Sheela Rao, MDS Consultant Medical Oncologist, The Royal Marsden NHS Foundation Trust discusses Incyte Announces Acceptance and Priority Review of BLA for Retifanlimab as a Potential Treatment for Patients with Squamous Cell Carcinoma of the Anal Canal (SCAC).

Link to Article -
https://investor.incyte.com/press-releases/press-releases/2021/Incyte-Announces-Acceptance-and-Priority-Review-of-BLA-for-Retifanlimab-as-a-Potential-Treatment-for-Patients-with-Squamous-Cell-Carcinoma-of-the-Anal-Canal-SCAC/default.aspx

WILMINGTON, Del.—(BUSINESS WIRE)—According to Incyte (Nasdaq: INCY) today, the U.S. The Food and Drug Administration (FDA) has approved its Biologics License Application (BLA) for retifanlimab, an intravenous PD-1 inhibitor, for Priority Review as a possible treatment for adult patients with locally advanced or metastatic anal canal squamous cell carcinoma (SCAC) who have advanced or are intolerant to platinum-based chemotherapy.

BLA submissions are based on evidence from the Phase 2 POD1UM-202 trial evaluating retifanlimab in previously treated locally advanced or metastatic SCAC patients who have progressed to or are intolerant to, standard platinum-based chemotherapy. 94 patients, including some with well-controlled human immunodeficiency virus (HIV) infection, were enrolled in the study. The research, recently presented at the Virtual Congress 2020 of the European Society for Medical Oncology (ESMO), resulted in a 14 percent objective response rate (ORR) for retifanlimab monotherapy as calculated by an independent central review (ICR) using RECIST v1.1. Responses were observed irrespective of PD-L1 status, liver metastases, age, or HIV+ status, and were long-lasting (median 9.5 months). Grade 3 adverse effects associated with treatment occurred in 11.7 percent of patients. Grade 3 immune-related adverse reactions in 6.4 percent of patients occurred. Fatigue and diarrhea were the most common adverse reactions (incidence ~ 20 percent).


Retifanlimab has been awarded the FDA Orphan Drug Status, along with the Priority Review, for the treatment of anal cancer. Priority Review is given by the FDA to medicines that could deliver a significant advance in therapy where none currently exists. Compared to the Regular Evaluation, this designation shortens the review duration by four months. Retifanlimab's target action date for the Prescription Drug User Fee Act (PDUFA) is July 25, 2021.


SCAC is associated with human papillomavirus (HPV) and HIV infections and accounts for approximately 3% of cancers of the digestive system.1 Metastatic SCAC patients have low 5-year survival, and patients who have progressed following first-line chemotherapy do not have FDA-approved treatments.


A Phase 3 trial of retifanlimab in combination with carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic SCAC, POD1UM-303/InterAACT 2 (NCT04472429), is now open and is recruiting patients.

Professor Thomas Powles, MD from Barts Cancer Centre, London, UK speaks about European Commission Approves BAVENCIO® (avelumab) for First-Line Maintenance Treatment of Locally Advanced or Metastatic Urothelial Carcinoma.

Link to Article -
https://www.prnewswire.com/news-releases/european-commission-approves-bavencio-avelumab-for-first-line-maintenance-treatment-of-locally-advanced-or-metastatic-urothelial-carcinoma-301213683.html?tc=eml_cleartime

ROCKLAND, Mass. and NEW YORK, Jan. 25, 2021 /PRNewswire/ — EMD Serono, Merck KGaA, Darmstadt, Germany, US, and Canada Healthcare Business Sector, and Pfizer Inc. (NYSE: PFE) today announced that BAVENCIO® (avelumab) has been approved by the European Commission (EC) as monotherapy for first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinomas.


BAVENCIO plus best supportive treatment (BSC) as first-line maintenance showed a substantial increase in median overall survival (OS) vs BSC alone in the prespecified interim analysis (data cut-off date Oct. 21, 2019) in the pivotal JAVELIN Bladder 100 study: 21.4 months (95% CI: 18.9 to 26.1) vs 14.3 months (95% CI: 12.9 to 17.8) in the coprimary population of all randomized randomized population


BAVENCIO also reported substantially extended OS for all randomized patients vs. BSC alone (HR 0.70; 95 percent CI, 0.56 to 0.86; two-sided P=0.0008), with a median OS of 22.1 months (95 percent CI, 19.0 to 26.1) vs 14.6 months (95 percent CI, 12.8 to 17.8), respectively, with revised OS findings with a data cut-off of Jan. 19, 2020.



BAVENCIO was first approved by the US Food and Drug Administration (FDA) in June 2020 in the US as a first-line maintenance treatment for advanced UC and is now approved for this indication in 38 countries. In 13 countries, including Japan, where approval is required in H1 2021, additional regulatory applications are under review.

Mehmet Asim Bilen, MD from Winship Cancer Institute of Emory University discusses the Evaluation of a novel blood pressure scoring method and its association with clinical response in cancer patients treated with anti-vascular endothelial growth factor therapy.

Link to Study -
https://pubmed.ncbi.nlm.nih.gov/24764123/

Instract

Background: In advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies, the aim of this study was to develop a novel blood pressure (BP) scoring method and correlate it with clinical response.


Methods: We retrospectively evaluated data from 23 clinical trials involving at least one anti-VEGF agent for 368 patients. Using the standard Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our latest system, BP scores were measured using both BP readings and the amount of anti-hypertensive drugs obtained by the patient. BP ratings at baseline and four months have been classified. Elevated scores were correlated with the clinical response through logistic regression analysis. An agreement was assessed between the CTCAE and the new system.



Results: Under the latest BP scoring system, partial response rates were 20 percent for four-month elevated patients versus 6 percent for non-elevated patients (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and number of anti-VEGF treatments, the odds ratio was 3.8 (95% confidence interval [CI]: 1.8, 8.2; P < 0.001) for elevated BP under the new scoring system. The kappa statistics were 0.57 (95 percent CI: 0.47, 0.67; P < 0.001) for agreement between the CTCAE and current scoring methods, suggesting substantial concordance.



Conclusion: The rise in BP scores was a proxy for favorable clinical response in patients receiving anti-VEGF therapy using the novel scoring system. Ultimately, this new approach offers details about the clinical tumor response over and above that given by the scoring method of CTCAE.

Emerens Wensink, MD, Ph.D. Candidate from University Medical Center Utrecht, Utrecht University discusses Survival of patients with deficient mismatch repair metastatic colorectal cancer in the pre-immunotherapy era.

Link to Abstract -
https://pubmed.ncbi.nlm.nih.gov/33046804/

Instract

Context: 
The analysis of single-arm immunotherapy research is complicated by negligible evidence on survival during systemic non-immunotherapy. A broad, systematic cohort of dMMR mCRC patients treated with or without systemic non-immunotherapy is provided with survival results.


Methods: 
Overall survival was analyzed based on mCRC (OS) diagnosis, first-line (OS1), and second-line (OS2) systemic treatment initiation. Prognostic variables were investigated by Cox regression analysis. Compared with OS 2746, MMR proficient mCRC patients have been reported.



Results: 
Median OS in untreated patients was 16.0 months (13.8-19.6) with antitumor treatment and 2.5 months (1.8-3.5). OS1 in treated dMMR patients was 12.8 months (10.7-15.2) and OS2 was 6.2 months (5.4-8.9). Treated patients with dMMR had a 7.6-month shorter median OS than patients with pMMR.



Conclusion: 
There is a lack of a control arm with standard systemic treatment available from immunotherapy trial results. Given the bad outcome relative to immunotherapy outcomes, our results clearly indicate that immunotherapy in dMMR mCRC patients has a survival advantage.

Melissa L. Johnson, MD Director, Lung Cancer Research, Sarah Cannon Research Institute at Tennessee Oncology speaks about A phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE®) immuno-oncology therapy against DLL3, in SCLC.

Link to Article:
https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.TPS8577

Conceptual -

TPS8577 77

Context:
SCLC is an active neuroendocrine tumor; recurrence, rapid growth, and resistance to current therapies are frequently accompanied by a response to initial chemotherapy and radiotherapy. Delta-like ligand 3 (DLL3) is a Notch receptor inhibitory ligand that is expressed but minimally expressed in normal tissues in most SCLC tumors. For T cell-redirecting immunotherapy, DLL3 may therefore be a promising target. AMG 757 is an extended half-life BiTE antibody construct designed to bind DLL3-positive cells to CD3-positive T cells temporarily and induce T cell-mediated cell lysis and proliferation of T cells concomitantly. In the SHP-77 human SCLC xenograft model in vivo, AMG 757 induces potent killing of SCLC cell lines in vitro and inhibits tumor growth. In a preclinical multi-dose toxicology analysis in cynomolgus monkeys, AMG 757 was well tolerated with no signs of tissue harm at weekly doses of up to 4.5 mg/kg.

Methodology:
An open-label, ascending, multiple-dose, phase 1 analysis evaluating AMG 757 is NCT03319940. The research will initially recruit adult patients who have progressed after at least 1 platinum-based chemotherapy regimen with relapsed/refractory SCLC. ECOG output status 0–2, at least 2 detectable lesions per changed RECIST 1.1, no untreated or symptomatic brain metastases, and sufficient organ function are additional inclusion requirements. The main objectives are to assess safety and tolerability and to determine the maximum tolerated dose (MTD) or the recommended dose for phase 2. (RP2D). Pharmacokinetics (PK) characterization and preliminary antitumor activity assessment are secondary objectives. During the dose discovery process, patients will be monitored during the first 28 days for dose-limiting toxicities. To inform decisions on dose escalation/de-escalation, a Bayesian logistic regression model will be used. The expansion step of the dose will confirm the MTD or RP2D and gather additional data on safety and efficacy. AMG 757 will be given once every 2 weeks as a short-term intravenous infusion. Based on evolving PK and safety data, alternative dosing schedules could be explored. Data on clinical trials: NCT03319940.

Takeo Fujii, MD, MPH from MD Anderson Cancer Center speaks about the Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience.

Link to Study -
https://link.springer.com/article/10.1007/s10637-017-0534-0

Overview -

Context
Immunotherapy is emerging as the cornerstone of treatment for patients with advanced cancer, but substantial toxicity (irAEs) associated with the unbridled activity of T cells remains a concern. Patients and Methods A retrospective review of the electronic medical records of 290 advanced cancer patients treated between February 2010 and September 2015 in an immunotherapy-based clinical trial at the Department of Investigative Cancer Therapeutics of the University of Texas MD Anderson Cancer Center was carried out. Clinical and laboratory parameters were obtained to assess the frequency of irAEs, risk factors, and their connection with treatment outcomes. Results Ninety-eight out of 290 patients (34%) experienced irAEs of any grade. Dermatitis and enterocolitis were the most common irAEs among the 15 (5.2 percent) patients with grade 3 irAEs. While systemic corticosteroids were required by 80% of patients with grade 3 irAEs, all 15 patients recovered from the irAEs. Four of the 5 patients who had received systemic corticosteroids for irAE continued to respond to re-challenge. No IrAE-related deaths have occurred. Importantly, compared with those without grade 3 irAEs, patients with grade 3 irAEs had an increased average response rate (25 vs. 6 percent; p = 0.039) and a longer median development period (30 weeks vs. 10 weeks; p = 0.0040). Conclusion The occurrence of irAEs with immunotherapy agents suggests an active immune status, suggesting the patient's future clinical gain. Further confirmation of this relationship is warranted in a broad prospective sample.

Jason M. Link, Ph.D., Department of Molecular and Medical Genetics, Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University Tumor-Infiltrating Leukocyte Phenotypes Distinguish Outcomes in Related Patients With Pancreatic Adenocarcinoma.

Link to Case Report -
https://ascopubs.org/doi/full/10.1200/PO.20.00287

One of the greatest mortality risks of all cancers includes pancreatic ductal adenocarcinoma (PDAC). Most patients have either metastatic PDAC (50 percent -60 percent) or locally advanced tumors (30 percent -40 percent), for which the median survival after diagnosis is 5-9 months. Oh, 1,2 For the limited subset (10 percent -20 percent) of patients who present with resectable tumors confined to the pancreas, outcomes are still suboptimal; < 50 percent of these patients, despite modern adjuvant chemotherapy, live 5 years after surgery. 3 In addition, in the autopsy, 88% of recurrences of the disease are metastatic and >80% have more than 10 distinct metastatic lesions4 that are genetically linked to the primary tumor5 and other metastases. 6 These results suggest that the majority of PDAC patients have non-radiographically clear, post-resection micrometastatic disease and that residual tumor cells evade or develop resistance to adjuvant chemotherapy. Though tropism to specific organs is still poorly understood during metastatic spread, patients with liver or peritoneum recurrence7 survive significantly shorter than patients with recurrent lung metastases.

Two major subtypes are generally known as PDAC tumors: one that shares certain characteristics with adenosquamous tumors (squamoid and/or basal) and the other that preserves a differentiated (ductal and/or classical) glandular and/or ductal morphology. Squamoid PDAC tumors are more glycolytic,11,12 are more hypoxic,13 are more likely to metastasize,14,15 are more likely to recruit inflammatory fibroblasts,16 have a worse prognosis than ductal tumors. Seventeen-21 More tumor-infiltrating leukocytes, denser collagen, and better results are associated with classical subtype tumors15,22, although substantial subtype heterogeneity within tumors13 complicates the relationship between subtype and outcome.



More cytolytic T cells than most other tumors invade PDAC tumors,23 but are ultimately ineffective to manage cancer. Among PDAC tumors, tumor-infiltrating T cell density is highly variable,24 and abundant CD8+ T cells (along with a high number of neoantigens) can exceptionally support long-term survival. 25 T cell-mediated tumor immunity can, however, be limited by several mechanisms: downregulation of HLA by tumor cells, immunosuppressive leukocytes, the proximity of T cells to tumor cells, and exhaustion of T cells. 26 to 30 A high diversity of functional T cell clones, tumor-specific recruitment of effector T cells, and abundant neoantigens improve efficient T cell-mediated tumor immunity. 23,25,31— It is essential to quantify leukocyte phenotypes, functions, and locations in order to recognize precise tumor immunity necessary for exceptional positive results.



Equally unusual, idiosyncratic patient genetics, tumor-specific somatic alterations, and gene expression, and/or stochastically generated tumor immunity can mediate rare, exceptional control of PDAC progression. This study describes the cases of Pt1, who lived for more than 46 months with occult metastatic PDAC resistant to chemotherapy, and her niece (Pt2) who, through intensive treatment, succumbed to progressive metastatic disease. These two patients compare clinical outcomes and primary and metastatic tumors, finding significant variations in the subtype, somatic changes, and leukocyte lineages that may have contributed to divergent disease courses in some combination or alone.