In part one of this three part video series update, presented in July of 2020, GRACE Board Members Drs. H. Jack West, Jared Weiss and Ben Levy have another candid discussion regarding cancer and Covid-19 and how the ongoing pandemic is effecting patient care.

In this series update, we discuss changes to management in patient care, the use of telemedicine and future challenges, as well as other issues relating to a cancer diagnosis in the middle of a pandemic.

For more, please visit http://cancerGRACE.org/. To join the conversation, visit https://cancergrace.org/forum.

Paul G. Richardson, MD of Dana-Farber Cancer Institute explains the abstract entitled First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).


Explanation:
The novel Cereblon E3 ligase modulator (CELMoD) agent CC-92480 is designed for the rapid, maximum degradation of Ikaros and Aiolos. In vitro, MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), have increased antiproliferative and tumoricidal activity, with high immune stimulatory activity.

Methodology:
Maximum tolerated dose (MTD), recommended phase 2 dose, protection, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts were evaluated in a phase 1, multicenter, dose-escalation trial. On or within 60 days of their last MM treatment, qualifying pts had progression and were either resistant to or intolerant to, or not otherwise candidate for, currently available therapies. The escalating doses of CC-92480 + DEX (40 mg; 20 mg if ⁇ 75 yrs) were evaluated in several treatment schedules.

Outcomes:
As of Dec 24, 2019, CC-92480 + DEX had earned 66 pts. The median age was 67 years ( range 40-78), while the median number of previous regimens was 6 (range 2-13). Stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%) is used in prior therapies. 0.1–1.0 mg QD (10/14 days ⁇ 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days ⁇ 2), and 1.6–2.0 mg QD (7/14 days ⁇ 2) were included in the CC-92480 doses studied. For both schedules of 10/14 x 2 and 21/28, MTD was 1.0 mg. In 58 (88 percent) pts, Grade 3–4 treatment-emergent adverse effects (TEAEs) were recorded. Neutropenia (53 percent), infections (30 percent), anemia (29 percent), and thrombocytopenia (17 percent), with 9 percent grade 3 fatigue, were the most common grade 3-4 TEAEs. 10 pts had dose-limiting toxicity (the majority linked to neutropenia) across various cohorts. The overall response rate (ORR) for the efficacy assessable population (n = 66) was 21 per cent (9 very strong partial responses [VGPRs]; 5 PRs). Efficacy was based on dose and schedule; 10 out of 21 (48 percent) pts responded (7 VGPR and 3 PR) through two 1.0 mg QD schedules (10/14 ⁇ 2 and 21/28), with response independent of refractory immunomodulatory drug (IMiD). Increases in plasma exposure and degradation of peripheral blood Ikaros and Aiolos is dose dependent. In bone marrow plasma cells, Ikaros and Aiolos decreased significantly in LEN- and POM-refractory pts.

Findings:
TEAEs of CC-92480 were predominantly associated with heavily pretreated myelosuppression, including triple-class-refractory, RRMM pts. Promising activity was observed at therapeutic doses of 48 percent ORR. In order to further refine the dosage and schedule, the research is continuing, with combination trials underway and cohorts for dosage expansion expected. Data on clinical trials: NCT03374085.

Ian Chau, MD from Royal Marsden Hospital speaks about the ESMO 2020 abstract Initial safety and efficacy findings with bavituximab plus pembrolizumab in patients with advanced gastric or gastroesophageal cancer.

1446P Abstract 

Background
In patients with advanced gastric and gastroesophageal junction (GEJ) cancer, bavituximab, an investigational, chimeric monoclonal antibody engineered to inhibit the immunosuppressive effects of phosphatidylserine, is being tested in combination with pembrolizumab. Post-hoc findings from the phase III Sunrise second-line lung cancer trial found that overall survival was substantially improved in patients who advanced on bavituximab plus docetaxel study treatment and proceeded with a checkpoint inhibitor as the next line of therapy. Cumulative data indicate that bavituximab can potentiate inhibition of the checkpoint mediated by pembrolizumab, possibly increasing overall clinical benefit.

Methodology
ONCG100 is a multicenter, open-label, single-arm, phase II global study designed to evaluate the safety, tolerability, and efficacy of bavituximab (3 mg/kg, QW) and pembrolizumab (200 mg, Q3W) in combination with advanced gastric or GEJ adenocarcinoma patients, irrespective of PD-L1 status, who have progressed to ⁇ 1 prior standard therapy (NCT04099641).

Outcomes
As of 23 Apr 2020, 24 out of 80 patients with a range of 1 to 4 previous therapies have been enrolled; 18 patients remain in the study. A total of 154 treatment-related emerging adverse events (TEAEs) were reported in 20 patients (83.3%) and 15 events were reported as combination-related. With the exception of anemia and dehydration, all TEAEs were reported as grade 1 or 2 (both grade 3, bavituximab-related). Tiredness (related to the combination) was the only TEAE recorded in > 2 patients. Five patients (20.8 percent) recorded sixteen severe adverse effects, all of which were recorded as unrelated to treatment, with the exception of 1 dehydration case (grade 3, bavituximab-related). There was at least one post-baseline scan assessable for anti-tumor activity in five patients: 2 partial responses, 2 stable diseases, and 1 progressive disease. Owing to an unrelated adverse condition, one patient gave up.

Findings
The 3 mg/kg dose of bavituximab with pembrolizumab with manageable adverse events and early preliminary activity was readily combined. It will present updated data from the report.

For this new addition to the GRACE Lung Cancer Video Library, Dr. Patel joins GRACE to discuss current updates in non small cell lung cancer.
In this video, Dr. Patel discusses updated information on emerging molecular targets in nsclc - KRAS.

For more, please visit http://cancerGRACE.org/. To join the conversation, visit https://cancergrace.org/forum.

For this new addition to the GRACE Lung Cancer Video Library, Dr. Ben Levy joins GRACE to discuss current updates in treatments for non small cell lung cancer.
In this video, Dr. Levy discusses updated information on immunotherapy in patients with driver mutations.

For more, please visit http://cancerGRACE.org/. To join the conversation, visit https://cancergrace.org/forum.

Edward S. Kim, MD, FACP of the Levine Cancer Institute/Carolinas HealthCare System speaks about IASLC NACLC 2020: Boehringer Ingelheim presents new data for Gilotrif® in metastatic, squamous cell carcinoma of the lung, and in EGFR mutation-positive NSCLC.


Ridgefield, Conn., October 13, 2020-Boehringer Ingelheim today announced new Gilotrif ® (afatinib) results, further confirming its activity in lung squamous cell carcinoma and non-small cell lung cancer ( NSCLC) epidermal growth factor receptor mutation-positive (EGFR M+) in a separate review. At the IASLC 2020 North America Conference on Lung Cancer organized by the International Association for the Study of Lung Cancer (NACLC 2020), the results are discussed.

A retrospective, real-world analysis of patients with metastatic squamous NSCLC who have transitioned to first-line pembrolizumab plus platinum-based chemotherapy offers efficacy and safety evidence for afatinib in this second-line setting following immunotherapy (IO). For patients who received second-line afatinib, the median average period to care (TOT) was 7.3 months (95 % confidence interval [CI]; 5.2-8.1). Six patients (pneumonitis, colitis, hepatitis) experienced an occurrence of serious immune-related adverse effects (irAEs). In this second-line setting, this study also assessed chemotherapy, with a median total TOT of 4.2 months (95 percent CI; 3.9-4.9). No irAES was identified in the chemotherapy cohort.

Researchers evaluated the use of afatinib in Asian and non-Asian patients with EGFRm+ NSCLC whose tumors have non-resistant G719X / L861Q / S768I mutations, pooled from randomized clinical trials and real-world studies, in a separate data collection presented at the conference. The analysis showed that afatinib is effective and ethnicity-free in these patients (overall response rate: 66% Asian/59% non-Asian; median response time: 14.7 months/15.9 months; G719X: 62%/65%; L861Q: 60%/50%; S768I: 80%/25%). The analysis showed that afatinib is effective in these patients.

Gilotrif is indicated for first-line treatment in patients with metastatic NSCLC whose tumors, as identified by an FDA-approved examination, have non-resistant EGFR mutations. Gilotrif is also approved for the treatment of patients with advanced lung squamous cell carcinoma whose cancer has progressed after treatment with chemotherapy based on platinum.

IASLC NACLC 2020 Data Presentations Featured:

Real-world efficacy and protection of Afatinib in the treatment of metastatic, squamous cell / mixed histology of lung carcinoma following immunotherapy (IO): a multi-site retrospective map analysis study in the US. October 16, Friday 17:00-18:00 CDT.
EGFR Mutation-positive (EGFRm+) NSCLC Harboring Major Uncommon Mutations Friday, October 16, 17:00-18:00 CDT. Afatinib in Asian and Non-Asian Patients (pts)

Andrea B. Apolo, MD of NIH National Cancer Institute speaks about the ESMO 2020 abstract New First-Line Treatment Option For Metastatic Kidney Cancer, According To Results Of Phase 3 Study.


LUGANO, Switzerland-For patients with metastatic kidney cancer, the findings of the phase 3 CheckMate 9ER trial have provided a potential first-line treatment choice. At ESMO 2020, the late break results are discussed. (1)

The research took two second-line monotherapy medications, nivolumab, and cabozantinib, and merged them for use as a first-line standard-of-care drug, sunitinib. The combination was superior for progression-free survival, overall survival, and response rate compared to sunitinib. In various subgroups, including age, gender, PD-L1 expression, bone metastases, the International Metastatic RCC Database Consortium (IMDC) risk group, and world zone, the combination has consistently benefited from sunitinib.

Due to adverse effects, more than 50 percent of patients in the combination arm required a dose reduction of cabozantinib. But as opposed to 9 percent of patients in the sunitinib arm, only 3 percent had to avoid both drugs due to toxicity. The overall incidence of severe adverse effects between the arms was comparable, but liver toxicity in the combination arm was more common. As for immune-related side effects, 19% of patients in the experimental arm required corticosteroids; for 30 days or longer, only 4% required corticosteroids.

The results lead to mounting evidence illustrating the benefits of combination therapy over single medications. The KEYNOTE-426 and JAVELIN Renal 101 trials (2,3) combined an immune checkpoint inhibitor with an anti-angiogenic drug in a similar way to the CheckMate 9ER experiment, while CheckMate 214 combined two immune checkpoint inhibitors. (4)

Matthew Tucker, Clinical Fellow at Vanderbilt University Medical Center discusses Predicting Response to Immunotherapy in Metastatic Renal Cell Carcinoma.


Quick Summary
Immunotherapy-based treatment methods for metastatic renal cell carcinoma have become the standard of care. The tumors in several patients will gradually progress, despite considerable improvement in overall survival with these therapies. This analysis highlights ongoing attempts to establish biomarkers to assist in determining which patients are most likely to benefit from immunotherapy care.

Abstract
The treatment environment for metastatic renal cell carcinoma (RCC) has been altered by immunotherapy-based combinations powered by PD-1, PD-L1, and CTLA-4 inhibitors. Many patients do not achieve deep or permanent benefits, despite major changes in clinical outcomes. Recent attempts have shown promise but have not yet influenced clinical practice to assess which patients are most likely to benefit from immunotherapy and immunotherapy-based combinations. In a few clinical trials, PD-L1 expression by immunohistochemistry ( IHC) has shown promise, while differences in the IHC assays as well as the use of different positivity values poses specific challenges for this potential biomarker. Several other candidate biomarkers have been studied, including tumor mutational burden, signatures of gene expression, single-gene mutations, endogenous human retroviruses, gastrointestinal microbiomes, and laboratory markers for peripheral blood. Although the heterogeneity of the treatment response to immunotherapy has yet to be clarified individually by these biomarkers, the use of aggregate information from these biomarkers-inform clinically useful predictive biomarkers.

Amrita Krishnan, MD, FACP of City of Hope S1803, Lenalidomide +/- Daratumumab/rHuPh20 as Post-ASCT Maintenance for MM w/MRD to Direct Therapy Duration (DRAMMATIC)


Summary Brief:
Patients are registered before or after ASCT for screening (Reg Step 1), but before Reg Step 2. Patients are monitored before they begin maintenance and are then registered (first randomization) for Reg Step 2. Between Lenalidomide for 2 years and Lenalidomide + Daratumumab/rHuPH20, patients are randomized. MRD is measured after 2 years of maintenance to guide further therapy. The assigned care will be continued by MRD-positive patients. In order to either proceed or discontinue the care assigned, MRD-negative patients will be further randomized (Reg Stage 3). Patients are handled for up to 7 years after step 2 and are monitored for up to 15 years after step 2.

Measures of key outcomes:
Overall Survival [Time Frame: measured up to 15 years from the date of initial randomization before death due to some cause]
Using a weighted log-rank test, overall survival will be measured and compared between the primary treatment arms. The review would include all qualifying patients with valid consent. At the date of last touch, patients who are last confirmed to be alive are censored.


Measures of Secondary Outcome:
Progression Free Survival [Time Frame: Measured up to 7 years from the date of initial randomization before progression or death due to some cause, whatever happens first]
Progression-free survival will be measured and compared between primary treatment arms using a weighted log-rank test. The review would include all qualifying patients with valid consent. At the date of last touch, patients who were last considered to be progression-free and alive are censored.

Answer (PR or better) [Time frame: from the date of initial randomization to the date of best response during treatment during the analysis. ]
Per International Uniform Response Requirements for Multiple Myeloma PR- ⁇ 50% decrease in the size of soft tissue plasmacytomas & plasma cells; ⁇ 50% decrease in serum & decrease in urine M protein ⁇ 90% or < 200 mg/24hr or ⁇ 50% decrease in difference in serum free light chain levels uninvolved & involved; VGPR- PR + Serum and urine M proteins detectable by immunofix

[Time frame: 24 months from initial randomization] MRD Negativity
The MRD response rate will be measured as the number of patients who have obtained an MRD response, divided by the number of qualified patients; non-responders will be included in patients without definitive MRD outcomes. A layered Cochran-Mantel-Haenszel test will be used to make comparisons between weapons.

MRD results, including the percentage of cells detected and total cells collected, will be collected from the central testing laboratory. For a typical multiple myeloma MRD sensitivity of 0.0001 percent, 5 x 106 events are collected unless the sample is small.

Negativity of MRDs will be characterized as no templates observed at a sensitivity of 1 per million cells evaluated, with at least 1 million cells evaluated.

MRD positivity will be defined as any of the templates observed irrespective of the number of cells or non-diagnostic specimens examined, even if it is not possible to sequence the reference diagnostic specimen.


Other Indicators of Outcome:
Toxicity evaluation [Time Frame: up to 7 years from the time of initial randomization. ]
For toxicity analyses, all randomized patients that have initiated treatment would be considered evaluable. For each patient, the maximum grade for each toxicity will be registered, and to assess toxicity trends, frequency tables will be checked.