Petros Grivas, MD, Ph.D. of the University of Washington; Fred Hutchinson Cancer Research Center speaks about the ESMO 2020 abstract Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): Association between clinical outcomes and exploratory biomarkers.


Abstract 699O

Context
Avelumab (anti-PD-L1 IgG1 antibody) 1L maintenance + BSC substantially extended overall survival ( OS) in the phase 3 JAVELIN Bladder 100 (NCT02603432) study vs BSC alone in patients (pts) with advanced disease-free UC progression with 1L induction chemotherapy in both randomized pts and pts with PD-L1 + tumors. We publish studies of exploratory biomarkers.

Methodology
Prior to randomization, tumor biopsies were obtained. Tumor studies included immunohistochemistry of PD-L1 (Ventana SP263 assay) and CD8, whole-exome sequencing (including genotypes of FCGR2A and FCGR3A), whole-transcriptome sequencing, and sequencing of T-cell receptors (TCR). Baseline C-reactive protein (CRP) level and neutrophil: lymphocyte ratio (NLR) as well as TCR sequencing were included in peripheral blood examination before and after treatment. Using the Cox proportional hazards model, associations between OS or progression-free survival and biomarkers were evaluated. Danger ratios and nominal p values were registered and no changes to multiplicity were made (statistical significance level of 5 percent).

Outcomes
Increased OS gain with avelumab 1L maintenance + BSC vs BSC alone was positively correlated with invasive margin or tumor center CD8 + T cells, high tumor mutation burden, and innate and adaptive immune response signatures of tumor gene expression. The number of FCGR2A / FCGR3A alleles encoding high-affinity Fcγ receptors for IgG1 was also positively correlated with increased OS advantage. Avelumab's OS benefits were negatively correlated with tumor epithelial cell gene signatures, fibroblast growth factor receptor signaling mutations, CRP, and NLR. Lower expression of TGFb was correlated with greater OS gain for avelumab in pts with elevated immune gene expression signatures. Further studies, including findings of exploratory PD-L1 cutoffs in tumor vs. immune cells, will be provided.

Findings
The OS benefits of the maintenance of avelumab 1L in pts with advanced UC are positively correlated with immune response biomarkers and negatively associated with tumor homeostasis and chronic inflammation biomarkers.

Identification of Clinical Trial
NCT02603432. NCT0.

Klaus Hoeflich, Ph.D. Senior Vice President, Biology at Blueprint Medicines Blueprint Medicines Presents Foundational Preclinical Data for BLU-945 Showing Robust Anti-Tumor Activity in Treatment-Resistant EGFR-Mutated Lung Cancer at ESMO Virtual Congress 2020.


Link to Poster -
https://www.blueprintmedicines.com/wp-content/uploads/2020/09/Blueprint-Medicines-ESMO-2020-BLU-945-Lung-Cancer-Poster.pdf

CAMBRIDGE, Mass., Sept. 17, 2020,/PRNewswire/ — Blueprint Medicines Corporation ( NASDAQ: BPMC), a genomically identified cancer, rare diseases, and cancer immunotherapy precision therapy business, today announced preclinical proof-of-concept data for BLU-945, an investigational precision therapy for non-small cell lung cancer patients with epidermal growth factor receptor-mutated (EGFRm) New preclinical data showed that BLU-945 inhibited triple-mutant EGFR strongly and selectively, harboring the most common on-target resistance mutations to standard EGFRm NSCLC therapies, resulting in robust anti-tumor activity in multiple models of lung cancer. The data was made available today in a poster presentation at the 2020 Virtual Congress of the European Society of Medical Oncology (ESMO).

Patients with osimertinib-resistant EGFRm NSCLC do not currently have approved therapies, and there is an urgent need for new therapies to overcome tumor resistance. In combination with the acquired T790 M and C797S mutations, BLU-945 was engineered to powerfully inhibit triple-mutant EGFR harboring either the activating L858R or exon 19 deletion mutations, the most common on-target resistance to standard EGFR inhibitors. Furthermore, BLU-945 was designed to be wild-type selective EGFR and kinome with the potential for enhanced tolerability and hybrid strategies.

BLU-945 inhibited triple mutant EGFR with sub-nanomolar potency in preclinical data presented at the ESMO congress and displayed greater than 900-fold selectivity over wild-type EGFR along with excellent overall selectivity of the kinome. BLU-945 potently inhibited the EGFR pathway in a triple mutant EGFR cell line, while osimertinib demonstrated minimal activity. In multiple cell line-derived and patient-derived xenograft (PDX) models of triple mutant EGFR NSCLC, BLU-945 monotherapy resulted in robust anti-tumor activity. In addition, BLU-945 treatment in conjunction with osimertinib or gefitinib resulted in tumor regression in a triple mutant EGFR NSCLC PDX model derived after five lines of previous therapy from a patient with progressive disease. Even, in an intracranial disease model, BLU-945 was highly active.

Blueprint Medicines plans to develop BLU-945 as a monotherapy and in combination with other agents for the treatment of patients with osimertinib-resistant EGFR NSCLC based on this preclinical proof-of-concept results. In the first half of 2021, the company plans to initiate an international Phase 1 dose-escalation trial of BLU-945.

Furthermore, in the fourth quarter of 2020, Blueprint Medicines expects to nominate a brain-penetrant development candidate targeting double mutant EGFR harboring the activating L858R or exon 19 deletion mutations and the acquired C797S mutation, the most common first-line osimertinib on-target resistance profile. As both a monotherapy and in conjunction with BLU-945, the company plans to grow this candidate.

John Kuruvilla, MD of the Princess Margaret Cancer Centre and the University of Toronto discusses KEYTRUDA Is the First Anti-PD-1 Therapy Approved for Adult Patients With Relapsed or Refractory cHL After Frontline Therapy.


KENILWORTH, N.J.—(BUSINESS WIRE)—Outside of the United States and Canada, Merck (NYSE: MRK), known as MSD, today reported that the U.S. The Food and Drug Administration (FDA ) has approved an extended label for the care of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) with KEYTRUDA, Merck's anti-PD-1 therapy, as monotherapy. The approval is based on findings from the KEYNOTE-204 Phase 3 study in which KEYTRUDA significantly decreased the risk of disease worsening or death by 35% (HR=0.65 [95 % CI, 0.48-0.88; p<0.0027]) as opposed to brentuximab vedotin (BV). In addition, median progression-free survival (PFS) was 13.2 months (95 % CI, 10.9-19.4) for KEYTRUDA treated patients and 8.3 months (95 % CI, 5.7-8.8) for BV treated patients. A revised pediatric label for KEYTRUDA was also approved by the FDA for the treatment of pediatric patients with refractory cHL or relapsed cHL after two or more lines of therapy.

Immune-mediated, serious or fatal adverse reactions, like pneumonitis, colitis, hepatitis, endocrinopathy, nephritis, severe skin reactions, rejection of solid organ transplants, and complications of allogeneic hematopoietic stem cell transplantation (HSCT), can occur with KEYTRUDA. KEYTRUDA should be withheld or withdrawn depending on the nature of the adverse reaction, and corticosteroids should be administered if necessary. KEYTRUDA can also cause serious or life-threatening reactions associated with the infusion. Based on its mechanism of action, when given to a pregnant woman, KEYTRUDA can cause fetal damage.

KEYTRUDA has already been approved as part of the FDA's accelerated approval process for the treatment of adult and pediatric patients with refractory cHL or who have relapsed after three or more prior therapy lines, based on evidence from the KEYNOTE-087 study. Continued approval depended on verification and explanation of the clinical benefit in compliance with the accelerated approval regulations; these accelerated approval criteria were met with KEYNOTE-204 results.

This approval was reviewed under the Orbis Project of the FDA, an initiative of the FDA Oncology Center of Excellence, which offers a forum for the simultaneous submission and evaluation between its foreign partners of oncology drugs. An updated Project Orbis was conducted for this application, and the FDA is working on its ongoing review of the application with the Australian Therapeutic Products Administration and Health Canada.

Information Supporting the Approval
The approval was based on evidence from a randomized, open-label, active-controlled study, KEYNOTE-204 (NCT02684292), performed in 304 patients with relapsed or refractory cHL. After at least one multi-agent chemotherapy treatment, the study recruited adults with relapsed or refractory illness. In order to receive either KEYTRUDA 200 mg intravenously every three weeks or BV 1.8 mg/kg intravenously every three weeks, patients were randomized to 1:1.

Until unacceptable toxicity, recorded worsening of the disease, or up to a maximum of 35 cycles (up to approximately two years), treatment was continued. The assessment of the disease was conducted every 12 weeks. Previous autologous HSCT (yes vs. no) and disease status after frontline therapy is stratified by randomization (primary refractory vs. relapse less than 12 months after completion vs. relapse 12 months or more after completion). As evaluated by the Blinded Independent Central Review (BICR) using the updated International Working Group (IWG) guidelines of 2007, the key efficacy indicator was PFS.

KEYTRUDA (n=151) or BV (n=153) patients were enrolled and randomized. The median age of 35 years was the study population characteristics (range, 18 to 84); 57 percent male; 77 percent white, 9 percent Asian, and 3.9 percent Black. The median number of prior therapies in the KEYTRUDA arm was two (range, 1 to 10) and three (range, 1 to 11) in the BV arm, with 18 percent having one prior line in both arms. Forty-two percent of patients were refractory to the last prior treatment, 29 percent had primary refractory disease, 37 percent had previous autologous HSCT, 5 percent had previous BV, and 39 percent had previous radiation treatment.

KEYTRUDA decreased the risk of disease development or death by 35% (HR=0.65 [95 % CI, 0.48-0.88; p=0.0027]) in KEYNOTE-204 and demonstrated a median PFS of 13.2 months (95 % CI, 10.9-19.4). For patients treated with BV, the median PFS was 8.3 months (95 % CI, 5.7-8.8). For PFS, 81 patients (54 percent) had an incident in the KEYTRUDA arm, compared to 88 patients (58 percent) in the BV arm. The objective response rate (ORR) was 66 percent (95 percent CI, 57-73) for patients treated with KEYTRUDA, with a 25 percent full response rate and a 41 percent partial response rate. The ORR was 54 percent for patients treated with BV (95 percent CI, 46-62), with a complete response rate of 24 percent and a partial response rate of 30 percent. Not statistically important is the gap in ORRs. The median period of response (DOR) among the responding patients was 20.7 months (range, 0.0 + to 33.2 +) with KEYTRUDA and 13.8 months (range, 0.0 + to 33.9 +) with BV.

The median period of KEYTRUDA exposure was 10 months for KEYNOTE-204 (range, 1 day to 2.2 years), with 68% receiving at least six months of treatment and 48% receiving at least one year of treatment. In 30 percent of patients who received KEYTRUDA, severe adverse effects occurred. Pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis were severe adverse effects in those greater than or equal to 1 percent of the patients. Three patients (2%) died due to factors other than disease progression: two due to allogeneic HSCT complications and one due to an unknown cause.

In 14 percent of patients, permanent discontinuation of KEYTRUDA due to an adverse reaction occurred; 7 percent of patients discontinued treatment because of pneumonitis. In 30 percent of patients, dose interruption of KEYTRUDA due to an adverse reaction occurred. Upper respiratory tract infection, pneumonitis, transaminase rise, and pneumonia were adverse reactions requiring dosage interruption are greater than or equal to 3 percent of patients. Thirty-eight percent of patients suffered an adverse reaction that involved treatment with systemic corticosteroids. Upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, weakness, rash, and cough (20 percent each) were the most common adverse reactions (greater than or equivalent to 20 percent).

Michael Wang, MD, ZUMA-2 Lead Investigator, and Professor at The University of Texas MD Anderson Cancer Center speaks to us about Management of a patient with mantle cell lymphoma who developed severe neurotoxicity after chimeric antigen receptor T-cell therapy in ZUMA-2.


Abstract 
Cerebral edema following T-cell therapy with chimeric antigen receptor (CAR) can be fatal. In relapsed / refractory mantle cell lymphoma, ZUMA-2 is a pivotal phase 2, multicenter trial testing KTE-X19, an autologous anti-CD19 CAR T-cell therapy. A 65-year-old ZUMA-2 patient who developed cerebral edema following CAR T-cell therapy and had complete recovery after clinical multimodality intervention including rabbit antithymocyte globulin (ATG) has been identified. Early and robust CAR T-cell expansion and associated activation of inflammatory cytokines are shown by biomarker findings, accompanied by rapid declines in CAR T-cell and proinflammatory cytokine levels after administration of ATG. This clinical profile underlines the possible importance of ATG in the treatment of serious neurotoxicity linked to CAR T cells.

Context
In relapsed / refractory B-cell malignancies, chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have shown impressive efficacy. However, with CAR T-cell therapy, neurological events (NE) are severe toxicities frequently encountered and remain a therapeutic obstacle. Although low-grade NE is normally reversible, grade 4 NE can be fatal and is commonly associated with cytokine release syndrome (CRS), increased permeability of the blood-brain barrier, endothelial activation, and poor survival. Disease recovery and treatment-related toxicity are associated with CAR T-cell expansion and associated increases in cytokine/chemokine levels. However, the early and rapid expansion of CAR T cells and associated development of cytokines, including cerebral edema, have also been correlated with extreme NE.

In patients with relapsed / refractory mantle cell lymphoma (MCL), ZUMA-2 is a phase 2, multicenter trial testing KTE-X19, an autologous anti-CD19 CAR T-cell therapy. KTE-X19 uses a manufacturing procedure that extracts CD19-expressing circulating cells for use in leukemic and MCL indications. Clinical management of a ZUMA-2 patient who developed grade 4 NE with cerebral edema that resolved after multimodal clinical intervention treatment including rabbit antithymocyte globulin (ATG), an immunosuppressant that in vivo depletes T lymphocytes, is presented.

Methodology
Patients in ZUMA-2 had relapsed / refractory MCL with one to five prior therapies, as previously stated. Prior treatment could include chemotherapy containing anthracycline or bendamustine, an anti-CD20 monoclonal antibody, and an inhibitor of Bruton tyrosine kinase (ibrutinib or acalabrutinib). One regimen was counted as induction plus consolidation/maintenance and/or all treatments that occur between sequential complete responses. Written, informed consent was given by all patients and the procedure was accepted at each site by the Institutional Review Board. In accordance with the principles of the Declaration of Helsinki, the ZUMA-2 analysis was conducted. The trial was registered with the List of ClinicalTrials.gov; NCT02601313.

As previously reported, patients underwent leukapheresis with optional bridging therapy accompanied by conditioning chemotherapy (cyclophosphamide 500 mg / m2 / day; fludarabine 30 mg / m2 / day) on days 5 to 3.4 KTE-X19 was injected at a target dose of 2 to 106 CAR T cells/kg on day 0.4 CRS per Lee et al.15 National Cancer Institute Common Terminology Criterion for Adverse Events, V.4.03, was used at a target dose of 2 to 106 CAR T cells/kg on day 0.4. Serum collected at baseline and on days 0 (postconditioning and prior to KTE-X19) and on days 3, 7, 14, and 28, using previously reported methods, was assessed for 44 cytokines, chemokines, circulating angiogenic factors, immune effector molecules, and macrophage activating syndrome markers. For the identification of T and myeloid lineage cells, a trained flow cytometry assay was carried out on immune cells isolated from cerebrospinal fluid ( CSF) and other normal immune markers. From central laboratory assessments, all measurements mentioned above were derived. Although the patient was enrolled in ZUMA-2 for comparison with the wider ZUMA-2 population in this study, this patient was excluded from the ZUMA-2 cohort medians and evaluations listed herein.

Outcomes
Report of the event
A 65-year-old man with relapsed / refractory pleomorphic MCL (ibrutinib-refractory; supplementary online methods) in stage IV has been enrolled. No history of prior neurological disorder has been reported. Prior to KTE-X19 infusion, the patient had a performance status score of 0, non-bulky disease, a Ki-67 proliferation index of 80 percent-90 percent, and 410 IU / L baseline lactate dehydrogenase levels in the Eastern Cooperative Oncology Community. There was an unremarkable initial brain MRI (online supplementary figure S1). The patient administered conditioning chemotherapy followed by KTE-X19 infusion following leukapheresis. Prophylactic levetiracetam was initiated prior to the infusion and there was no sign of fever or infection. The serum levels of cytokines measured before and after lymphodepletion were close to those in other ZUMA-2 patients. The product properties of KTE-X19 were also equivalent to those of other patients. A timeline of clinical activities, including imaging tests and treatments, is represented in Figure 1. The level of evidence behind the interventions used is given by the online supplementary table S1. Serum levels of cytokines and blood levels of CSF and CAR T cells.

Marcia S. Brose, MD, Ph.D. of the Pearlman School of Medicine at The University of Pennsylvania speaks on the ESMO 2020 abstract Larotrectinib treatment of advanced TRK fusion thyroid cancer.


Abstract 1916P

Context
Larotrectinib is an EMA and FDA approved first-in-class, central nervous system active, highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of adult and pediatric TRK fusion cancer patients (pts). In pts with TRK fusion cancer across different tumor types (Hong et al. Lancet Oncol. 2020), Larotrectinib provided an objective response rate (ORR) of 79 percent and a median period of response (DoR) of 35.2 months. We report the efficacy and protection of larotrectinib in the TRK fusion thyroid cancer subset of pts here.

Methodology
Data from two larotrectinib clinical trials (NCT02122913 and NCT02576431) were pooled in pts of locally advanced or metastatic thyroid cancer containing neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Adult and pediatric patients received 100 mg and 100 mg / m2 of larotrectinib twice daily, respectively, on a 28-day, continuous schedule. Investigator-assessed responses were per RECIST v1.1 (data cut-off: 15 July 2019).

Outcomes
With TRK fusion thyroid cancer, a total of 28 pts were included: 19 papillary, 7 anaplastic, and 2 follicular. The median age (range of 6-80) was 62 years. Twelve (43%) pts had a fusion of NTRK1 and 16 (57%) pts had a fusion of NTRK3. Prior treatment, including surgery (100 percent), radiotherapy (61 percent), radioiodine (75 percent), and about 1 prior systemic therapy (89 percent) were obtained by all pts. 3 previous systemic therapies were received by eleven (44 percent) pts. ORR was 75% (95 % confidence interval [CI] 55–89), including 29% for anaplastic disease pts (Table). The DoR range was between 1.9 + and 41.0 + months. Median progression-free survival (PFS) was not attained (95 percent CI 16.6-NE) and 81 percent was the 12-month PFS average. There were mainly Grade 1-2 adverse events (AEs). Grade 3 AEs occurred in 46 percent of pts and grade 3 AEs linked to larotrectinib occurred in 7 percent of pts.

Findings
Larotrectinib was highly successful and a favourable safety profile was demonstrated. These results help regular monitoring of non-medullary, advanced thyroid cancer for NTRK gene fusions in pts.

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Drs. Charu Aggarwal and Jack West host Dr. Mark Lewis of Intermountain Healthcare to explore different styles of how physicians use social media for education, connection in building community, and determining boundaries in what to share with #MedTwitter.

Kunal Sindhu, MD from the Icahn School of Medicine at Mount Sinai speaks about the ASTRO 2020 Abstract 3009 Identifying Existing Knowledge Gaps in Palliative Radiation Oncology.

Link to Poster -
https://astro.multilearning.com/astro/2020/annualmeeting/299954?evname=u42P5_6f3xRUr5o4erxthw&evsign=xxA2-A3l2isLpbxsuiedLFC6WvM7vwTnWMLbgy_jeDc

Body
Purpose / Objective(s): In patients with cancer, palliative radiation therapy can greatly improve symptoms and function. Previous research, however, has reported major differences with respect to palliative care in radiation oncology residency curricula. The Mednet, an online group of doctors whose aim is to "improve the exchange of information between doctors so that patients receive high-quality treatment wherever they are treated," has become an increasingly used resource for radiation oncologists with clinical management questions in recent years. In this research, by analyzing all of the related questions posted on the Mednet, we tried to identify knowledge gaps in palliative radiation oncology.

Materials/Methods:
"We checked on or before January 7, 2020, for all questions posted on theMedNet and marked with the words" Radiation Oncology "or" General Radiation Oncology "and" Palliation. All questions found have been grouped into related thematic categories. For each question, four social interaction metrics were recorded: the number of times it was seen, marked as a "good question," and answered; and the total number of comments posted in response to any answers. Using the Kruskal-Wallis and Mann-Whitney U Studies, variations in social commitment between the thematic question groups were evaluated.

Outcomes:
There were 161 questions listed, 147 of which (91 percent) were answered. Seven broad thematic categories were identified: 42 questions (26%) relating to the decision to treat a patient, 36 (22%) relating to treatment preparation, 26 (16%) relating to suitable palliative dose regimens, 19 (12%) relating to treatment logistics, 10 (6%) relating to supportive care, 8 (5%) relating to patient guidance, and 7 (4%) relating to pre-radiation therapy work-up. As an eighth thematic group, the remaining 13 disparate questions (8 percent) were graded.

Palliative radiation oncology questions were viewed 497.7 times on average (range 7-4657), 2.2 times (range 0-29) marked as a 'reasonable question', and 1.7 times answered (range 0-10); responses to each question earned an average of 0.4 comments (range 0-7). Among thematic question classes, the most average views (702.5) and answers (2.1) were given to questions about dose regimens. Questions about care logistics were most often identified as 'positive question[s]' (2.9 times on average) and the most average responses (0.8) were received in response to questions about the decision to treat a patient. There were no substantial differences in the statistical analysis of any of the four social interaction indicators between questions in the various thematic groups (p > 0.05).

The Conclusion:
Among palliative radiation oncology questions posted on the Mednet, we found several common query themes. These findings indicate that in terms of palliative care, major knowledge gaps exist among radiation oncologists. Modifications to the residency curriculum in radiation oncology can help reduce potential clinical uncertainties.