Nichole Tucker

The FDA has granted an Orphan Drug designation to CPI-613 (devimistat) for the treatment of soft tissue sarcoma, Rafael Pharmaceuticals announced in a press release.

In the soft tissue sarcoma treatment landscape, few treatment options exist due to the rarity of the disease. To address the unmet medical need for a new therapy in this space, Rafael Pharmaceuticals recently launched a phase 1/2 study to find the maximum tolerated dose (MTD) of CPI-613 in patients with relapsed/refractory soft tissue sarcoma and determine the efficacy and safety of the drug.

“There is a significant unmet need in treatment for soft tissue sarcoma,” said Sanjeev Luther, president and chief executive office of Rafael Pharmaceuticals, in a statement. “When a disease is rare, it often does not receive the attention and focus necessary to develop effective treatments for it,” he added.

In addition to the goal of finding the MTD of CPI-613, the open-label trial is measuring objective response rates to determine efficacy, and the dose-limiting toxicities of CPI-613 as coprimary end points of the study. The secondary end points include duration of response, progression-free survival, and overall survival.

To be eligible for enrollment, patients are required be aged 11 to 75 years with either a Karnofsky performance status of 60 or an ECOG performance status of 0 to 1. Patients are also required to have adequate bone marrow function, renal function, liver function, and neurological function as well as good laboratory results at baseline.

The study will exclude patients who have received chemotherapy within 7 days of treatment initiation, who have other curative anticancer treatment options, are hypersensitive to CPI-613 or hydroxychloroquine. Patients are also ineligible for this trial is f they have any medical or phycological condition that may interfere with study treatment, uncontrolled infection, of any life-threatening or severe malignancy complications.

CPI-613 is an experimental anti-mitochondrial agent that is currently under investigation in different tumors. Notably, Rafael Pharmaceutical recently announced progressed in the enrollment of a phase 3 clinical trial of CPI-613 in patients with acute myeloid leukemia. In addition to AML, this drug is under investigation in clinical trials of patients with pancreatic cancer, myelodysplastic syndrome, peripheral T-cell lymphoma, and Burkitt lymphoma.

FDA Grants Rafael Pharmaceuticals Orphan Drug Designation for CPI-613® (devimistat) for treatment of soft tissue sarcoma. News release. Rafael Pharmaceuticals. October 29, 2020. Accessed October 29, 2020. 

Articles

The FDA has granted an Orphan Drug designation to CPI-613 for the treatment of soft tissue sarcoma.

FDA Grants Orphan Drug Designation to Devimistat for Soft Tissue Sarcoma

The FDA has accepted the supplemental Biologics License Application (sBLA) for cemiplimab-rwlc (Libtayo) and granted it Priority Review for the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with ≥50% PD-L1 expression.

 The Prescription Drug User Fee Act target action date for this potential approval is set to February 28, 2021.

The sBLA for cemiplimab as treatment of this patient population was supported by findings from the phase 3 EMPOWER-Lung1 clinical trial of cemiplimab versus chemotherapy in patients with advanced or metastatic PD-L1–positive NSCLC, for which topline results were recently presented during the European Society of Medical Oncology (ESMO) Virtual Annual Congress 2020.

In the intention-to-treat (ITT) population of the study, 710 patients were included and 88 of those patients were identified as having a PD-L1 expression of ≥ 50%, as identified by the PD-L1 IHC 22C3 pharmDx kit. All patients in the study were evaluated for the coprimary end points of overall survival (OS) and progression-free survival (PFS). The secondary end points assessed were objective response rate (ORR), duration of response (DOR), health-related quality of life (HRQoL), and safety.

The ITT population had a median OS of 22.1 months (95% CI, 17.7 to not evaluable [NE]) in the cemiplimab arm versus 14.3 months (95% CI, 11.7-19.2) in the chemotherapy arm (HR, 0.68; 95% CI, 0.53-0.87; 

 = .0022). At 12 months, the OS rate in this population was 70.3% (95% CI, 64.4%-75.4%) with cemiplimab compared with 55.7% (95% CI, 49.2%-61.7%) with chemotherapy. The 24-month OS rate was 48.6% (95% CI, 39.2%-57.3%) in the cemiplimab arm versus 29.7% (95% CI, 18.8%-41.4%) in the chemotherapy arm.

Also, in the overall ITT population, the median PFS was 6.2 months (95% CI, 4.5-8.3) with cemiplimab compared with 5.6 months (95% CI, 4.5-6.1) with chemotherapy (HR, 0.59; 95% CI, 0.49-0.72; 

 = .0001). Treatment with cemiplimab showed a 12-month PFS rate of 37.8% (95% CI, 31.9%-43.6%) with cemiplimab compared with 7.2% (95% CI, 4.3%-11.25) with chemotherapy. The 18-month PFS rate was 28.0% (95% CI, 21.7%-34.7%) with cemiplimab versus only 3.9% (95% CI, 1.8%-7.5%) with chemotherapy.

Among the group of patients with high PD-L1 expression, the median OS was not reached (95% CI, 17.9-NE) in the cemiplimab arm compared with 14.2 months (95% CI, 11.2-17.5) in the chemotherapy arm (HR, 0.57; 95% CI, 0.42-0.77; 

 = .0002). At the 12-month mark, the OS rate in the cemiplimab arm was 72.4% (95% CI, 65.6%-78.1%) versus 53.9% (95% CI, 46.2-61.1) in the chemotherapy arm. At 24 months, the OS rate was 50.4% (95% CI, 36.4%-62.9%) in the cemiplimab arm compared with 27.1% (95% CI, 13.7%-42.5%) in the chemotherapy arm.

The median PFS observed in the high PD-L1 expression group was 8.2 months (95% CI, 6.1-8.8) with cemiplimab versus 5.7 months (95% CI, 4.5-6.2) with chemotherapy (HR, 0.53; 95% CI, 0.43-0.68; 

 = .0001). Cemiplimab achieved a 12-month PFS rate of 40.7% (95% CI, 33.7%-47.5%) compared with the 7.1% (95% CI, 3.6%-12.1%) observed with chemotherapy. At 18 months, the PFS rate was 27.8% (95% CI, 19.4%-36.7%) in the cemiplimab arm and NE in the chemotherapy arm.

The OS and PFS benefits observed with cemiplimab over chemotherapy in the overall and high PD-L1 populations were carried across the subgroup populations assessed in the study.

In terms of the study’s secondary end points, the ORR in patients with and without PD-L1 expression ≥50% favored the cemiplimab arm, however, the high PD-L1 expression group had higher response rates. The overall ITT population achieved an ORR of 36.5% (95% CI, 31.5%-41.8%) with cemiplimab compared with only 20.6% (95% CI, 16.5%-25.2%) with chemotherapy (

 <.0001). Notably, 3.1% of the responses observed in the cemiplimab arm were complete responses (CRs) compared with only 0.8% of the chemotherapy group. The median DOR in this population was 21.0 months (95% CI, 14.9-NE) in the cemiplimab arm versus 6.0 months (95% CI, 4.3-6.4) in the chemotherapy arm.

Patients with high PD-L1 expression had an ORR of 39.2% (95% CI, 33.5%-45.2%) with cemiplimab versus 20.4% (95% CI, 15.8%-25.6%) with chemotherapy (

 <.0001). With cemiplimab, the CR rate was 2.1% compared with 1.1% in the chemotherapy arm. The median DOR in the high PD-L1 group was 16.7 months (95% CI, 12.5-22.8) with cemiplimab compared with 6.0 months (95% CI, 4.3-6.5) in the chemotherapy arm.

Cemiplimab therapy led to improved HRQoL scores in patients, defined as a ≥10-point increase from outcomes assessed at baseline. In comparison, chemotherapy led to a ≥10-point deterioration of HRQoL in patients.

The safety analysis of EMPOWER-Lung1 supported the positive benefit-risk profile of cemiplimab. Treatment-emergent adverse events (TEAEs) were observed in 88.2% of the study population with 37.2% being grade 3 to 5 in severity. TEAEs led to treatment discontinuation in 6.5% of the population and death in 9.6%. Immune-related AEs were also observed in the study (17.5%), leading to discontinuation in 2.5% of patients, and death in 0.3%.

The most common TEAEs of any-grade observed in the study were anemia (14.6%), decreased appetite (11.8%), fatigue (10.1%), pneumonia (9.3%), and constipation (7.6%).

EMPOWER-Lung1 is an open-label, randomized, multicenter trial for which analyses are ongoing. In addition to the FDA, the European Medicines Agency is also reviewing the study data while considering cemiplimab for approval as treatment of advanced NSCLC with ≥50% PD-L1 expression. A decision is expected in the second quarter of 2021.

Cemiplimab is a monoclonal antibody which targetes the immune checkpoint receptor PD-1 on T cells. Studies of this agent are ongoing across multiple tumor types, including cutaneous squamous cell carcinoma and advanced basal cell carcinoma.

1. FDA accepts for Priority Review Libtayo® (cemiplimab-rwlc) for advanced non-small cell lung cancer with pd-l1 expression of ≥50%. News release. Regeneron Pharmaceuticals. October 29, 2020. Accessed October 29, 2020. 

2. Sezer A, Kilickap S, Gumus M, et al. EMPOWER-Lung 1: Phase 3 first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (Chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract LBA52.

The FDA has accepted the supplemental Biologics License Application for cemiplimab-rwlc and granted it Priority Review for the frontline treatment of patients with locally advanced or metastatic non–small cell lung cancer with ≥50% PD-L1 expression.

FDA Grants Priority Review to Frontline Cemiplimab for PD-L1-High Advanced or Metastatic NSCLC

In evaluating MYC rearrangement and its correlation with disease burden and prognostics in newly diagnosed multiple myeloma, a group of Mayo Clinic investigators found that the alteration is associated with high disease burden and independently prognosticates adverse outcomes in patients.

The study was a retrospective analysis of database information on patients with multiple myeloma treated in the real-world setting. Prior to this study, the prognostic value of MYC had not been established, but such understanding is needed in the field considering the commonality of MYC rearrangements in this patient population.

A total of 1342 patient records were retrospectively reviewed from patients treated at the Mayo Clinic in Rochester, Minnesota from January 2006 through January 2018. These patients were newly diagnosed with multiple myeloma by fluorescence in-situ hybridization (FISH). Testing for MYC was conducted with the break apart FISH probe at baseline, at which time it was determined that 111 patients (8%) had an MYC rearrangement.

Patients were treated with either a proteasome inhibitor (PI)-based therapy, an immunomodulatory agent (IMiD), or a combination of both a PI-based therapy and IMiD. The 2 PI-based regimens used were bortezomib (Velcade)-containing combinations (n = 373), or ixazomib-containing regimens ([Ninlaro], n = 38) . The IMiD regimens contained lenalidomide ([Revlimid], n = 411) or thalidomide ([Thalomid], n = 18). Finally, the regimens combining PIs and IMiDs that some patients received included bortezomib plus lenalidomide (n = 358), carfilzomib plus lenalidomide (n = 27), bortezomib plus thalidomide (n = 11), ixazomib plus lenalidomide (n = 8), and carfilzomib plus thalidomide (n = 7).

Among the population of patients with newly diagnosed multiple myeloma and an MYC rearrangement, no differences in overall response rates (ORRs) were observed. Patients who were treated with either bortezomib combination or ixazomib combination achieved ORRs of 76% vs. 80%, respectively (

 =.53). Those treated with the IMiD regimens of either lenalidomide or thalidomide had ORRs of 91% vs. 82%, respectively (

 =.02). In terms of combination therapy with a PI and IMiD, the ORR was 88% compared with 95% (

The achievement of very good partial responses (VGPRs) was were assessed in the study and showed that the presence of MYC rearrangement led to fewer VGPRs compared with those who did not have MYC rearrangements in the population treated with a PI plus an IMiD. No significant difference in VGPR rates in patients treated with the PI-based regimens compared with the IMiD-based regimens. The VGPRs rate were 35% vs. 60% for PI-based regimens (

 =.73), 36% vs. 29% for IMiD-based regimens (

 =.33). It was also notable that all patients who underwent post-induction transplant had a PR to treatment and 85% of those treated with PI-containing regimens versus 80% of those treated with IMiD-containing regimens, regardless of MYC rearrangement status (

In terms of survival, it appeared that MYC rearrangement led to significantly shorter overall survival (OS) in patients with multiple myeloma. The median OS observed in patients with MYC rearrangement was 5.3 years (95% CI, 4.4-6.1) compared with 8.0 years (95% CI, 6.9-8.9) in patients who did not have MYC rearrangements (

Notably, MYC rearrangements in patients with multiple myeloma were associated with increased mortality compared to absence of MYC rearrangements with a risk ratio of 1.7 (95% CI, 1.3-2.2; 

Looking at characteristics of patients gathered at baseline, it was also revealed that the presence of MYC rearrangements versus the absence of MYC rearrangements was indicative of elevated β2-microglobulin (71% vs. 58%; P = .01), respectively. MYC rearranged multiple myeloma also led to more than 50% bone marrow plasma cells (70% vs. 54%; 

=.003), respectively, as well as lytic lesion (78% vs. 58%; P =.04), and immunoglobulin G multiple myeloma (35% vs. 24%; 

It was determined based on these real-world data that MYC rearrangements may play a role in risk stratification of patients with newly diagnosed multiple myeloma.

Abdallah N, Baughn LB, Rajkumar SV, et al. Implications of MYC rearrangements in newly diagnosed multiple myeloma. 

. Published online October 2, 2020. doi: 10.1158/1078-0432.CCR-20-2283

MYC Status Relevant to Risk Stratification in Newly Diagnosed Multiple Myeloma

The FDA has granted approval to the FoundationOne®Liquid CDx as a companion diagnostic indicated for the to identify patients who may derive benefit from treatment with 3 FDA-approved targeted therapies, including alpelisib (Piqray), rucaparib (Rubraca), and alectinib (Alecensa).

In addition, the FDA expanded the label indication of the FoundationOne Liquid CDx as a tool to report select copy number alterations and genomic rearrangements.

“FoundationOne Liquid CDx offers oncologists an important and minimally invasive tool to consider when making treatment decisions for their patients, regardless of the type of cancer they have,” said Brian Alexander, MD, MPH, chief medical officer at Foundation Medicine, in a statement.

Alpelisib was granted approval by the FDA in May 2019 for the treatment of postmenopausal women and men with hormone receptor (HR)-positive, HER2-negative, 

-mutated, advanced or metastatic breast cancer following progression on or after treatment with an endocrine-based regimen. This agent was approved for this indication based on data from the phase 3 SOLAR-1 clinical trial (NCT02437318).

The FDA approval for rucaparib was granted in December 2016 as treatment of patients with deleterious 

-mutated advanced ovarian cancer who have received at least 2 prior lines of chemotherapy. The approval of the Biologic License Application for rucaparib under this indication was supported by findings from 2 multicenter, single-arm, open label clinical trials of rucaparib in 106 patients with advanced ovarian cancer. One study was a phase 1/2 study (NCT01482715), and the other was the phase 2 ARIEL2 study (NCT01891344).In these studies, FoundationFocus CDxBRCA test was utilized to determine to verify presence of 

Alectinib received FDA approval in November 2017 for the treatment of patients with ALK-positive metastatic non–small cell lung cancer (NSCLC), as detected by an FDA-approved test. This approval was based on data from the phase 3 ALEX clinical trial (NCT02075840) of alectinib plus crizotinib (Xalkori) in patients with 

-positive NSCLC who had not received prior systemic therapy for metastatic disease.

Based on the indications of these FDA-approved targeted therapies, FoundationOne Liquid CDx is now expanded to include detection of women or men with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, 

 mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen who may benefit from the combination of alpelisib and fulvestrant. The assay is also expanded for use as an identifier of adult patients with a deleterious 

 mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapy agents who may derive benefit from rucaparib. Finally, the indication for FoundationOne Liquid CDx is expanded to include the detection of patients with 

-positive metastatic NSCLC who could benefit from treatment with alectinib.

These 3 additional companion diagnostic claims expand the test’s clinical utility into breast and ovarian cancer, demonstrating our commitment to bringing precision medicine to more patients, and we plan to continue working with our biopharma partners to increase that reach,” said Alexander in a statement.

FoundationOne Liquid CDx is a comprehensive liquid biopsy assay that profiles tumors according to the testing guidelines for the various solid tumors. The assay is able to evaluate more than 300 cancer-related gene for genomic alteration. Results from testing with FoundationOne Liquid CDx are provided in an integrated report that shows alteration in patients and the match FDA-approved therapies to target these alterations.

In addition to its expanded indications, the assay was granted approval as a companion diagnostic to assist in identifying patients with metastatic castration-resistant prostate cancer patients with qualifying 

/2 alterations who may derive benefit from an FDA-approved PARP inhibitor, and to identify those with NSCLC who may do well on treatment with an EGFR tyrosine kinase inhibitor.

1. FDA approves new FoundationOne®Liquid CDx companion diagnostic indications for three targeted therapies that treat advanced ovarian, breast and non-small cell lung cancer. News release. Foundation Medicine, Inc. October 27, 2020. Accessed October 28, 2020. 

2. FDA approves alpelisib for metastatic breast cancer. News release. FDA. May 24, 2019. Accessed October 28, 2020. 

3. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed October 28, 2020. 

4. Alectinib approved for (ALK) positive metastatic non-small cell lung cancer (NSCLC). News release. FDA, November 6, 2017. Accessed October 28. 2020. 

The FDA has granted approval to the FoundationOne Liquid CDx as a companion diagnostic indicated for the to identify patients who may derive benefit from treatment with 3 FDA-approved targeted therapies, including alpelisib, rucaparib, and alectinib.

Author | Nichole Tucker

Articles

FDA Grants Orphan Drug Designation to Devimistat for Soft Tissue Sarcoma

FDA Grants Priority Review to Frontline Cemiplimab for PD-L1-High Advanced or Metastatic NSCLC

MYC Status Relevant to Risk Stratification in Newly Diagnosed Multiple Myeloma

FoundationOne Liquid CDx Granted New and Expanded FDA Indications in Various Solid Tumors