On June 3, 2022 Kite, a Gilead Company (Nasdaq: GILD), reported findings from a safety and efficacy retrospective analysis by race and ethnicity from the ongoing post-authorization study of Yescarta (axicabtagene ciloleucel) in adult patients with relapsed or refractory large B-cell lymphoma (LBCL) (Press release, Kite Pharma, JUN 3, 2022, View Source [SID1234615544]). In the largest real-world analysis of its kind evaluating data from the CIBMTR (Center for International Blood and Marrow Transplant Research), overall outcomes including overall survival (OS) and progression-free survival (PFS) rates were consistent with Yescarta in the real-world setting, regardless of race and ethnicity. The findings were presented today in an oral session during the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Abstract #7571).

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The incidence of diffuse LBCL in the U.S. is 4.8 per 100,000 per year in non-Hispanic Black or African Americans and 7.1 per 100,000 per year in non-Hispanic Whites. Clinical trials of Yescarta in the U.S. have enrolled an average of 6% Black or African American patients, consistent with the roughly 5% of patients in the real-world CIBMTR registry.* Further research is ongoing to investigate whether or not there is under-representation by race and ethnicity in both clinical trials and the real-world usage of CAR T-cell therapy.

"The investigation of CAR T-cell therapy outcomes by race and ethnicity is important to the continued understanding of the impact of these innovative therapies, and an area in which there is a significant deficit in clinical trials and real-world studies published to date," said Frederick L. Locke, MD, lead author and Co-Leader of the Immuno-Oncology Program at Moffitt Cancer Center, Tampa, Florida. "The results of this analysis are encouraging in that axi-cel was safe and effective regardless of race or ethnicity, and also warrant further investigation to understand the lower rate of response among Black or African American patients and the potential role of factors such as higher disease burden, disease biology and, importantly, differential access to care."

A total of 1,389 adult patients with LBCL treated with Yescarta in the commercial setting in the U.S. from October 2017 to August 2020 were included in the analysis. Race and ethnicity (Hispanic or Latino vs. not Hispanic or Latino) were self-reported and included: White (81%); Black or African American (5%); Asian (6%); American Indian or Alaska Native <1%; Native Hawaiian or other Pacific Islander <1%; More than one race <1%; Race not reported (7%). Eleven percent of patients evaluated self-identified as Hispanic or Latino.

At a median follow-up of 12.7 months, outcomes for objective response rate (ORR), complete response (CR), duration of response (DOR) at 6 months, PFS at 12 months, and OS were as follows:

Black or
African American

Asian

White

Hispanic
or Latino

Objective response rate (ORR)

57%

67%

74%

73%

Complete response (CR)

45%

53%

57%

55%

Duration of response (DOR; 6-month)

66%

81%

70%

71%

PFS at 12 months

36%

55%

48%

50%

OS at 12 months

62%

65%

63%

65%

Multivariable analyses found no statistical differences in OS and PFS across races. Efficacy outcomes across patients who were Hispanic or Latino and not Hispanic or Latino were also consistent. Among Black or African American patients, ORR and CR were lower compared to White patients [(Odds Ratio (OR) 0.40; 95% Confidence Interval [CI], 0.24–0.69) and (OR 0.55; 95% CI 0.32–0.93), respectively]. Black or African American patients, compared to White patients, were more likely to have moderate to severe pulmonary impairment (41% vs. 28%) and tended to have a longer time from diagnosis to infusion of Yescarta (≥12 months: 71% vs. 59%). DOR rates among Asian patients were more favorable compared to both White patients (Hazard Ratio (HR) 0.46; 95% CI 0.24–0.87) and Black or African American patients (HR 0.39; 95% CI 0.17–0.88). No differences in cytokine release syndrome (CRS; any grade) and Grade ≥3 CRS by race and ethnicity were observed. Asian patients (OR 0.52; 95% CI 0.29–0.96 vs. White) and Hispanic or Latino patients (OR 0.51; 95% CI 0.31–0.85 vs. not Hispanic or Latino) experienced a lower risk of Grade ≥3 ICANS (ASTCT consensus grade).

"As the global leader in CAR T-cell therapy, it is important to Kite that we support research to help better understand outcomes of CAR T-cell therapy across different races and ethnicities," said Frank Neumann, MD, PhD, SVP & Global Head of Clinical Development, Kite. "Through ongoing data generation, increasing diversity in Kite’s clinical trials, and partnerships with patient advocacy organizations and community partners to reduce barriers to care, we are actively working to increase our understanding of CAR T-cell therapy in diverse populations and treatment settings."

Yescarta was the first CAR T-cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy. Yescarta was also approved by the FDA in April 2022 as the first CAR T-cell therapy for adult patients with LBCL that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy. The Yescarta U.S. Prescribing Information has a BOXED WARNING for the risks of CRS and neurologic toxicities, and Yescarta is approved with a Risk Evaluation and Mitigation Strategy (REMS) due to these risks; see below for Important Safety Information.

*Average is based on combined enrollment in ZUMA-1 and ZUMA-7 trials. Terminology for self-reporting of race has changed during the time period of these trials.

About LBCL

Globally, LBCL is the most common type of non-Hodgkin lymphoma (NHL). In the United States, more than 18,000 people are diagnosed with LBCL each year. The incidence of diffuse LBCL per 100,000 people per year in the U.S. is 4.8 in non-Hispanic Black or African American, 7.1 in non-Hispanic White, 6.8 in Hispanic or Latino, and 5.9 in Asian/Pacific Islander populations, respectively.

About Yescarta

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

YESCARTA is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

Limitations of Use: YESCARTA is not indicated for the treatment of patients with primary central nervous system lymphoma.
Adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on the response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).
U.S. IMPORTANT SAFETY INFORMATION

BOXED WARNING: CYTOKINE RELEASE SYNDROME AND NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving YESCARTA. Do not administer YESCARTA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving YESCARTA, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with YESCARTA. Provide supportive care and/or corticosteroids as needed.
YESCARTA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program.
CYTOKINE RELEASE SYNDROME (CRS)

CRS, including fatal or life-threatening reactions, occurred. CRS occurred in 90% (379/422) of patients with non-Hodgkin lymphoma (NHL), including ≥ Grade 3 in 9%. CRS occurred in 93% (256/276) of patients with large B-cell lymphoma (LBCL), including ≥ Grade 3 in 9%. Among patients with LBCL who died after receiving YESCARTA, 4 had ongoing CRS events at the time of death. For patients with LBCL in ZUMA-1, the median time to onset of CRS was 2 days following infusion (range: 1-12 days) and the median duration was 7 days (range: 2-58 days). For patients with LBCL in ZUMA-7, the median time to onset of CRS was 3 days following infusion (range: 1-10 days) and the median duration was 7 days (range: 2-43 days). CRS occurred in 84% (123/146) of patients with indolent non-Hodgkin lymphoma (iNHL) in ZUMA-5, including ≥ Grade 3 in 8%. Among patients with iNHL who died after receiving YESCARTA, 1 patient had an ongoing CRS event at the time of death. The median time to onset of CRS was 4 days (range: 1-20 days) and the median duration was 6 days (range: 1-27 days) for patients with iNHL.

Key manifestations of CRS (≥ 10%) in all patients combined included fever (85%), hypotension (40%), tachycardia (32%), chills (22%), hypoxia (20%), headache (15%), and fatigue (12%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, cardiac failure, respiratory failure, cardiac arrest, capillary leak syndrome, multi-organ failure, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events, CRS occurred in 93% (38/41), including 2% (1/41) with Grade 3 CRS; no patients experienced a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1-8 days) and the median duration of CRS was 7 days (range: 2-16 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Thirty-one of the 39 patients (79%) developed CRS and were managed with tocilizumab and/or therapeutic doses of corticosteroids with no patients developing ≥ Grade 3 CRS. The median time to onset of CRS was 5 days (range: 1-15 days) and the median duration of CRS was 4 days (range: 1-10 days). Although there is no known mechanistic explanation, consider the risk and benefits of prophylactic corticosteroids in the context of pre-existing comorbidities for the individual patient and the potential for the risk of Grade 4 and prolonged neurologic toxicities.

Ensure that 2 doses of tocilizumab are available prior to YESCARTA infusion. Monitor patients for signs and symptoms of CRS at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

NEUROLOGIC TOXICITIES

Neurologic toxicities (including immune effector cell-associated neurotoxicity syndrome) that were fatal or life-threatening occurred. Neurologic toxicities occurred in 78% (330/422) of all patients with NHL receiving YESCARTA, including ≥ Grade 3 in 25%. Neurologic toxicities occurred in 87% (94/108) of patients with LBCL in ZUMA-1, including ≥ Grade 3 in 31% and in 74% (124/168) of patients in ZUMA-7 including ≥ Grade 3 in 25%. The median time to onset was 4 days (range: 1-43 days) and the median duration was 17 days for patients with LBCL in ZUMA-1. The median time to onset for neurologic toxicity was 5 days (range: 1-133 days) and the median duration was 15 days in patients with LBCL in ZUMA-7. Neurologic toxicities occurred in 77% (112/146) of patients with iNHL, including ≥ Grade 3 in 21%. The median time to onset was 6 days (range: 1-79 days) and the median duration was 16 days. Ninety-eight percent of all neurologic toxicities in patients with LBCL and 99% of all neurologic toxicities in patients with iNHL occurred within the first 8 weeks of YESCARTA infusion. Neurologic toxicities occurred within the first 7 days of infusion for 87% of affected patients with LBCL and 74% of affected patients with iNHL.

The most common neurologic toxicities (≥ 10%) in all patients combined included encephalopathy (50%), headache (43%), tremor (29%), dizziness (21%), aphasia (17%), delirium (15%), and insomnia (10%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events, including aphasia, leukoencephalopathy, dysarthria, lethargy, and seizures occurred. Fatal and serious cases of cerebral edema and encephalopathy, including late-onset encephalopathy, have occurred.

The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in 2 subsequent cohorts of LBCL patients in ZUMA-1. Among patients who received corticosteroids at the onset of Grade 1 toxicities, neurologic toxicities occurred in 78% (32/41), and 20% (8/41) had Grade 3 neurologic toxicities; no patients experienced a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range: 1-93 days) with a median duration of 8 days (range: 1-144 days). Prophylactic treatment with corticosteroids was administered to a cohort of 39 patients for 3 days beginning on the day of infusion of YESCARTA. Of those patients, 85% (33/39) developed neurologic toxicities, 8% (3/39) developed Grade 3, and 5% (2/39) developed Grade 4 neurologic toxicities. The median time to onset of neurologic toxicities was 6 days (range: 1-274 days) with a median duration of 12 days (range: 1-107 days). Prophylactic corticosteroids for management of CRS and neurologic toxicities may result in a higher grade of neurologic toxicities or prolongation of neurologic toxicities, delay the onset of and decrease the duration of CRS.

Monitor patients for signs and symptoms of neurologic toxicities at least daily for 7 days at the certified healthcare facility, and for 4 weeks thereafter, and treat promptly.

REMS

Because of the risk of CRS and neurologic toxicities, YESCARTA is available only through a restricted program called the YESCARTA and TECARTUS REMS Program which requires that: Healthcare facilities that dispense and administer YESCARTA must be enrolled and comply with the REMS requirements and must have on-site, immediate access to a minimum of 2 doses of tocilizumab for each patient for infusion within 2 hours after YESCARTA infusion, if needed for treatment of CRS. Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer YESCARTA are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

HYPERSENSITIVITY REACTIONS

Allergic reactions, including serious hypersensitivity reactions or anaphylaxis, may occur with the infusion of YESCARTA.

SERIOUS INFECTIONS

Severe or life-threatening infections occurred. Infections (all grades) occurred in 45% of patients with NHL; ≥ Grade 3 infections occurred in 17% of patients, including ≥ Grade 3 infections with an unspecified pathogen in 12%, bacterial infections in 5%, viral infections in 3%, and fungal infections in 1%. YESCARTA should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 36% of all patients with NHL and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received YESCARTA, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells, including YESCARTA. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

PROLONGED CYTOPENIAS

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. ≥ Grade 3 cytopenias not resolved by Day 30 following YESCARTA infusion occurred in 39% of all patients with NHL and included neutropenia (33%), thrombocytopenia (13%), and anemia (8%). Monitor blood counts after infusion.

HYPOGAMMAGLOBULINEMIA

B-cell aplasia and hypogammaglobulinemia can occur. Hypogammaglobulinemia was reported as an adverse reaction in 14% of all patients with NHL. Monitor immunoglobulin levels after treatment and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during YESCARTA treatment, and until immune recovery following treatment.

SECONDARY MALIGNANCIES

Secondary malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-7 included fever, CRS, fatigue, hypotension, encephalopathy, tachycardia, diarrhea, headache, musculoskeletal pain, nausea, febrile neutropenia, chills, cough, infection with an unspecified pathogen, dizziness, tremor, decreased appetite, edema, hypoxia, abdominal pain, aphasia, constipation, and vomiting.

The most common adverse reactions (incidence ≥ 20%) in patients with LBCL in ZUMA-1 included CRS, fever, hypotension, encephalopathy, tachycardia, fatigue, headache, decreased appetite, chills, diarrhea, febrile neutropenia, infections with an unspecified, nausea, hypoxia, tremor, cough, vomiting, dizziness, constipation, and cardiac arrhythmias.

The most common non-laboratory adverse reactions (incidence ≥ 20%) in patients with iNHL in ZUMA-5 included fever, CRS, hypotension, encephalopathy, fatigue, headache, infections with an unspecified, tachycardia, febrile neutropenia, musculoskeletal pain, nausea, tremor, chills, diarrhea, constipation, decreased appetite, cough, vomiting, hypoxia, arrhythmia, and dizziness.

On June 3, 2022 Parker Institute for Cancer Immunotherapy reported that Researchers have identified certain patients with pancreatic cancer who may be more likely to benefit from combination treatment regimens consisting of immunotherapy and chemotherapy (Press release, Parker Institute for Cancer Immunotherapy, JUN 3, 2022, View Source [SID1234615543]). These new data, stemming from a long-term collaboration between academia, biotech, pharma and nonprofits within the Parker Institute for Cancer Immunotherapy (PICI) network, were shared with the medical community at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago today . The comprehensive clinical and immunologic findings of the Phase II clinical trial, known as the PRINCE study, were published simultaneously in the peer-reviewed journal Nature Medicine.

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Approximately 60,000 people are diagnosed with pancreatic cancer every year in the U.S., and the prognosis is typically poor. For the subset of patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the disease studied in PRINCE, the five-year survival rate is less than 5%1.

The findings are part of a recent analysis of data from the PRINCE trial, sponsored by PICI, and designed on the basis of decades of research by lead Principal Investigator Robert Vonderheide, M.D., D.Phil., and others at the University of Pennsylvania. The trial involved seven PICI network institutions, and uncovered various predictive biomarkers associated with longer overall survival for a subset of mPDAC patients.

The PRINCE trial evaluated the combination of standard-of-care chemotherapy (gemcitabine + nab-paclitaxel) and nivolumab, a PD-1 inhibitor, and/or sotigalimab, an experimental antibody that is an agonist of the CD40 protein. As part of exploratory analyses, PICI researchers discovered distinct biosignatures associated with survival for the nivolumab-chemotherapy and sotigalimab-chemotherapy treatment arms, which reflect each immunotherapy’s distinct mechanisms of action. Few biomarkers predicted survival in patients receiving the sotigalimab-nivolumab-chemotherapy regimen.

"While the data from the trial suggest that these treatment regimens may not be appropriate for all PDAC patients, we uncovered various predictive biomarkers from the circulation and tumor that may correlate with longer survival and warrant further study," said Lacey Padron, Ph.D., Vice President, Informatics at PICI and lead study author. "We are encouraged by the data and believe chemoimmunotherapy combinations may improve outcomes for some patients with metastatic PDAC. Following up on these results, the scientific community can work to better understand who is most likely to benefit and why."

The PRINCE trial was conducted in collaboration with:

Bristol Myers Squibb, which provided nivolumab
Apexigen, which provided sotigalimab
Cancer Research Institute
In addition to the University of Pennsylvania, participating research sites from the PICI network include the Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, Stanford Medicine, University of California, Los Angeles, University of California, San Francisco and The University of Texas MD Anderson Cancer Center.

"The PRINCE trial illustrates how this groundbreaking clinical research fostered collaboration between clinicians, researchers, nonprofits and industry, with the goal of bringing innovative treatments to patients faster," said Ute Dugan, M.D., Ph.D., Chief Medical Officer of PICI. "We look forward to building on these interesting results."

PDAC remains one of the most intractable challenges in oncology. Pancreatic cancer, the third-leading cause of cancer death in the U.S. in 2020, is predicted to become the No. 2 cause of cancer death in the U.S. by 20402. In the metastatic setting, while combination chemotherapy reliably offers tumor control and clinical stabilization, both standard regimens of gemcitabine plus nab-paclitaxel and FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) are limited in response durability and incur toxicity. Thus, new treatment strategies for this disease are urgently needed.

"The identification of signals that may help predict clinical outcomes for pancreatic cancer patients receiving combination treatment with chemotherapy and immunotherapy has significant potential to save more lives, as oncologists will be better equipped to design optimal treatment plans for their patients based on the presence or absence of these signals," said Jill O’Donnell-Tormey, Ph.D., Chief Executive Officer and Director of Scientific Affairs at the Cancer Research Institute.

The PRINCE trial is a collaborative research effort designed to work towards advancing more efficacious therapies that can create durable response, and ultimately remission, in patients. The translational work highlighted at ASCO (Free ASCO Whitepaper) and in Nature Medicine has identified biological signals in the blood and tumor that may uncover which patients have longer survival after these combination treatment regimens. The goal of this research is to one day predict via a simple test ahead of time whether a patient stands to benefit from a particular chemoimmunotherapy regimen.

"While scientific and medical advances in immunotherapy are helping to turn cancer into a curable disease for many patients, pancreatic cancer presents unique challenges that deserve the attention of the greatest scientific minds," said William Hoos, cancer research and collaboration lead at 1440 Foundation, a nonprofit that funds innovative pancreatic cancer research and collaboration, including support for the REVOLUTION study of novel immunotherapy combinations in pancreatic cancer, at PICI. "The potential for a biomarker selection strategy to identify the right immunotherapy combination for each patient holds potential for progress in pancreatic cancer. These new findings suggest next steps for researchers, and hope for pancreatic cancer patients and their families. We look forward to continued progress in this promising field."

More Information about the ASCO (Free ASCO Whitepaper) Presentation

Title: Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer
Abstract No.: 4010
Session: Clinical Science Symposium: Can We Begin to Predict Responders to Targeted Therapy in Gastrointestinal Cancer?
Location: McCormick Place, Hall D1 (in person and via livestream)
Date and Time: Friday, June 3, 2022, 5:30-7 p.m. ET/4:30-6 p.m. CT/2:30-4 p.m. PT
Lead Author and Presenter: Lacey Padron, Ph.D., Vice President, Informatics at PICI

The study’s comprehensive clinical and immunologic findings, "Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: Clinical and immunologic analyses from the randomized Phase 2 PRINCE trial," were published in the peer-reviewed journal Nature Medicine. The study authors conclude the Phase Ib/II study is a first step toward characterizing which patients may derive clinical benefit from these chemoimmunotherapy regimens by having identified potential biomarkers that can now be validated prospectively to determine if this allows for minimally invasive biomarker-enrichment designs for chemoimmunotherapy treatment in metastatic PDAC.

"The presentation and publication of these results in pancreatic cancer underscore PICI’s commitment to advancing our understanding of the toughest tumor types," said John Connolly, Ph.D., Chief Scientific Officer of PICI. "This shared knowledge can help patients, clinicians and researchers, alike, combat this deadly disease."

About Pancreatic Cancer

Pancreatic cancer is one of the deadliest types of tumors, and the number of diagnosed cases continues to rise each year. The disease is often difficult to catch early, such that by the time most people are diagnosed, their cancer is advanced and may have already spread. In addition, the tumors usually contain a variety of mutations, which often means a single targeted therapy isn’t enough to stop the disease by itself. For patients diagnosed with advanced metastatic pancreatic ductal adenocarcinoma (mPDAC), the five-year survival rate is less than 5%.

On June 3, 2022 Dxcover Limited, a clinical stage diagnostics company developing spectroscopic liquid biopsy technology for early detection of multiple cancers, reported that new data from a large-scale study on multi-cancer detection at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, Dxcover, JUN 3, 2022, View Source [SID1234615542]).

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Presented by Dr. Matthew Baker, co-founder and Chief Technology Officer at Dxcover, the results showcase the need for an effective test that accurately identifies patients with non-specific symptoms who have cancer in its earliest stages, while it is still treatable. Dxcover has pioneered the early detection and identification of cancer by employing infrared spectroscopy of circulating pan-omic biomarkers. Its platform combines novel hardware with artificial intelligence algorithms to analyze a patient’s blood and detect the presence or absence of disease.

The study, which recruited 2,094 patients, set out to distinguish cancer from non-cancer, as well as differentiate organ specific detection from other forms of cancer including brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. Results from the research, which applied the Dxcover Cancer Liquid Biopsy, proved the importance and impact of early cancer detection. At a 99% specificity the model achieved 64% sensitivity for stage I cancers. For overall cancer classification, the model achieved 90% sensitivity and 61% specificity when tuned for sensitivity. Detection rates were 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV.

"Our mission is to lead the way in liquid biopsy detection of cancers to improve survival and overall quality of life. We have successfully completed two groundbreaking studies on earlier diagnosis of brain cancer using the Dxcover platform, and today’s study demonstrates its ability to detect multiple cancers at their earliest stages, which we know is critical in providing the necessary care and treatment while it can be most impactful to patient outcomes," said Dr. Matthew Baker, co-founder and Chief Technology Officer at Dxcover.

Additionally, Dxcover released results from its proof-of-concept study investigating the use of Dxcover’s liquid biopsy as a novel approach for pancreatic cancer, the 7th most deadly cancer worldwide. The study focused on the discrimination between both cancer and control samples, and cancer and symptomatic non-malignant control samples.

Results showed that the two groups were significantly distinguished, achieving up to a sensitivity of 91.0%, specificity of 87.6% and accuracy of 89.3% with PLS-DA, underscoring that early-stage detection of pancreatic cancer would be key in improving prognosis and survival rates of patients in combination with targeted earlier surgery and treatments.

On June 3, 2022 Scorpion Therapeutics, Inc. ("Scorpion Therapeutics"), a pioneering oncology company redefining the frontier of precision medicine through its Precision Oncology 2.0 strategy, reported that Axel Hoos, M.D., Ph.D., Chief Executive Officer of Scorpion Therapeutics, will present a corporate overview at the Jefferies Healthcare Conference on Friday, June 10, 2022 at 9:30 a.m. ET in New York City (Press release, Scorpion Therapeutics, JUN 3, 2022, View Source [SID1234615541]).

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On June 3, 2022 Daiichi Sankyo it’s New data from (TSE: 4568) patritumab deruxtecan (HER3-DXd) showed clinically meaningful and durable responses in two early-stage trials in previously treated patients with HER3 expressing metastatic breast cancer or advanced non-small cell lung cancer (NSCLC) without EGFR-activating mutations (Press release, Daiichi Sankyo, JUN 3, 2022, View Source [SID1234615540]). These data will be presented during an oral presentation (Abstract #1002) and a poster discussion session (Abstract #9017) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO22) Annual Meeting.

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Patritumab deruxtecan is a potential first-in-class HER3 directed antibody drug conjugate (ADC) discovered and being developed by Daiichi Sankyo.

Advanced breast and lung cancer are two of the leading causes of cancer-related death in the U.S. with five-year survival rates of 30% and 7%, respectively.1,2 New therapeutic approaches are needed to improve outcomes for these cancers and HER3 is a promising target for therapeutic development. HER3 is broadly expressed in these tumors and is associated with an increased incidence of metastases, reduced survival and is one of the mechanisms of resistance to standard of care treatment.3,4

"Results of these two trials of patritumab deruxtecan in patients with certain subtypes of advanced breast or lung cancer further support the potential of Daiichi Sankyo’s DXd antibody drug conjugate technology across different types of cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "These data also reinforce the potential emerging role of targeting HER3 with an antibody drug conjugate to overcome resistance to standard of care treatment in patients with HER3 expressing metastatic breast cancer as well as in patients with advanced non-small cell lung cancer without EGFR activating mutations, which we plan to continue to explore in additional trials."

HER3 Expressing Metastatic Breast Cancer Results

Pooled analysis from a three-part, first-in-human phase 1/2 trial evaluating patritumab deruxtecan (n=182) showed clinically meaningful and durable responses after a median follow-up of 31.9 months (range, 15-56) in patients with three different subtypes of HER3 expressing metastatic breast cancer, including HR positive/HER2 negative, triple negative and HER2 positive disease. Responses were seen across a broad range of HER3 expression.

A confirmed objective response rate (ORR) of 30.1% (95% CI: 21.8-39.4) was observed with patritumab deruxtecan in the cohort of 113 patients with HER3 high or HER3 low, HR positive/HER2 negative metastatic breast cancer, as assessed by blinded independent central review (BICR). Partial responses (PRs) were observed in 30.1% of patients and 50.4% of patients had a best overall response (BOR) of stable disease (SD). Median duration of response (DOR) was at 7.2 months (95% CI: 5.3-NE). Median progression-free survival (PFS) was 7.4 months (95% CI: 4.7-8.4) and median overall survival (OS) was 14.6 months (95% CI: 11.3-19.5).

In the cohort of 53 patients with HER3 high metastatic triple negative breast cancer (TNBC), an ORR of 22.6% (95% CI: 12.3-36.2) was observed with patritumab deruxtecan, as assessed by BICR. PRs were observed in 22.6% of patients and 56.6% of patients had a BOR of SD. Median DOR was 5.9 months (95% CI: 3.0-8.4). Median PFS was 5.5 months (95% CI: 3.9-6.8) and the median OS was 14.6 months (95% CI: 11.2-17.2).

An ORR of 42.9% (95% CI: 17.7-71.1) was observed with patritumab deruxtecan in the cohort of 14 patients with HER3 high, HER2 positive metastatic breast cancer, as assessed by BICR. PRs were observed in 42.9% of patients and 50.0% of patients had a BOR of SD. Median DOR was 8.3 months (95% CI: 2.8-26.4). Median PFS was 11.0 months (95% CI: 4.4-16.4) and median OS was at 19.5 months (95% CI: 12.2-NE).

"Significant unmet need still remains for the treatment of patients with metastatic breast cancer and new treatment strategies need to be continuously explored," said Ian E. Krop, MD, PhD, Chief Clinical Research Officer, Associate Cancer Center Director for Clinical Research, Yale Cancer Center. "Results from this trial show that patritumab deruxtecan produces clinically meaningful and durable antitumor activity in patients and further study is warranted to further evaluate the efficacy and safety of this HER3 directed antibody drug conjugate across patients with HR positive/HER2 negative, HER2 positive and triple negative breast cancer."

Pooled safety was analyzed for all patients (n=182) enrolled in the trial. Treatment-emergent adverse events (TEAEs) associated with treatment discontinuation was 9.9%. Treatment-related Grade ≥ 3 TEAEs occurred in 120 patients (65.9%) and included neutrophil count decrease, platelet count decrease, white blood cell count decrease, anemia, alanine aminotransferase increase, aspartate aminotransferase increase, decreased appetite, nausea, fatigue, diarrhea, malaise, stomatitis and vomiting. Overall, 12 patients (6.6%) had confirmed treatment-related interstitial lung disease (ILD) or pneumonitis as determined by an independent adjudication committee. Most ILD events were low-grade with three (1.6%) grade 1 and five (2.7%) grade 2 events; three grade 3 (1.6%) and one grade 5 (death) event occurred (0.5%).

Patients were heavily pre-treated, and those with HR positive/HER2 negative metastatic breast cancer had received a median of six (range, 2-13) prior lines of therapy in the advanced setting; patients with metastatic TNBC had received a median of two (range, 1-13) prior therapies; and patients with HER2 positive breast cancer had received a median of 5.5 (range, 2-11) prior therapies. Median treatment duration was 5.9 months (range, 0.7-30.6). As of the data cut-off on August 16, 2021, four patients remained on study treatment with patritumab deruxtecan.

Summary of Results of HER3 Expressing Breast Cancer Phase 1/2 Trial

Efficacy Measures

HR positive/

HER2 negative

HER3 high and

HER3 low

n=113

TNBC

HER3 high

n=53

HER2 positive

HER3 high

n=14

Confirmed ORR, % (95% CI)i

30.1% (21.8-39.4)

22.6% (12.3-36.2)

42.9% (17.7-71.1)

Confirmed BOR

PR, % (n)

30.1% (34)

22.6% (12)

42.9% (6)

SD, % (n)

50.4% (57)

56.6% (30)

50.0% (7)

PD, % (n)

11.5% (13)

17.0% (9)

7.1% (1)

NE, % (n)

8.0% (9)

3.8% (2)

0% (0)

DOR, median (95% CI), months

7.2 months

(5.3-Not Estimable)

5.9 months (3.0-8.4)

8.3 months (2.8-26.4)

PFS, median (95% CI), months

7.4 months (4.7-8.4)

5.5 months (3.9-6.8)

11.0 months (4.4-16.4)

6-month PFS rate, % (95% CI)

53.5% (43.4-62.6)

38.2% (24.2-52.0)

51.6% (22.1-74.8)

OS, median (95% CI), months

14.6 months (11.3-19.5)

14.6 months (11.2-17.2)

19.5 months

(12.2-Not Estimable)

BOR, best overall response; DOR, duration of response; HER, human epidermal growth factor receptor; HR, hormone receptor; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; NE, not evaluable; TNBC, triple negative breast cancer

i 95% exact binomial confidence interval using Clopper-Pearson method

NSCLC Without Common EGFR-Activating Mutations Results

First preliminary results from one cohort of an ongoing phase 1 trial reported durable responses with patritumab deruxtecan after a median follow-up of 19.7 months (range, 13.8-29.2) in patients with locally advanced or metastatic NSCLC without most frequent EGFR activating mutations (EX19del, L858R, L861Q or G719X) or without identified driver genomic alterations.

An ORR of 28.6% (95% CI: 11.3-52.2), as assessed by BICR, was observed with patritumab deruxtecan in 21 patients with advanced NSCLC with identified driver genomic alterations other than EGFR activating mutations. Six patients had PRs and 10 patients had a best overall response of stable disease. Median DOR was 9.4 months (95% CI: 4.2-NE) and a disease control rate (DCR) of 76.2% (95% CI: 52.8-91.8) was observed. Median PFS was 10.8 months (95% CI: 2.8-16.0). Responses with patritumab deruxtecan were seen in patients with a broad range of driver genomic alterations, including KRAS/NRAS mutations and ALK fusions.

In patients with NSCLC without identified driver genomic alterations, an ORR of 26.9% (95% CI: 11.6-47.8) was observed with patritumab deruxtecan in 26 patients, as assessed by BICR. One patient had a complete response (CR), six had PRs and 12 patients had stable disease as a best overall response. Median DOR was 9.6 months (95% CI: 1.6-NE) and a DCR of 73.1% (95% CI: 52.2-88.4) was observed.

"Similar to previously reported results in patients with EGFR mutated non-small cell lung cancer, patritumab deruxtecan shows promising durable responses in patients with heavily pretreated advanced non-small cell lung cancer with or without driver genomic alterations," said Conor E. Steuer, MD, Assistant Professor, Department of Hematology and Medical Oncology, Emory University School of Medicine. "Further research is warranted to further confirm whether targeting HER3 is an effective treatment strategy to overcome treatment resistance in these patients."

Safety of patritumab deruxtecan seen in this cohort was consistent with that previously observed in patients with EGFR-mutated NSCLC. Treatment-related Grade ≥ 3 TEAEs occurred in 24 patients (51.1%) and included neutropenia, fatigue, thrombocytopenia, hypokalemia, anemia, leukopenia and pneumonia. Five patients (10.6%) had confirmed treatment-related ILD as determined by an independent adjudication committee. Most of these ILD events were low-grade with one grade 1 (2.1%) and four grade 2 (8.5%) events. As of data cut-off of January 28, 2022, five patients (10.6%) remained on treatment with patritumab deruxtecan.

About the Phase 1/2 Breast Cancer Trial

The global, open-label, three-part phase 1/2 trial is evaluating the safety and efficacy of patritumab deruxtecan in patients with HER3 expressing advanced/unresectable metastatic breast cancer who are refractory or intolerant to standard treatment, or for whom no standard treatment is available.

The dose escalation part of the trial is assessing the safety and tolerability of increasing doses of patritumab deruxtecan to determine the maximum tolerated dose. The dose finding part of the trial assessed the safety and efficacy of patritumab deruxtecan at selected dosing levels to determine the recommended dose for expansion. Patients in the dose escalation and dose finding parts of the trial must have received six or fewer prior chemotherapy regimens, at least two of which were administered for treatment of advanced/unresectable metastatic disease, and at least one prior chemotherapeutic regimen must have included a taxane, administered in the neoadjuvant, adjuvant or advanced setting.

The phase 2 part of the trial is evaluating the safety and efficacy of patritumab deruxtecan at the recommended dose for expansion in four different cohorts of patients with HER3 expressing and HER2 negative locally advanced or metastatic breast cancer, including HR positive and triple negative breast cancer. For more information, visit ClinicalTrials.gov.

About the Phase 1 Non-Small Cell Lung Cancer Trial

The global, multicenter, open label, two-part phase 1 trial is evaluating patritumab deruxtecan in previously treated patients with metastatic or unresectable NSCLC.

The dose escalation part of the trial is evaluating patients with EGFR-mutated disease either with progression on osimertinib or T790M-negative after progression on erlotinib, gefitinib or afatinib. The primary objective of this part of the trial was to assess the safety and tolerability of patritumab deruxtecan and determine the recommended dose for expansion (RDE).

The dose expansion part of the trial is evaluating patritumab deruxtecan at the RDE (5.6 mg/kg every three weeks) in three cohorts. Cohort 1 includes patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression after taking one or more EGFR TKIs and one or more platinum-based chemotherapy regimens. Cohort 2 includes patients with squamous or non-squamous NSCLC without EGFR-activating mutations following platinum-based chemotherapy and following an anti-PD-1 or anti-PD-L1 antibody regimen. Cohort 3 includes patients with NSCLC with EGFR-activating mutations including any histology other than combined small cell and non-small cell lung cancer; patients in Cohort 3 are randomized 1:1 to receive the 5.6 mg/kg RDE regimen (Cohort 3a) or an escalating up-titration regimen of patritumab deruxtecan (Cohort 3b).

The primary objective of the dose expansion part of the trial is to assess efficacy of patritumab deruxtecan as measured by confirmed objective response rate (ORR) assessed by blinded independent central review. Secondary trial endpoints include investigator-assessed ORR, safety and pharmacokinetics. The trial enrolled patients at multiple sites in Asia, Europe and North America. For more information, visit ClinicalTrials.gov.

About Breast Cancer and Non-Small Cell Lung Cancer

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.5 More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.5 The five-year survival rate of advanced breast cancer is 30% in the U.S.1

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths worldwide.6 More than 2.2 million cases of lung cancer were diagnosed in 2020, resulting in nearly 1.8 million deaths globally.6 NSCLC accounts for about 84% of all lung cancers.7 About half of patients with NSCLC are diagnosed at an advanced stage and they often have a poor prognosis with worsening outcomes after each line of subsequent therapy.8,9,10 The five-year survival rate of advanced lung cancer is 7% in the U.S.2

About HER3

HER3 is a member of the EGFR family of receptor tyrosine kinases, which are associated with aberrant cell proliferation and survival.3 It is estimated that about 83% of all NSCLC tumors express the HER3 protein. Overexpression is associated with metastatic progression and decreased relapse-free survival.11 Currently, no HER3 directed medicines are approved for the treatment of any cancer.

About Patritumab Deruxtecan

Patritumab deruxtecan (HER3-DXd) is one of three lead DXd ADCs in the oncology pipeline of Daiichi Sankyo. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, patritumab deruxtecan is comprised of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Patritumab deruxtecan is currently being evaluated as both a monotherapy and in combination with other anticancer therapies. The development program includes HERTHENA-Lung01, a pivotal phase 2 study in patients with locally advanced or metastatic EGFR-mutated NSCLC previously treated with a TKI and platinum-based chemotherapy; a phase 1/2 study in HER3 expressing metastatic breast cancer; a phase 1 study in combination with osimertinib in locally advanced/metastatic EGFR-mutated NSCLC; and, a phase 1 study in previously treated patients with metastatic or unresectable NSCLC.

In December 2021, patritumab deruxtecan was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) for the treatment of patients with metastatic or locally advanced EGFR-mutated NSCLC with disease progression on or after treatment with a third-generation TKI and platinum-based therapies.

Patritumab deruxtecan is an investigational medicine that has not been approved for any indication in any country. Safety and efficacy have not been established.