 In March 2022, the FDA approved the combination of nivolumab and relatlimab-rmbw (Opdualag) for the treatment of patients 12 years of age and older with unresectable or metastatic melanoma.

 Relatlimab is the first drug targeting the LAG-3 pathway to gain FDA approval.

 The fixed-dose regimen combines relatlimab, an anti–LAG-3 monoclonal antibody, with nivolumab (Opdivo), a PD-1 inhibitor approved for the treatment of 13 tumor types.

Although expanding the repertoire of ICIs has been a major research priority,

 the approval of relatlimab in the combination regimen represents just the third successfully targeted checkpoint to enter the oncology armamentarium. Of the 8 previously approved ICIs, 7 are directed at the PD-1/PD-L1 pathway and 1, ipilimumab (Yervoy), targets CTLA-4.

The regimen’s approval validates the concept of targeting LAG-3 for cancer therapeutics and is expected to generate interest in developing additional therapies directed at this checkpoint.

 More than 100 clinical trials evaluating 35 LAG-3–inhibitory drugs are ongoing.7 Although most novel agents are being evaluated in phase 1 studies, several therapies have moved into later stages of development in a range of cancer types (TABLE

LAG-3 is a type I transmembrane cell-surface protein that functions as an inhibitory coreceptor in the immune system, similar to PD-1 and CTLA-4.

 The gene that encodes LAG-3 was identified in 1990 by Frédéric Triebel, MD, PhD, and colleagues at Gustave Roussy in Villejuif, France, through analysis of complementary DNA clones expressed in an IL-2–dependent CD3-negative natural killer–cell line. They observed that the 

 gene encodes a membrane protein with 4 extracellular immunoglobulin superfamily domains.

Investigators have described the role that LAG-3 and other inhibitory immune checkpoints play in cancer in the context of T-cell exhaustion. When T cells undergo prolonged exposure to an antigen, such as neoantigens expressed on cancer cells, they become desensitized and less able to activate and multiply in the presence of the antigen, a state called T-cell exhaustion.

 Exhausted T cells may also downregulate production of tumor-killing cytokines.

 Increased expression of inhibitory receptors such as LAG-3 is also associated with T-cell exhaustion.

 LAG-3 limits activation of T cells, reducing their ability to attack and destroy tumor cells, whereas inhibition of LAG-3 restores T-cell functioning.

Research has shown that levels of LAG-3 expression and infiltration of LAG-3–positive cells in tumors correlate with unfavorable clinical outcomes, tumor progression, and poor prognosis in a range of cancer types, including colorectal cancer, renal cell carcinoma, lymphomas, breast cancer, non–small cell lung cancer (NSCLC), and head and neck squamous cell carcinoma (HNSCC).

 Investigators initially studied LAG-3 inhibition as monotherapy but found that a single-agent strategy had limited efficacy. Rather, targeting LAG-3 in combination therapy has proven more effective.

 Investigators showed in mouse models that dual blockade of LAG-3 and PD-1 receptors resulted in synergistic activity to decrease tumor growth and promote antitumor immunity.

 Although further research is needed to delineate the exact mechanism underlying this synergy, it may be due to differences in inhibitory mechanisms and/or expression profiles of LAG-3 and PD-1.

Since his discovery, Triebel has continued to explore the therapeutic potential of LAG-3 inhibition at Immutep SA, a biotechnology company that he founded.

, Triebel discussed the rationale behind dual checkpoint inhibition in melanoma. “The hope is to have more patients responding to anti–PD-1 therapy,” he said.

 Triebel now serves as chief medical officer and chief scientific officer at Immutep.

Although ICIs have improved outcomes in a broad range of tumor types, treatment resistance poses a significant challenge. Most patients do not respond to treatment with ICIs, exhibiting primary resistance, and many patients who initially respond eventually relapse due to acquired resistance.

 The need to improve responses with fewer adverse effects (AEs) is helping to fuel research efforts to develop therapies targeting novel immune coreceptors.

“We have to find new pathways, inhibitory pathways, and LAG-3 is certainly an immune checkpoint now validated through phase 3,” Triebel said in an interview with BioSpace in December 2021 in reference to nivolumab/ relatlimab data.

The FDA approval of the nivolumab-relatlimab combination therapy was based on findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922).

 This global, double-blind trial compared the fixed-dose combination of relatlimab plus nivolumab against nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. Eligible patients were at least aged 12 years with measurable stage III or IV melanoma per RECIST 1.1. LAG-3 and PD-L1 had to be evaluable in tumor tissue, and patients were stratified for each biomarker based on level of expression (≥ 1% or < 1%) as determined via immunohistochemistry.

From May 2018 through December 2020, 714 patients were randomly assigned to receive relatlimab-nivolumab (n = 355) or nivolumab alone (n = 359). Patients received relatlimab 160 mg and nivolumab 480 mg intravenously in a fixed-dose combination or 480 mg of nivolumab.

 The primary end point of the study was progression-free survival (PFS), and secondary end points included overall survival (OS) and objective response rate (ORR).

After a median follow-up of 13.2 months, the median PFS was 10.1 months (95% CI, 6.4-15.7) in the relatlimab-nivolumab group compared with 4.6 months (95% CI, 3.4-5.6) in the nivolumab-alone group (HR for progression or death, 0.75; 95% CI, 0.62-0.92; log-rank 

 = .006). The 12-month PFS rate was 47.7% (95% CI, 41.8%-53.2%) in the relatlimab-nivolumab group compared with 36.0% (95% CI, 30.5%-41.6%) in the nivolumab group.

The ORR was 43% (95% CI, 38%-48%) in the relatlimab-nivolumab arm vs 33% (95% CI, 28%-38%) with nivolumab alone. Median OS was not reached (NR; 95% CI, 34.2-NR) with the combination compared with 34.10 months (95% CI, 25.2-NR) for nivolumab alone. OS was numerically superior in the combination group (HR, 0.80; 95% CI, 0.64-1.01), but the difference did not achieve statistical significance at the trial’s alpha threshold of 

Data from exploratory analyses indicated that PFS favored combination therapy vs monotherapy in prespecified subgroups. Patients with traits commonly associated with worse prognosis, such as visceral metastases, high tumor burden, elevated lactate dehydrogenase levels, or mucosal or acral melanoma, had better outcomes with relatlimab-nivolumab than with nivolumab alone.

In terms of LAG-3, patients with expression of 1% or greater had longer median PFS in both treatment groups, and participants treated with the combination had better PFS regardless of LAG-3 expression level. At the same time, the median PFS with relatlimab-nivolumab was greater than with nivolumab monotherapy for those with LAG-3 of 1% or more (12.58 vs 4.76 months, respectively) than for patients with LAG-3 less than 1% (4.83 vs 2.79 months, respectively).

However, these trends were not seen in the PD-L1 data. Median PFS was similar in patients whose tumors had PD-L1 expression of 1% or greater for combination therapy compared with nivolumab alone (15.7 months vs 14.7 months, respectively). For participants with PD-L1 expression of less than 1%, median PFS was 6.4 months (95% CI, 4.6-11.8) with the combination and 2.9 months (95% CI, 2.8-4.5) for nivolumab alone (HR, 0.66; 95% CI, 0.51-0.84).

The RELATIVITY-047 investigators concluded that neither biomarker was clearly useful in selecting patients for ICI therapy. In terms of AEs, 18.9% of the patients in the relatlimab-nivolumab group experienced grade 3 or 4 treatment-related AEs (TRAEs) compared with 9.7% of the nivolumab-alone group. The most frequent grade 3 or 4 TRAEs in the relatlimab-nivolumab group included increased levels of lipase, alanine aminotransferase, and aspartate aminotransferase (1.7%, 1.4%, and 1.4% of patients, respectively), as well as fatigue (1.1%).

Furthermore, 14.6% of patients in the relatlimab-nivolumab group discontinued treatment due to TRAEs compared with 6.7% in the nivolumab group, but no new safety signals were identified with relatlimab-nivolumab treatment.

Three treatment-related deaths occurred in the combination-therapy group (0.8%) and 2 in the monotherapy group (0.6%).

Although OS data from RELATIVITY-047 are not yet mature, results so far suggest that the relatlimab-nivolumab combination could become the new frontline standard of care for patients with advanced melanoma.19 In this clinical setting, the median PFS associated with the relatlimab-nivolumab regimen has been similar to that seen with the combination of nivolumab plus ipilimumab, the current first-line standard, in the CheckMate 067 trial (NCT01844505), but with a lower incidence of grade 3 or 4 TRAEs (19% with relatlimab-nivolumab vs 59% with nivolumab-ipilimumab).

However, the long-term OS results with the nivolumab-ipilimumab combination have set the bar high. After a minimum follow-up of 6.5 years, the median OS reached an unprecedented 72.1 months (95% CI, 38.2-NR) in CheckMate 067.

The nivolumab-ipilimumab results represent the longest median OS reported in a phase 3 advanced melanoma study, CheckMate 067 investigators said. The milestone is “staggering” and sets a benchmark for judging whether relatlimab-nivolumab will be a new standard for previously untreated patients, according to a commentary in the 

Longer-term data also may clarify the role of LAG-3 expression as a biomarker in guiding therapy for patients.

 Although higher LAG-3 expression correlated with longer median PFS in the RELATIVITY-047 trial, a recent study in NSCLC described a negative association between LAG-3 expression and response to anti–PD-1 therapy. The study evaluated LAG-3, PD-1, and TIM-3 protein expression in NSCLC tissue specimens. Investigators found that patients whose tumor samples had elevated LAG-3 expression were less susceptible to PD-1 inhibitors (associated with a shorter PFS). More research is needed to fully delineate the association between expression of these biomarkers and treatment response in patients with cancer.

Investigators are exploring several novel strategies to target LAG-3 besides monoclonal antibodies, including bispecific antibodies directed at PD-1/PD-L1 in addition to LAG-3. Based on where antibodies bind to LAG-3, they can alter its interactions with its ligands in different ways.

One novel candidate, tebotelimab, is a PD-1/ LAG-3 bispecific antibody that inhibits both checkpoints on a single T cell.4 MacroGenics, Inc, the company developing the drug, plans to study tebotelimab in combination with a cell-killing antibody specific to tumor cells. However, in July 2022, the company closed a phase 2 study (NCT04634825) evaluating enoblituzumab, a B7-H3 mAb, plus tebotelimab or retifanlimab, a PD-1 inhibitor, in recurrent or metastatic HNSCC after 7 fatalities potentially associated with hemorrhagic events, including 1 possibly related to the study treatment, were reported among 62 participants.

Roche’s candidate, RG6139, is also a bispecific antibody that targets PD-1 and LAG-3. This agent has higher affinity for PD-1 than for LAG-3, causing it to preferentially target tumor-infiltrating activated T cells rather than regulatory T cells.

Merck is developing favezelimab (MK-4280), a humanized anti–LAG-3 monoclonal antibody, as combination therapy with pembrolizumab (Keytruda), a PD-1 inhibitor, to treat hematologic malignancies and solid tumors including NSCLC, small cell lung cancer, renal cell carcinoma, and colorectal cancer.

 The combination, called MK-4280A, has advanced to the phase 3 MK-4280A-007 study (NCT05064059) in patients with previously treated, metastatic, PD-L1–positive colorectal cancer.

At the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, investigators reported data from a different MK-4280A trial, an ongoing phase 1/2 study (NCT03598608) evaluating the combination in hematologic malignancies. In a cohort of 29 patients with relapsed classical Hodgkin lymphoma refractory to anti–PD-1 therapy who received the recommended phase 2 dose of 800 mg favezelimab plus 200 mg pembrolizumab every 3 weeks, the ORR was 31% (95% CI, 15%-51%) at a median follow-up of 16.5 months. This included 2 compete responses and 7 partial responses.

Immutep Limited’s candidate, eftilagimod alpha, is a soluble LAG-3 fusion protein that binds major histocompatibility complex class II proteins on the surface of antigen-presenting cells (APCs) to modulate APCs and CD8 T cells.

 Unlike LAG-3 inhibitors, eftilagimod alpha does not bind to LAG-3 on the T cell; instead, the agent “pushes the accelerator on the immune response” by activating APCs and increasing the supply of activated T cells. Investigators theorize that enhanced T-cell activation may result in an improved response to PD-1/PD-L1 inhibitors.

Eftilagimod alpha was evaluated in HER2negative/hormone receptor–positive metastatic breast cancer previously treated with endocrine therapy in the phase 2b AIPAC study (NCT02614833). Patients received either eftilagimod plus paclitaxel or paclitaxel alone. The combination therapy led to a nonsignificant increase in OS in the overall population of 226 evaluable patients. The median OS was 20.4 months (95% CI, 14.3-25.1) in the eftilagimod-paclitaxel group vs 17.5 months (95% CI, 12.9-21.9) in the paclitaxel group (HR, 0.88; 95% CI, 0.64-1.19; 

 = .197). However, median OS was significantly improved with eftilagimod-paclitaxel therapy in 3 subgroups: patients who were younger than 65 years, had low baseline monocytes (< 250/µL), or had the more aggressive luminal B subtype, with HRs of 0.66, 0.44, and 0.67, and 

 values of .017, .008, and .049, respectively.

Eftilagimod alpha also is being studied in combination with pembrolizumab in patients with NSCLC and HNSCC. At the 2021 ASCO Annual Meeting, Immutep reported interim results from the phase 2 TACTI-002 trial (NCT03625323). The ORR was 41.7% for firstline treatment of 36 patients with NSCLC and 29.7% for second-line treatment of 37 patients with HNSCC. These results reflect an improvement compared with anti–PD-1 monotherapy for first-line NSCLC, investigators said.

The exciting results in first-line NSCLC prompted an expansion of this cohort, and updated findings were presented at the 2022 ASCO Annual Meeting. After a median follow-up of 11.2 months, the ORR by iRECIST criteria (modified RECIST 1.1 for immune-based therapeutics) was 38.6% (95% CI, 29.6%-48.2%) in 114 patients in the intention-to-treat population and 42.7% (95% CI, 33.0%-52.9%) in 103 participants evaluable for response (≥ 1 on-study tumor staging after baseline).

Patients were not selected for the study based on PD-L1 expression status, but results were stratified by 5 tumor proportion score (TPS) groups (< 1%, 1% to 49%, ≥ 50%, ≥ 1%, and < 50%). Approximately 70% of trial participants had a TPS of less than 50%. Responses were observed across all PD-L1 expression subgroups, with higher ORRs in patients with higher PD-L1 expression. The ORR was 52.6 % (95% CI, 28.9%75.6%) in 19 patients with a TPS of 50% or greater by central assessment and 51.6% (95% CI, 33.1%-69.9%) in 31 patients assessed for PD-L1 status both centrally and locally.

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A study of coformulated favezelimab/pembrolizumab (MK-4280A) versus standard of care in subjects with previously treated metastatic PD-L1 positive colorectal cancer (MK-4280A-007). ClinicalTrials.gov. Updated June 16, 2022. Accessed June 21, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05064059?term=NCT05064059&draw=2&rank=1

Felip E, Majem M, Doger B, et al. A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: updated results from a PD-L1 unselected population. 

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Wildiers H, Dirix L, Armstrong A, et al. Final results from AIPAC: a phase IIb comparing eftilagimod alpha (a soluble LAG-3 protein) vs. placebo in combination with weekly paclitaxel in HR+ HER2- MBC. 

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Immutep reports positive data from its TACTI-002 phase II study of LAG-3 therapy, Efti, at ASCO 2021. News release. Immutep Limited. June 2, 2021. Accessed May 31, 2022. 

The LAG-3 pathway has emerged as the next target for the use of immune checkpoint inhibitors in oncology.

LAG-3 Fills a Complex Role  in the Immune System

Despite significant advances in donor selection, conditioning regimens, and supportive care, graft-vs-host disease (GVHD) continues to afflict 30% to 50% of patients who undergo allogeneic hematopoietic cell transplantation (AHCT).

GVHD occurs when immunocompetent T lymphocytes in the graft attack immunodeficient tissues of the AHCT recipient within 100 days of transplantation because of histocompatibility differences, leading to tissue damage and significant transplant- related morbidity and mortality.

There is a significant unmet need in effectively treating chronic GVHD. “Unfortunately, when we see patients with chronic GVHD in the clinic, we still are treating them with steroids in the first line, just like in the acute setting.…That treatment strategy hasn’t changed in a couple of decades,” 

Chen was joined by a panel of hematology experts who discussed use of steroids in the first-line setting as well as several subsequent-line treatments that have recently received FDA approval for patients with steroid-refractory chronic GVHD, which affects up to 50% of patients.

 They provided an overview of the clinical trial data that led to these agents’ approval and shared how they sequence these agents at their institutions.

Steroids for First-Line Treatment of Chronic GVHD

The initial choice for treating chronic GVHD is a systemic steroid, frequently prednisone, administered at a dose between 0.5 and 1 mg/ kg daily. This can be difficult on patients, Chen said. “Some [patients] have been on steroids in the past for acute GVHD and adding steroids again at that juncture often creates a lot of morbidity...which can present as anything from infections to changes in bone health, hypertension, mood swings, and so forth,” he explained. Subsequently, there has been a push to improve steroid administration and identify alternative treatment options for patients with chronic GVHD.

One area of research involves using GVHD biomarkers to identify high-risk patients for intervention before they become symptomatic. “We need to do the same approach as we have done for acute GVHD, to get the response to treatment and get the samples after you start a treatment,” 

, said. The panelists noted that several ongoing studies are seeking to identify predictive biomarkers and encouraged clinicians to commit any available samples from patients to such research. GVHD is a heterogeneous disease affecting a wide range of organ systems; a broad range of biomarkers is likely to have prognostic, diagnostic, or predictive value. Another important issue the panelists discussed is knowing when to initiate a secondline therapy. 

, said clinical f indings are sometimes not obvious or particularly remarkable; quality of life and performance status are key components of knowing when additional treatment is necessary. “Usually, the patient will tell you…they’re probably the best markers,” Chao said. Nevertheless, tools are available to help identify early symptoms, such as the National Institutes of Health consensus criteria measurements and the modified Lee Symptom Scale.

Newly Approved Treatments for Steroid-Refractory Chronic GVHD

Since 2017, 3 agents have received FDA approval to treat chronic GVHD, including ruxolitinib (Jakafi), belumosudil (Rezurock), and ibrutinib (Imbruvica), each of which has a unique mechanism of action and drug profile (

Ruxolitinib is a JAK inhibitor that selectively inhibits JAK1 and JAK2, mediating the signaling of the JAK-STAT pathways that play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis (eg, inflammatory cytokines).

 The approval of ruxolitinib was based on data from the phase 3, open-label REACH3 trial (NCT03112603), which randomly assigned 329 patients aged at least 12 years with moderate or severe glucocorticoid-refractory or glucocorticoid-dependent chronic GVHD 1:1 to receive ruxolitinib 10 mg twice daily (n = 165) or best available therapy (BAT; n = 164).

“BAT in this case was an investigator’s choice of 10 commonly used immunosuppressive or chronic GVHD therapies, which for the most part was ECP [extracorporeal photopheresis], mycophenolate, and ibrutinib, but also included infliximab [Remicade], pentostatin [Nipent], and others,” 

, said. She noted that the patients in the trial were not heavily pretreated. “Most of the patients had only received corticosteroids or calcineurin inhibition. Only roughly 14% to 15% had received an additional systemic therapy on top of that,” she said.

At week 24, the overall response rate (ORR) was 49.7% in the ruxolitinib arm and 25.6% in the BAT arm (odds ratio [OR], 2.99; 

 Most responses were partial responses (PRs); however, 11 patients (6.7%) in the ruxolitinib arm had a complete response (CR) vs 5 (3.0%) patients in the BAT arm. A higher ORR was observed with ruxolitinib than BAT regardless of the organs involved. Ruxolitinib vs BAT led to a median failure-free survival (FFS) of 18.6 and 5.7 months, respectively (HR, 0.37; 

 < .001), and a higher symptom response rate of 24.2% vs 11.0%, respectively (OR, 2.62; 

 = .001). “It was the first big step for chronic GVHD to finally get phase 3–level support for FDA approval,” Choe said. Based on the REACH-3 data, Chen said ruxolitinib has become the standard second-line treatment at his institution for patients with chronic GVHD.

More recent reports have shown additional benefits with ruxolitinib. Data from a presentation at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in 2021 showed that ruxolitinib resulted in substantial improvements in patient-reported outcomes vs BAT. Categories included continued symptom improvement and benefits across chronic GVHD–specific modified Lee symptom subscales.

 Additionally, patients reported greater improvements in organ-specific symptoms with ruxolitinib, a finding consistent with physician-assessed objective organ responses, which also favored ruxolitinib. More recent reports have shown additional benefits with ruxolitinib.

Unlike belumosudil and ibrutinib, ruxolitinib has also been approved by the FDA for the treatment of steroid-refractory acute GVHD.

 A presentation at the European Hematology Association 2021 Virtual Congress reported high response rates with ruxolitinib among the patients with steroid-refractory acute GVHD in the REACH2 trial (NCT02913261) who crossed over from BAT to ruxolitinib (n = 49/309).

 At day 28 after crossover, ORR was 67.3% (95% CI, 52.5%-80.1%), with 23 (46.9%) CRs and 10 (20.4%) PRs. At day 56 after crossover, durable ORR was 42.9% (95% CI, 28.8%57.8%), with 19 (38.8%) CRs and 2 (4.1%) PRs. These findings were consistent with observations in the ruxolitinib arm at the primary analysis. Collectively, these data in combination with the REACH3 data in patients with chronic GVHD lend support for using ruxolitinib in patients with steroid-refractory GVHD who previously failed treatment with other systemic therapies.

Belumosudil stems profibrotic activity by inhibiting ROCK2—rho-associated, coiled-coil containing protein kinase 2—thereby controlling inflammatory T helper 17 (Th17) cells while enhancing regulatory T cells. Because of its mechanism of action, belumosudil is expected to control chronic GVHD without significantly increasing immunosuppression.

Belumosudil was approved based on data from the phase 2 ROCKstar study (NCT03640481). This open-label, dose-ranging trial included 66 patients with chronic GVHD treated with belumosudil 200 mg once daily, which became the FDA-approved dose, and 66 patients treated with 200 mg twice daily.

 “The study was well designed but it wasn’t a randomized trial. The investigators didn’t feel it could be randomized because these patients had failed at least 2 different lines of therapy,” Chao said.

ROCKstar’s primary end point was best ORR, which was 74% for belumosudil 200 mg daily (95% CI, 62%-84%) and 77% for belumosudil 200 mg twice daily (95% CI, 65%-87%), with high response rates observed in all subgroups. The median duration of response was 54 weeks, with 44% of patients on therapy for at least 1 year. Symptom reduction was reported in 59% of patients treated with the once-daily dose vs 62% of those treated with the twice-daily dose.

“What was most interesting to me was the toxicity profile, which was quite impressive. It was well tolerated. As with ibrutinib, we must see what it’s going to look like in the real world as [patients] start to use it,” Chao said.

In ROCKstar, the median relative dose intensity (RDI), used as a surrogate measure of drug tolerability, was 99.7%, with 81% of patients receiving an RDI greater than 95%. RDI was defined as actual dose intensity/planned dose intensity, with dose intensity being the cumulative dose/duration of exposure (mg/d).

Although the 200-mg twice-daily dose was associated with higher responses in certain organs, including the skin, and slightly fewer adverse effects (AEs), the difference in safety and efficacy was not deemed significant. Subsequently, the lower dose of 200 mg once daily was chosen as the recommended dosage.

In a presentation at the 63rd ASH Annual Meeting and Exposition, treatment with belumosudil resulted in high FFS rates vs historic benchmarks in chronic GVHD after failure of 1 to 3 lines of systemic therapy.

 The median FFS for all doses was 14 months. Among patients who received the recommended 200-mg belumosudil dose once daily, the Kaplan-Meier estimate of FFS was 75% at 6 months (95% CI, 64%-83%), 56% at 12 months (95% CI, 45%-66%), and 37% at 24 months (95% CI, 23%-52%).

Ibrutinib inhibits inducible T-cell kinase (ITK) and Bruton tyrosine kinase (BTK). “Basically, ITK is on the T cell and BTK is on the B cell,” Paczesny said.

Approval of ibrutinib as a treatment for chronic GVHD was based on the phase 1b/2 PCYC1129-CA study (NCT02195869), an open-label, multicenter, single-arm clinical trial enrolling 42 patients with chronic GVHD who required additional therapy after failure of first-line corticosteroid therapy.

 “[Ibrutinib] was the first FDA approval based on a small clinical trial, with some efficacy in the second line. That was the first improvement in the first FDA-approved drug in the field, even before acute GVHD,” Paczesny said.

All patients in PCYC-1129-CA were treated with ibrutinib 420 mg daily until GVHD progression. The primary end point was chronic GVHD response based on the 2005 National Institutes of Health criteria.

After a median follow-up of 13.9 months, the best overall response was 67%. Among responders, 71% had a sustained response lasting at least 20 weeks. All organs assessed showed response, and most patients with chronic GVHD affecting multiple organs showed multiorgan response. At week 49, the median corticosteroid dose in responders decreased from 0.29 mg/kg daily at baseline to 0.12 mg/kg daily, with 5 responders discontinuing corticosteroids.

“[Ibrutinib is] maybe a little more difficult to give, and there’s some toxicity, so it seems that ruxolitinib is better tolerated and [individuals] will go more often to ruxolitinib rather than ibrutinib. In pediatrics, ibrutinib is still used and can help some patients,” Paczesny said.

In 2019, the 1-year update of PCYC-1129-CA was published, reaffirming the clinically meaningful benefit of ibrutinib and its acceptable safety profile.

 At a median follow-up of 26 months, the best ORR was 69% (29 of 42 patients), with 31% (n = 13) achieving a CR and 38% (n = 16) achieving a PR. Sustained responses were seen in 69% of patients (n = 20) for at least 20 weeks, 62% (n = 18) for at least 32 weeks, and in 55% (n = 16) for at least 44 weeks. Among the patients with multiorgan involvement, 73% (19 of 26) with at least 2 organs affected showed responses in 2 or more organs and 60% (6 of 10) with 3 or more organs affected showed responses in at least 3 organs. Additionally, 61% (11 of 18) of patients with sclerosis at baseline showed a sclerotic response, 39% with a CR and 22% with a PR. Reductions in corticosteroid dose to less than 0.15 mg/kg daily were observed in 64% of all study patients (N = 42), with 8 discontinuing corticosteroid treatment and remaining off corticosteroids at study closure.

Sequencing Treatment for Steroid-Refractory GVHD

“We’ve been excited about the fact that we have ruxolitinib and belumosudil as options for patients. They have decently durable responses and give patients an improvement in quality of life,” Choe said. She noted that belumosudil’s favorable response rate even in patients who experienced treatment failure with ruxolitinib is encouraging; the expectation has been that failure of one therapy usually leads to a lower response rate with subsequent treatments.

“In this case, we can give ruxolitinib first. We have more experience with it because it’s been used off-label for much longer. Then we can transition to belumosudil in case of failure or intolerance [and] can still potentially get another year of response with belumosudil with a response rate of 68%. It’s nice to have that in our armamentarium for these patients,” she said.

Chen and Chao agreed with this approach; however, Chao said in patients with skin involvement, his institution (Duke Cancer Institute) primarily uses ECP. In contrast, Choe said her institution (The Ohio State University Comprehensive Cancer Center) places belumosudil before ECP. She also emphasized the importance of considering the AE profile when selecting between the FDA-approved agents. “Ruxolitinib and belumosudil are very well tolerated, but the cytopenias with ruxolitinib can be difficult,” she said.

Subsequently, if she is concerned about cytopenias in patients, she will select belumosudil over ruxolitinib.

The panelists said they are eagerly anticipating real-world data to help guide treatment decision-making, including optimal treatment sequencing, use of combination treatments, and how and when to taper patients off treatments. “Not only do we not know how long we use these agents for—it’s usually guided by how our patients are doing—but when we transition, we also don’t know whether to stop or decrease. If we’re tapering, we don’t know how long to taper. Hopefully real-world experience will shed some more light on it,” Chen said.

Hamilton BK. Updates in chronic graft-versus-host disease. 

. 2021;2021(1):648654. doi:10.1182/hematology.2021000301

Justiz Vaillant AA, Modi P, Mohammadi O. Graft versus host disease. In: StatPearls [Internet]. StatPearls Publishing; January 2022. Updated May 1, 2022. Accessed June 14, 2022. bit.ly/3ACTvw4

Wolff D, Fatobene G, Rocha V, et al. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. 

A panel of hematology experts discuss use of steroids in the first-line setting as well as several subsequent-line treatments that have recently received FDA approval for patients with steroid-refractory chronic GVHD, which affects up to 50% of patients.

Vol. 23/No. 14 | Oncology Live®

Direct Partnership With Patients May Accelerate Cancer Research and Precision Oncology

LAG-3 Fills a Complex Role in the Immune System

New Approvals Help Fill Unmet Need in Treating Chronic GVHD

Immune Checkpoint Inhibitors at ASCO: Long-term Efficacy Data Mount

Is It Time to Formally Recognize That PFS Is More Than a "Surrogate" End Point?