Nichole Tucker, MA, is the Senior Editor for Targeted Oncology and host of the Targeted Talks podcast. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin. 

Nichole Tucker

The novel agent, eprenetapopt (APR-246) combined with azacitidine (Vidaza) has shown positive efficacy as post-transplant maintenance therapy for patients with TP53-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated in a phase 2 study (NCT03588078), Aprea Therapeutics, Inc, announced, in a press release.

The findings observed in the phase 2 stud will be shared with the FDA in the second half of 2021 and presented during an upcoming medical meeting.

“The post-transplant RFS and OS data with eprenetapopt and azacitidine maintenance therapy in these very difficult-to-treat 

-mutant MDS and AML patients are incredibly exciting,” said trial principal investigator Asmita Mishra, MD, of the H. Lee Moffitt Cancer Center and Research Institute, in a statement.

In the phase 2 study, investigators sought to determine the safety and efficacy of eprenetapopt with azacitidine and to achieved complete remission with the combination in patients with TP53-mutant MDs or AML. Patients enrolled received the combination for 6 cycles until inter-current illness, unacceptable toxicity, patient withdrawal, or disease progression. The primary end point of the study was overall survival (OS), and the secondary end point is the duration of response. Response data were previously published in the Journal of Clinical Oncology. The data announced most recently by the developer are related to remission and OS.

-mutant MDS or AML were evaluated. At 1 year, the relapse-free survival (RFS) rate post-transplant was 58% and the median RFS was 12.1 months. Also, at 1 year, the OS rate post-transplant was.79%, and the median OS was 19.3 months. In comparison with prior study data which revealed a 1-year post-transplant RFS of roughly 30% and a median OS of about 5-8 months in this patient population, the eprenetapopt and azacitidine results are an improvement.

In terms of safety, eprenetapopt plus azacitidine was also a well-tolerated post-transplant regimen for patients with 

For the study, patients were eligible given they were 18 years or older with documented MDS, chronic myelomonocytic leukemia, or AML. Patients were required to have adequate organ function a document 

 gene mutant, intermediate or high-risk status, and an ECOG performance status of 0 to 2.

Individuals were ineligible for the study if they had known human immunodeficiency virus, hepatitis B or C infection, cardiac abnormalities, or concomitant malignancies. In terms of prior therapy, patients were ineligible if they had received azacitidine, decitabine, or an investigational hypomethylating agent, cytotoxic chemotherapy within 14 days of screening, concurrent use of erythroid stimulating agents, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, and allogeneic stem cell transplant.

“Although transplant is currently the only potentially curative treatment for patients with 

-mutant MDS and AML, the risk of relapse with current standard of care remains unacceptably high and the median OS post-transplant is very limited at 8 months or less. Post-transplant maintenance therapy with eprenetapopt and azacitidine could, if approved, represent a new treatment paradigm that meaningfully improves outcomes for these patients with limited treatment options.”

Eprenetapopt is a small molecule that has shown the ability to reactivate mutant p53 protein in multiple hematologic malignancies, including MDS and AML. The agent also has demonstrated synergy with traditional anti-tumor agents like chemotherapy and immunotherapy.

Aprea Therapeutics announces positive results from phase 2 trial of eprenetapopt + azacitidine for post-transplant maintenance therapy in TP53 Mutant MDS and AML. News release. Aprea Therapeutics. July 21, 2021. Accessed July 23, 2021. 

Articles

Eprenetapop combined with azacitidine has shown positive efficacy as post-transplant maintenance therapy for patients with TP53-mutant myelodysplastic syndrome and acute myeloid leukemia treated in a phase 2 study.

Eprenetapopt With Azacitidine Demonstrates Efficacy in TP53-Positive MDS and AML

The overall survival (OS) benefit of immunotherapy combinations compared with sunitinib (Sutent) for the treatment of patients with metastatic renal cell carcinoma (mRCC) who have favorable risk may differ from those who have intermediate or poor risk, according to a pooled analysis of frontline combination therapy conducted by the US Food and Drug Administration (FDA).

“We know the possible differential benefit is larger for the combined intermediate/poor-risk group, compared to the favorable risk group. The caveat is that follow up is ongoing in each study, therefore the results and conclusion from this analysis are exploratory, noted Daniel Lee, MD, PhD of the FDA, during his presentation.

Across all mRCC risk groups, clinical trial data have shown that the outcomes are consistent for anti-VEGF therapy. For immunotherapy combinations, however, the low number of patients with favorable risk who are included in the analyses makes the outcomes observed less reliable. Although investigators are uncertain about the benefit of combination immunotherapy in this patient population, they did hypothesize that outcomes may differ and therefore studied the matter further.

Data from 3447 patients were pooled from 4 randomized phase 3 clinical trials. One of the trials combined 2 immunotherapy agents, and the 3 others studied combinations of immunotherapy and anti-VGF therapy. Utilizing an International Metastatic RCC Database Consortium (IMDC) risk model, each patient assessed was classified as either intermediate/poor risk or favorable risk. Then, Kaplan-Meier and Cox Proportional Hazards methods were used to compare the OS between the immunotherapy combination to the sunitinib control arm.

In total, 422 patients were treated with an immunotherapy combination in the favorable risk group and 404 were treated with sunitinib. The death rate in the arms was 22.0% versus 23.0%, respectively. The median OS was not reached (NR) in either arm (95% CI, NR, NR). The hazard ratio (HR) was 0.953 (95% CI, 0.72-1.27).

In the intermediate/poor risk population, 1,308 patients received an immunotherapy combination compared 1,313 who received sunitinib. There were deaths rates in the study arms of 40.8% versus 50.9%, respectively. The median OS observed in the combination arm was 46.8 months (95% CI, 39.9 to not reached). In comparison, the median OS was 29.3 months with sunitinib (95% CI, 26.0-32.9), showing an HR of 0.696 (95% CI, 0.62-0.78).

Providing an explanation of these data, Lee stated during his presentation, “In looking at the hazard ratios, there was an absence of benefit for the favorable risk group, whereas there was a benefit in the combined intermediate poor-risk group. And looking at the survival curves, for the favorable risk there was no difference in survival, whether the patients received the combination therapy or sunitinib. In comparison, for the combined intermediate poor-risk group, there was a difference in survival, which favored the combination therapy.”

. 2021;39(suppl 15):4559. doi: 10.1200/JCO.2021.39.15_suppl.4559

The overall survival benefit of immunotherapy combinations compared with sunitinib for the treatment of patients with metastatic renal cell carcinoma who have favorable risk may differ from those who have intermediate or poor risk, according to a pooled analysis of frontline combination therapy conducted by the FDA.

Overall Survival Results of I/O Combinations Differ Across Risk Groups of Metastatic RCC

The management of immune-related adverse events (irAEs) resulting from treatment with immune checkpoint inhibitor (ICI) monotherapy or in combination regimens was probed by an expert panel brought together by the Society for Immunotherapy of Cancer (SITC). Based on the review, SITC has published a clinical practice guideline, which provides key recommendations for managing irAEs.

According to research, IRAEs contribute significantly to the toxicity profile of immunotherapies. Specifically, programmed death-ligand 1 (PD-L1) inhibitors lead to irAEs in 74% of patients and these irAEs are grade 3 or higher for 14% of patients. The incidence of irAEs is even higher with anti-CTLA-4 agents at 84%. Anti-CTLA-4 therapies also have a 34% incidence of grade 3 or higher irAEs. ICI combination regimens led to irAEs in 90% of patients with 55% being grade 3 or higher in severity.

“Over the past decade or so, the role of immuno-oncology has expanded dramatically, particularly with the introduction of immune checkpoint inhibitors, Marc Ernstoff, MD, chief of the ImmunoOncology Branch at the NCI Division of Cancer Treatment and Diagnosis, Developmental Therapy Program at the National Institute of Health told Targeted Oncology (TO), in an interview.

“The use of these agents is now in many different cancers, and the spectrum of toxicities associated with immune checkpoint inhibitors is unique and differs dramatically from the standard chemotherapy or radiation. It's critical that SITC as well as other societies put forward understanding the mechanism, the breath mechanism, and treatment of these toxicities,” Ernstoff added.

In characterizing irAEs associated with ICI therapy further, it was shown that more common events like thyroiditis and dermatitis, are different from chemotherapy-related AEs, and the timing of these irAEs is less predictable. The unique mechanisms of action found with ICIs combined with data from clinical trials make clinical practice guidelines for managing irAEs an important need for oncologists.

The experts modeled the clinical practice guidelines according to The Institute of Medicine’s (IOM) Standards for Developing Trustworthy Clinical Practice Guidelines. Literature review along with open communication and scientific debate was used by the experts to develop the recommendations, then a draft of the clinical practice guidelines was released to the public for comment before being finalized. The finalized SITC panel clinical practice guidelines included general panel recommendations, recommendations by type of toxicity, and recommendations for the use of ICI combinations.

First, the general panel recommendations provide guidance around treatment hold and discontinuation, timing and dosing for corticosteroids and similar agents, baseline screening and testing, and what to do for patients who have various grade levels of irAEs.

For oncologists, the panel recommends performing a complete blood count (CBC) with differential, comprehensive metabolic panel (CMP), thyroid-stimulating hormone (TSH), free thyroxine (fT4) before beginning any ICI therapy. In addition, urinalysis should be performed for patients who have kidney disease at baseline to evaluate their condition. The panel also advises that oncologists should consider performing an electrocardiogram for patients who have a higher probability of developing myocarditis. Troponin test at baseline may also be appropriate if a patient has potential for future cardiac toxicity.

During treatment, oncologists should also carry out CBC with differential, CMP, TSH, and fT4 tests intermittently for patients being treated with ICIs.

Oncologists are also encouraged to counsel their patients well regarding irAEs and the possibility of exacerbation or flare-ups that may follow ICI therapy if they have a history of a non-life-threatening autoimmune disease.

For patients with cancer, treating physicians should encourage contraception while giving immunotherapy and fertility should be discussed before treatment. The risk-benefit profiles of ICI therapy should be discussed with patients with an autoimmune disease before they are treated. During ICI therapy, patients should be referred to a specialist in the event of grade 3 toxicity that does not respond to steroids.

In terms of continuing, holding, or discontinuing ICIs, the expert panel advises that grade 1 irAEs do not warrant holding or discontinuing therapy, but the issue should be monitored for worsening symptoms. In the case of grade 2 irAEs, treatment should be temporarily withheld, and patients should receive corticosteroids if appropriate.

Regarding re-challenging patients with ICI, the recommendations are that the decision is thought through to consider the potential threat on the patient’s life, prolonged or multiple immunosuppressants, history of long-term therapy on an ICI, and whether patients have had complete responses or durable clinical benefit when previously on the ICI. For patients who have a grade 3 or 4 irAE, the oncologist should weigh the benefits and risks before re-challenging.

The final general panel recommendation states that any grade myositis, myocarditis, or neurological toxicities in patients performing erythrocyte sedimentation rate, C reactive protein, creatine kinase, antibody tests acetylcholine, muscle-specific kinase, striational, aldolase, troponin, EKG, nerve conduction, and electromyography testing on patients. Frequent pulmonary assessment and the usual irAE treatment should be performed on patients. All recommendations should be followed unless otherwise specified.

“The toxicities of these agents are different and unique, and the identification and diagnosis of the toxicities, therefore, become important to recognize. The treatment or the management of the toxicities are also different than other standard therapies. It needed to be outlined for individuals and that the toxicity profile is such that it's not always immediate and doesn't necessarily follow immediately upon therapy but can be delayed. Also, the management of the toxicities many times requires multiple specialties,” Ernstoff stated.

Aside from the general panel recommendations, the toxicity type-based recommendations offer more in-depth details on what oncologists should do if a patient with cancer who is receiving ICI therapy experiences the following toxicity types:

Covering the section in its totality, Ernstoff told TO, “independent of whether the toxicities are gastrointestinal, or skin, or related to the central nervous system, the grading of the toxicities are significant. The toxicities associated with each of organ that can be involved is critical because it could be life-threatening. Although it's exceedingly rare, bullous formation in skin toxicity could be potentially life-threatening, if not recognized early and managed. Cardiomyocyte and the development of type 1 diabetes can be life-threatening, if not identified, and associated gastrointestinal toxicity, which is usually diarrhea associated with colitis, if not recognized can cause perforation and catastrophic events, explained Ernstoff. “So, it's important to recognize that while many of these agents, particularly single-agent therapies are well tolerated in general, we shouldn't be lulled into complete compliance complacency in querying our patients and making sure we follow them closely for the development of the side effects.”

Ernstoff further explained the treatment of irAEs in patients with cancer often requires the expertise of more than just the treating oncologist.

“The first identification of the event and the severity of the event many times requires a collaboration with a multidisciplinary team. Recognizing early in the development of toxicity, whether it be gastrointestinal, cardiovascular, or neurological, that collaboration with appropriate subspecialty is critical in managing that toxicity,” said Ernstoff.

The key concern related to the use of ICI combinations is that patients are at a higher risk of experiencing toxicities in comparison to patients being treated with a single agent. The panel recommends counseling patients about this fact, especially if 1 of the agents in their regimen is ipilimumab (Yervoy) dosed at 3 mg/kg. These patients should also be monitored frequently for signs of irAEs.

The panelists recommend counseling patients to monitor their blood pressure regularly when receiving the combination of pembrolizumab (Keytruda) and axitinib (Inlyta). Patients who develop hypertension because of an ICI combination should receive medication for hypertension and the axitinib should be held if the event is grade 2 or higher.

Moreover, the recommendations state that physicians should uncover the source of the irAEs because in the event that the irAE is not related to ICI therapy, the dose does not require reduction. Patients should be referred to a specialist if the oncologist cannot determine the origin of the irAE.

“Managing toxicities is a complicated area. The key message is that one must recognize that this is a different therapy that has its unique toxicities. To be able to use ICI therapies effectively, one has to be able to recognize and manage those toxicities,” Ernstoff concluded about the clinical practice guidelines.

1 Society for Immunotherapy of Cancer publishes clinical practice guideline on immune checkpoint inhibitor-related adverse events. News release. July 14, 2021. Accessed July 18, 2021. 

2 Brahmer JR, Abu-Sheih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6): e002435. doi: 10.1136/jitc-2021-002435.

3 Hargadon KM, Johnson CE, Williams CJ, et al. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. 

Based on a review of immune checkpoint inhibitor mechanisms of action and clinical trial data, SITC has published a clinical practice guideline, which provides key recommendations for managing immune-related adverse events.

SITC Releases Clinical Practice Guideline to Aid in the Management of Immune-Related Adverse Events from ICI Therapy

The FDA has granted breakthrough therapy designation (BTD) to the combination of venetoclax (Venclexta) and azacitidine (Vidaza) for the treatment of adult patients with previously untreated intermediate-, high- and very high-risk myelodysplastic syndromes (MDS) per the revised International Prognostic Scoring System (IPSS-R), according to a press release issued by Roche.

Results from the phase 1b M15-531 study (NCT02942290) supported the BTD. M15-531 is an ongoing study investigating the safety and pharmacokinetics of venetoclax plus azacitidine in approximately 137 patients with treatment-naïve higher-risk MDS. The study was initiated to address the short median survival of the population, which is about 18 months. The co-primary end points being explored include area under the curve for both agents, maximum plasma concentration, time of maximum plasma concentration, half-life for azacitidine, clearance for azacitidine, and the recommended phase 2 dose (RP2D) of the combination of venetoclax and azacitidine. The secondary end points include duration of response, rate of red blood cell transfusion independence, progression-free survival (PFS), overall survival (OS), hematologic improvement rate, and other efficacy end points. 

“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development. “We are pleased that the FDA has granted Venclexta its sixth Breakthrough Therapy Designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine.”

Results from the M15-531 study, presented during the 2020 American Hematology Association Annual Meeting and Exposition, showed that venetoclax plus azacitidine has promising efficacy with response durability and a tolerable safety profile.

The analysis included 57 patients followed-up for a median of 13.0 months (95% CI, 11.3-15.6). The population was largely male (75%) and had a median age of 71 years (range, 26-85 years). Also, 89% of the patients had an ECOG performance status of 0 or 1.

Treatment with venetoclax plus azacitidine led to an objective response rate of 77%, which included complete responses in 42% and marrow CRs in 35%. Of the patients who achieved a CR, 40% had CR with hematological improvement. Responses lasted for a median duration of 14.8 months (95% CI, 12.9 to not estimable [NE])

In terms of survival, the median OS was not reached (95% CI, 16.2 to NE). The median PFS was 17.5 months (95% CI, 14.5 months to NE).

At least 1 adverse event (AE) was observed in all patients treated. The most common AEs observed were constipation (54%), neutropenia (51%), and nausea (51%). Grade ≥3 AEs were experienced by 97% of patients, with neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%). Of the serious AEs observed, febrile neutropenia was the most common. The patients also had a 2% 30-day mortality rate.

Quality of life measurement were also assessed during the analysis. It was shown that of those who received the RP2D venetoclax (400 mg for 14 days per every 28-day cycle) combined with azacitidine, physical functioning was maintained through 48 weeks. Further, clinically meaningful improvement in dyspnea and fatigue were seen within the firs 48 weeks of treatment.

The BTD granted for treatment-naïve MDS is the 6th BTD for venetoclax. The agent also has BTDs for previously untreated chronic lymphocytic leukemia (CLL), 2 for relapsed or refractory CLL, 2 for patients with previously untreated acute myeloid leukemia, and 1 for those with myelodysplastic syndromes.

1. FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. July 21, 2021. Accessed July 21, 2021. 

2. Garcia JS, Wei AH, Borate U, et al. 656 Safety, Efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. 

The FDA has granted breakthrough therapy designation to the combination of venetoclax and azacitidine for the treatment of adult patients with previously untreated intermediate-, high- and very high-risk myelodysplastic syndromes.


Nichole Tucker | Authors

Articles

Eprenetapopt With Azacitidine Demonstrates Efficacy in TP53-Positive MDS and AML

Overall Survival Results of I/O Combinations Differ Across Risk Groups of Metastatic RCC

SITC Releases Clinical Practice Guideline to Aid in the Management of Immune-Related Adverse Events from ICI Therapy

FDA Breakthrough Therapy Designation Granted to Venetoclax/Azacitidine for Treatment-Naïve MDS