The FDA has approved atezolizumab (Tecentriq) plus cobimetinib (Cotellic) and vemurafenib (Zelboraf) for the treatment of patients with 

 mutation-positive advanced melanoma, according to Genentech, atezolizumab’s developer.

The approval was based on results from the multi-center, double-blind, placebo-controlled, randomized, phase 3 IMspire150 study, which evaluated individuals with previously untreated 

 mutation-positive metastatic or unresectable locally advanced melanoma. The study compared the efficacy and safety of atezolizumab plus cobimetinib and vemurafenib to the combination of placebo plus cobimetinib and vemurafenib.

The primary end point of the study was investigator-assessed progression-free survival (PFS). Key secondary end points included PFS by an independent review committee, overall survival (OS), objective response rate, duration of response, and other safety and pharmacokinetic measures.

Overall, the addition of atezolizumab to cobimetinib and vemurafenib led to a longer PFS, compared to placebo plus cobimetinib and vemurafenib (median PFS, 15.1 months vs 10.6 months, respectively; HR, 0.78; 95% CI, 0.63-0.97; 

“When receiving a cancer immunotherapy combined with targeted therapies, patients with 

 mutation-positive advanced melanoma were able to live for more than 15 months without their disease worsening,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a press release. “Today’s FDA approval of this [atezolizumab] combination represents an important step forward for many patients living with advanced melanoma.”

The safety profile observed in the atezolizumab combination was consistent with the known safety profiles of the individual medicines. The most common adverse events (AEs; rate ≥20%) observed in patients who received atezolizumab plus cobimetinib and vemurafenib were rash (75%), musculoskeletal pain (62%), fatigue (51%), hepatotoxicity (50%), pyrexia (49%), nausea (30%), pruritus (26%), edema (26%), stomatitis (23%), hypothyroidism (22%), and photosensitivity reaction (21%).

The supplemental Biologics License Application (sBLA) for atezolizumab was granted under priority review. Moreover, the review was also conducted under the FDA’s Project Orbis.

FDA Approves Genentech’s Tecentriq plus Cotellic and Zelboraf for People With Advanced Melanoma [news release]. South San Francisco, CA. Published July 30, 2020. gene.com/media/press-releases/14868/2020-07-30/fda-approves-genentechs-tecentriq-plus-c. Approved July 30, 2020.

This article originally appeared on CancerNetwork.com.

Articles

The FDA approved atezolizumab plus cobimetinib and vemurafenib for the treatment of patients with BRAF V600 mutation-positive advanced melanoma.

FDA Approves Atezolizumab Combo for Advanced Melanoma

 indicated that there has been a significant nationwide decrease in all cancer-related patient encounters as a result of the coronavirus disease 2019 (COVID-19) pandemic.

The findings also inherently suggest the possibility of a future increase in patients with later-stage cancer being seen, as well as an increased demand for cancer screening procedures due to delayed tests being rescheduled.

“These findings are truly striking, as modeling from the National Cancer Institute has predicted thousands of expected increases in cancer death as a result of deferred breast and colorectal screening alone,” Karen E. Knudsen, MBA, PhD, executive vice president of Oncology Services at Jefferson Health and enterprise director of the Sidney Kimmel Cancer Center (SKCC), said in a press release.

 “This report is a nationwide call to arms, underscoring the urgent need to resume cancer screening and early detection.”

Using the TriNetX platform, researchers analyzed 20 different healthcare institutions with relevant, up-to-date encounter data from January 1, 2019 through April 30, 2020 to create the COVID and Cancer Research Network (CCRN). They then compared the data from cohorts of patients with cancer pre-COVID (January 2019 to April 2019) to current cohorts (January 2020 to April 2020). Notably, cohorts were generated for all patients with neoplasms (malignant, benign, in situ, and of unspecified behavior), with new incidence neoplasms (first encounter), with exclusively malignant neoplasms, and with new incidence malignant neoplasms.

Overall, unambiguous trends were identified which suggested a significant decline in all current cohorts evaluated, with April 2020 displaying the largest decrease in the number of patients with cancer having encounters. More specifically, among the cancer types identified, the lung, colorectal, and hematologic cancer cohorts demonstrated smaller decreases in size in April 2020 versus 2019 (-39.1%, -39.9%, -39.1%, respectively) compared with cohort size decreases for breast cancer, prostate cancer, and melanoma (-47.7%, -49.1%, -51.8%, respectively).

In addition, the investigators also found that mammograms declined 89.2% in April 2020 compared with April 2019, and colorectal cancer screenings declined by 84.5% during the same period. Moving forward, the researchers indicated that they intend to track screenings in the coming months as virus mitigation efforts are eased to help predict how many patients are continuing to delay cancer screenings due to the pandemic.

“The most significant finding in our study was the considerable drop in cancer screenings. The fact that this trend was so drastic nationwide is telling of the widespread effect of the pandemic and mitigation efforts — even in regions that had not seen a significant impact from the virus at the time,” senior author Christopher McNair, PhD, director of Cancer Informatics at SKCC, said in the release.

Throughout the summer and into the fall, the researchers will continue to observe the trends in care of patients with cancer, especially as more states become more drastically affected. According to McNair, it will be important to understand trends in cancer diagnoses to determine if delays in screening are resulting in an increased number of patients presenting with later-stage disease.

“Ultimately, these observed trends have serious implications for future cancer care and validate the need to study and monitor the effect of COVID-19 mitigation on cancer diagnosis and treatment moving forward,” the study authors wrote.

1. London JW, Fazio-Eynullayeva E, Palchuk MB, Sankey P, McNair C. Effects of the COVID-19 Pandemic on Cancer-Related Patient Encounters. JCO Clinical Cancer Informatics. doi:10.1200/CCI.20.00068.

2. Nationwide Trends Show Fewer Cancer Patients Seeking Care Since Start of Pandemic [news release]. Philadelphia. Published July 27, 2020. Accessed July 28, 2020.

These findings have serious implications for future cancer care and underscore the need to resume cancer care and screening.

Nationwide Decrease Seen in Cancer-Related Encounters Due to the COVID-19 Pandemic

The FDA has accepted 2 new supplemental biologics license applications (sBLAs) for pembrolizumab (Keytruda) to treat certain patients with triple-negative breast cancer (TNBC), according to Merck, the developer of the agent.

The FDA has accepted and granted priority review for a new sBLA seeking accelerated approval for pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (combined positive score [CPS] ≥10). The application was based on results observed in the phase 3 KEYNOTE-355 trial. A prescription drug user fee act (PDUFA) date was set by the FDA for November 28, 2020.

In addition, the FDA accepted for standard review a new sBLA for pembrolizumab for the treatment of patients with high-risk early-stage TNBC, in combination with chemotherapy as neoadjuvant treatment, and then as a single agent as adjuvant treatment after surgery, based on findings from the phase 3 KEYNOTE-522 trial. A PDUFA date for this application was set for March 29, 2021.

“There is a real need to advance new treatment options for triple-negative breast cancer, an aggressive form of the disease. The FDA’s acceptance of these [pembrolizumab] applications for review is an important step toward helping patients with both early-stage and metastatic disease,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development as well as chief medical officer at Merck Research Laboratories, said in a press release. “These acceptances mark the first US applications for [pembrolizumab] in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible.”

In the randomized, double-blinded, phase 3 KEYNOTE-355 trial, researchers evaluated pembrolizumab in combination with 1 of 3 different chemotherapies (investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) compared with placebo plus 1 of the 3 chemotherapy regimens for the treatment of locally recurrent inoperable or metastatic TNBC. Patients were eligible to be enrolled in the trial if they had a disease-free interval of at least 6 months or were 

The dual primary end points were progression-free survival (PFS) and overall survival (OS) in patients whose tumors expressed PD-L1 (CPS ≥1 and CPS ≥10) and in all participants (intention-to-treat population). Moreover, key secondary end points included objective response rate, duration of response, disease control rate, and safety. 

In total, 847 patients were enrolled and randomized 2:1 to receive 200 mg of pembrolizumab every 3 weeks plus investigator’s choice of chemotherapy or placebo plus nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin.

Pembrolizumab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS compared with chemotherapy alone in patients whose tumors expressed PD-L1 at CPS ≥10. Notably, approximately 38% of patients enrolled in KEYNOTE-355 had tumors expressing PD-L1 at CPS ≥10.

These data were presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting. As previously announced at the meeting, the trial will continue without changes to evaluate the other dual primary end  point of OS.

In the randomized, double-blinded, phase 3 KEYNOTE-522 trial, pembrolizumab was evaluated in combination with chemotherapy compared with placebo plus chemotherapy as neoadjuvant therapy, followed by pembrolizumab monotherapy compared with placebo as adjuvant therapy in patients with TNBC.

The dual primary endpoints were pathologic complete response (pCR) and event-free survival (EFS). The secondary end points included pCR rate using alternative definitions of no invasive or noninvasive residual cancer in breast or nodes at the time of definitive surgery, OS, EFS in patients whose tumors express PD-L1 (CPS ≥1), safety, and patient-reported outcomes. Researchers enrolled 1174 patients in the study and randomized them 2:1 to receive either:

Pembrolizumab every 3 weeks plus paclitaxel weekly and carboplatin (weekly or every three weeks) for 4 cycles, followed by pembrolizumab plus cyclophosphamide and either doxorubicin or epirubicin every 3 weeks for 4 cycles as neoadjuvant therapy prior to surgery, followed by 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy post-surgery; or

Placebo every 3 weeks plus paclitaxel weekly and carboplatin (weekly or every 3 weeks) for 4 cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin every 3 weeks for 4 cycles, followed by 9 cycles of placebo every 3 weeks as adjuvant therapy post-surgery.

Overall, neoadjuvant pembrolizumab plus chemotherapy resulted in a statistically significant increase in pCR in patients with early-stage TNBC, regardless of PD-L1 expression. Even further, the pembrolizumab regimen also demonstrated a positive trend for the other dual primary endpoint of EFS.

Data from the KEYNOTE-522 trial were presented at the European Society for Medical Oncology (ESMO) 2019 Congress and the 2019 San Antonio Breast Cancer Symposium (SABCS). As previously announced at the meetings, pembrolizumab plus chemotherapy was granted breakthrough therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk early-stage TNBC.

Merck Announces Two US Regulatory Milestones for KEYTRUDA

 (pembrolizumab) in Triple-Negative Breast Cancer (TNBC) [news release]. Kenilworth, NJ. Published July 30, 2020. businesswire.com/news/home/20200730005275/en/Merck-Announces-Regulatory-Milestones-KEYTRUDA%C2%AE-pembrolizumab-Triple-Negative. Accessed July 30, 2020.

Marking the first US applications for pembrolizumab in breast cancer, the applications are based on data from the KEYNOTE-355 and KEYNOTE-522 trials, respectively.

FDA Accepts 2 New Supplemental Biologics License Applications for Pembrolizumab in TNBC

A study of the impact of the coronavirus disease 2019 (COVID-19) on childhood cancer, published in 

found that the methods by which childhood cancer treatment delivery are approached during crises need to be reassessed, as treatment interruptions and delays are anticipated to affect patient outcomes in those otherwise largely curable disease settings.

Moving forward, the researchers indicated that continued collaborative efforts are needed to better understand the direct and indirect impact of COVID-19.

“Health care system and resource-appropriate modifications are needed to ensure sustained curative outcomes for children with cancer while maintaining their safety and that of their families and health care workers,” the authors wrote. “Assessment of the pandemic regarding access to timely, accurate diagnosis, appropriate curative therapy, and lifesaving supportive care is essential to inform appropriate interventions at the health care system, social support, and advocacy levels during this crisis and to provide readiness for a potential similar future crisis.”

To determine the impact of COVID-19, researchers created a 34-item survey focused on barriers to pediatric oncology management during the pandemic and distributed the survey to the heads of pediatric oncology units within the Pediatric Oncology East and Mediterranean (POEM) collaborative group, from the Middle East, North Africa, and West Asia. Corresponding rates of proven COVID-19 cases and deaths were culminated from the World Health Organization database.

Ultimately, 34 centers across 19 different countries participated in the survey. Overall, the majority of centers were found to have applied guidelines to optimize resource utilization and safety, including delaying off-treatment visits, rotating and reducing staff, and implementing social distancing, hand hygiene measures, and personal protective equipment use.

“The results indicate that most centers applied policies and guidelines aligned with those recommended by international societies to optimize resource utilization and safety, consistent with other regional single-center reports,” the authors noted.

Essential treatments, including chemotherapy, surgery, and radiation therapy, had to be delayed in 29% to 44% of the centers surveyed, and 24% of centers restricted acceptance of new patients. Additionally, clinical care delivery was also reported as negatively affected in 28% of centers.

Moreover, more than 70% of centers reported shortages in blood products, and 47% to 62% reported interruptions in surgery and radiation as well as medication shortages. However, bed availability was affected in less than 30% of centers, reflecting the low rates of COVID-19 hospitalizations in the corresponding countries at the time of the survey.

“The reported blood product and medication shortages point to the potential disruption of lifesaving supportive care,” the authors highlighted. “The survey also confirmed an effect of families’ fear of exposure to COVID-19, barriers to travel (including halted public transport), and economic duress (because of the crisis and loss of daily wages) as well as interruptions in social services support, which adds to the impact caused by a compromised health care service.”

Importantly though, researchers identified unexpected positive outcomes of the pandemic, including resilience, innovation, and collaboration spirit, which were all suggested to be helping hospitals and physicians navigate the changing landscape of healthcare delivery. Given this finding, the investigators recommended that efforts moving forward should focus on initiatives to apply lessons learned and be better prepared to meet future similar challenges.

With few centers surveyed within each country, the researchers noted that the generalizability of the current results cannot be entirely ascertained. Furthermore, the survey was only completed by 1 recipient per hospital, and therefore could not be further cross-checked for independent validation.

“Despite these limitations, we believe that the results are meaningful in identifying both objective and subjective measures of the impact of the pandemic and its response on patients, physicians, and the health care system as they relate to pediatric cancer care delivery in countries of different income levels in the region,” the authors concluded.

Saab R, Obeid A, Gachi F, et al. Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Pediatric Oncology Care in the Middle East, North Africa, and West Asia Region: A Report From the Pediatric Oncology East and Mediterranean (POEM) Group. 

This research suggested the need for reassessment of the methods by which childhood cancer treatment delivery are approached during crises.

In Light of COVID-19 Pandemic, Reassessment of Childhood Cancer Care Delivery May Be Needed

A randomized trial of a hospice video educational tool for patients with advanced cancer, as well as their caregivers, found that those who were assigned to watch the video appeared to be more informed about hospice care and reported more favorable perceptions of hospice.

In addition, having watched the video was associated with an increase in hospice use and hospice length-of-stay.

“These findings are particularly relevant given the suboptimal use of hospice care noted among patients with advanced cancer,” the authors wrote.

The single-site randomized trial, published in 

, evaluated the use of the video tool compared with a verbal description of hospice in 150 hospitalized patients with advanced cancer, along with their caregivers. However, patients without a caregiver remained eligible. In total, 75 patients and 18 caregivers viewed a 6-minute video depicting hospice, while 75 patients and 26 caregivers received a verbal description identical to the video narrative.

The primary outcome was patient preference for hospice. Key secondary outcomes included patient and/or caregiver knowledge and perceptions of hospice, as well as hospice use.

Importantly, following the video or verbal intervention, there was no significant difference noted concerning patients' preferences for hospice (86.7% vs 82.7%; 

However, patients included in the video group reported a greater understanding of hospice (9.0 vs 8.4; 

 = 0.049) and were less likely to affirm that hospice is only about death (6.7% vs 21.6%; 

 = 0.010). Moreover, of the now deceased patients, those who were assigned to the video intervention were more likely to have used hospice (85.2% vs 63.6%; 

 = 0.01) and to have had a longer hospice length of stay (median, 12 days vs 3 days; 

“It remains unclear how the hospice video led to substantial differences in rates of hospice use without significantly impacting patients’ preferences for hospice care,” the authors wrote. “Future studies should examine the impact of the hospice video on the frequency and timing of hospice discussions as a potential mediator for higher use of hospice.”

With regard to the caregivers, those who were assigned to watch the video were more likely to prefer hospice for their loved ones (94.4% vs 65.4%; 

 = 0.031), reported greater familiarity with hospice care (9.7% vs 8.0%; 

 = 0.001), and were less likely to affirm that hospice is only about death (0.0% vs 23.1%; 

 = 0.066). Researchers suggested that because of the critical role caregivers may play in decision making regarding hospice, future studies of hospice educational tools should enhance efforts to enroll caregivers.

“Although prior studies have focused primarily on the early involvement of palliative care and other interventions targeting physicians and health care systems to increase hospice use, the findings of the current study have highlighted the value of a simple and inexpensive video to educate patients and families about hospice,” the authors wrote. “A hospice video represents a potentially scalable intervention targeting the informational needs of patients with advanced cancer and their caregivers to overcome barriers to hospice use.”

Of note, the research assistants who were collecting participant-reported outcomes were not blinded to the randomization, which may have introduced bias. Even further, some patients refused to participate in the study because they did not want to discuss hospice, which may have introduced a selection bias. Additionally, the investigators lacked data with which to compare characteristics between participants versus nonparticipants.

“Given the potential for this scalable and low-cost intervention to improve hospice use, and thereby improve the quality of EOL care and reduce EOL care costs, a future multisite trial to confirm the efficacy and generalizability of this intervention across care settings is warranted,” the authors concluded.

El-Jawahri A, Traeger L, Greer JA, et al. Randomized Trial of a Hospice Video Educational Tool for Patients With Advanced Cancer and Their Caregivers. 

Though the video did not have a statistically significant impact, those assigned to watch the video appeared to be more informed about hospice care and reported more favorable perceptions of hospice.

Educational Tool Assists Patients, Caregivers of Cancer in Learning About Hospice

Relugolix (Relumina) demonstrated superiority over leuprolide (Lupron) in sustained testosterone (T)-suppression through 48 weeks, fast T-recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE) in patients with advanced prostate cancer, according to findings from the phase 3 HERO trial, presented at the 2020 ASCO Virtual Scientific Meeting.

Additionally, relugolix achieved castration as early as day 4, suggesting the potential for this agent to become a new standard for T-suppression in this patient population.

“Relugolix is a novel, oral GnRH receptor antagonist that achieves both LH and FSH suppression to its direct inhibitory effect on the pituitary GnRH receptors,” Neal D. Shore, FACS, MD, medical director for the Carolina Urologic Research Center, said in a press release. “This direct inhibition does not result in a testosterone surge.”

The 48-week, global, pivotal phase III trial, which also published in The New England Journal of Medicine, randomized 934 patients with androgen-sensitive advanced prostate cancer in a 2:1 fashion to receive either 120 mg of relugolix orally once daily after a one-time 360 mg loading dose or a 3-month depot injection of leuprolide acetate.2 Testosterone recovery was also evaluated in a subset of 184 patients.

The primary end point of the study was to achieve and maintain serum T-suppression to castrate levels (< 50 ng/dL) through 48 weeks. Key secondary endpoints included castration rates at day 4 and day 15, profound castration (< 20 ng/dL) rates at days 4 and 15, PSA response rate at day 15, and FSH levels at week 24.

In order to be included in the study, patients had to have confirmed advanced prostate cancer, ≥1 years of androgen deprivation therapy (ADT), a serum PSA > 2.0 ng/mL, and an ECOG score of 0 or 1. Patients who were expecting to under chemotherapy or surgical therapy within 2 months of initiating ADT, had previous ADT for >18 months for previous systemic cytotoxic therapy for prostate cancer, had active liver disease, or severe cardiovascular risk conditions were excluded from the study.

Of the 624 patients randomized to the relugolix arm, 563 (90.2%) completed treatment compared to 276 of the 310 (89.0%) who were given leuprolide. Moreover, 59 of the 624 (9.5%) and 32 of the 310 (10.3%), respectively, terminated their treatment early. The remaining patients were randomized, but not treated.

The characteristics of the patients at baseline were well balanced between the 2 treatment groups. Moreover, 50.2% of the men enrolled had biochemical recurrence after definitive treatment for prostate cancer, 28.9% were enrolled in North America, and 11.5% were from Japan. More than 90% of the patients also had at least 1 cardiovascular risk factor.

Overall, 96.7% (95% CI, 94.9%-97.9%) of men treated with relugolix achieved and maintained castration through 48 weeks compared to 88.8% on leuprolide. Notably, the difference of 7.9% (95% CI, 4.1%-11.8%) demonstrated noninferiority (margin -10%) and superiority (P < 0.0001) of relugolix to leuprolide. All key secondary endpoints tested also demonstrated superiority over leuprolide (P < 0.0001).

In the subset of patients evaluated for testosterone recovery, median T-levels were 270.76 ng/dL in the relugolix group compared to 12.26 ng/dL in the leuprolide group 90 days after discontinuation of therapy.

In a prespecified analysis, the incidence of MACE was found to be lower in the relugolix group than in the leuprolide group (2.9% vs 6.2%, respectively). Otherwise, the safety and tolerability profiles of the 2 agents were generally similar. Adverse events (AEs) reported for >10% of patients treated with relugolix or leuprolide were hot flush (54.3% vs 51.6%, respectively), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), arthralgia (12.1% vs 9.1%), and hypertension (7.9% vs 11.7%). Notably, AEs of diarrhea were of grade 1 or 2 and did not result in study discontinuation.

“Relugolix once daily was well tolerated with an adverse event profile consistent with T-suppression,” Shore said. “Most notably, the risk of major adverse cardiovascular events was 54% lower in the relugolix group compared to leuprolide.”

Furthermore, though oral treatments are now commonly used for men with advanced and castration-resistant prostate cancer, concerns remain about adherence to oral ther-apies. However, the investigators indicated that treatment adherence with oral relugolix was more than 99% and similar to that seen with injectable leuprolide.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for ADT in advanced prostate cancer,” Shore concluded.

1. Shore ND, George DJ, Saad F, et al. HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist versus leuprolide acetate for advanced prostate cancer. Presented at: 2020 ASCO Virtual Scientific Program. Abstract 5602.

2. Shore ND, Saad F, Cookson MS, et al. Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. N Engl J Med. doi:10.1056/NEJMoa2004325.

This article was originally published on OncLive as, "

HERO Trial Suggests Relugolix to Become New Standard for T-Suppression in Advanced Prostate Cancer.

Relugolix (Relumina) demonstrated superiority over leuprolide (Lupron) in sustained testosterone (T)-suppression through 48 weeks, fast T-recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE) in patients with advanced prostate cancer.

Relugolix May Become New Standard of Care for Advanced Prostate Cancer

The FDA granted priority review to a new drug application (NDA) for CC-486 for the maintenance treatment of adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or CR with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment, and who are not candidates for, or who choose not to proceed to, hematopoietic stem cell transplantation.

The FDA has set a prescription drug user fee act (PDUFA) goal date of September 3, 2020.

“Often, newly diagnosed adult patients with AML achieve a complete response with induction therapy, however many patients will relapse and experience a poor outcome. Patients in remission are seeking treatment options that decrease the likelihood of relapse and extend overall survival,” Noah Berkowitz, MD, PhD, senior vice president for Global Clinical Development and Hematology at Bristol Myers Squibb. “Today’s acceptance of our submission for CC-486 represents an important step towards a potential new maintenance treatment to address an urgent medical need for AML patients and we look forward to working with the FDA during its review of CC-486.”

The NDA was based on efficacy and safety results from the pivotal phase III QUAZAR AML-001 study, which met the primary endpoint of improved overall survival for patients receiving AML maintenance treatment with CC-486, an investigational oral hypomethylating agent, versus placebo.

The primary endpoint of the study was overall survival (OS). Key secondary endpoints included relapse-free survival (RFS), safety and tolerability, healthcare resource utilization, and patient-reported outcomes per the FACIT-Fatigue Scale and EQ-5D questionnaire.

In the phase III trial, 472 patients were enrolled within 4 months of CR or CR with CRi.

 Trial participants were randomized to receive either daily CC-486 (n = 238) or placebo (n = 234), plus best supportive care. Moreover, CC-486 was administered at 300 mg daily for 14 days followed by 14 days off therapy. However, if a CR/CRi was not maintained, the CC-486 dose could be escalated to 21 days on CC-486 with 7 days off therapy. Patients remained on treatment until unacceptable toxicity or disease progression.

In patients receiving CC-486, the best responses to prior therapy included CR for 79% of patients and CRi for 21%. In the placebo arm, the best responses were found to be CR for 84% of patients and CRi for 16%. Overall, approximately one-fifth of patients had not previously received consolidation therapy and approximately half of patients tested negative for minimal residual disease.

After a median follow-up of 41.2 months, the median OS with CC-486 was 24.7 months (95% CI, 18.7-30.5) compared with 14.8 months for placebo (95% CI, 11.7-17.6), which represented a 31% reduction in the risk of death with CC-486 (HR, 0.69; 95% CI, 0.55-0.86; 

 = .0009). Further, the median relapse-free survival (RFS) was 4.8 months with placebo compared with 10.3 months for CC-486 (HR, 0.65; 95% CI, 0.52-0.81; 

At 1 year, 47% of patients were free of relapse in the CC-486 arm compared with 29% in the placebo group. Notably, the benefits in both RFS and OS were seen across key prognostic AML subgroups.

The safety profile for CC-486 was consistent with injectable azacitidine (Vidaza), with infrequent treatment discontinuation related to adverse events (AEs). Additionally, there were no treatment-related deaths. The most common all-grade AEs with CC-486 included nausea (65%), vomiting (60%), diarrhea (50%), and constipation (39%). The most common grade 3 or 4 AEs in both treatments groups were neutropenia (41% vs 24%), thrombocytopenia (23% vs 22%), anemia (14% vs 13%), diarrhea (5% vs 1%), vomiting (3% vs 0%), fatigue (3% vs 1%), and nausea (3% vs 0.4%), respectively.

CC-486 is not currently approved for use in any country.

1. U.S. Food and Drug Administration (FDA) Accepts for Priority Review Bristol Myers Squibb’s Application for CC-486 for Maintenance Treatment of Adult Patients in Remission with Acute Myeloid Leukemia [news release]. Princeton, NJ. Published May 1, 2020. news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-fda-accepts-priority-review-br. Accessed May 1, 2020.

2. Wei AH, D&#1255;hner H, Pocock C, et al. The QUAZAR AML-001 Maintenance Trial: Results of a Phase III International, Randomized, Double-Blind, Placebo-Controlled Study of CC-486 in Patients with Acute Myeloid Leukemia (AML) in First Remission. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract LBA3.

The FDA granted priority review to a new drug application for CC-486 for the maintenance treatment of adult patients with acute myeloid leukemia based on efficacy and safety results from the pivotal phase III QUAZAR AML-001 study.
 

FDA Grants Priority Review to CC-486 for the Treatment of Acute Myeloid Leukemia

The FDA has granted priority review to the new drug application (NDA) for sodium thiosulfate (Pedmark) for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to <18 years of age with localized, non-metastatic, solid tumors, according to Fennec Pharmaceuticals, the drug’s developer.

A prescription drug user fee act (PDUFA) target action date of August 10, 2020 was set by the FDA for the completion of the review.

"The FDA filing acceptance of our NDA and granting of priority review represents a significant milestone in the development of Pedmark and we look forward to working closely with the Agency during this review process,” Rosty Raykov, chief executive officer of Fennec, said in a press release.

Sodium thiosulfate has been studied by cooperative groups in 2 phase III clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. Both studies have already been completed.

ACCL0431 was a multicenter, randomized, open-label, phase III trial that enrolled participants at 38 participating Children’s Oncology Group hospitals in the US and Canada.

 Eligible patients were aged 1-18 years with newly diagnosed cancer and normal audiometry. The participants were randomized 1:1 to receive sodium thiosulfate or observation in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of 4.

Overall, 125 eligible patients were randomly assigned, and of those, 104 participants were assessable for the primary endpoint of hearing loss 4 weeks after final cisplatin dose (sodium thiosulfate, n = 49; control, n = 55). Hearing loss was identified in 14 (28.6%; 95% CI, 16.6-43.3) participants in the sodium thiosulfate group compared with 31 (56.4%; 42.3-69.7) in the control group (

= 0.00022). After adjusting for stratification variables, the likelihood of hearing loss was found to be significantly lower in the sodium thiosulfate group compared with the control group (OR, 0.31; 95% CI, 0.13-0.73; 

The most common grade 3-4 hematological adverse events reported, regardless of attribution, were neutropenia (117 [66%] of 178 participant cycles in the sodium thiosulfate group vs 145 [65%] of 224 in the control group), whereas the most common non-hematological adverse event was hypokalemia (25 [17%] of 149 vs 22 [12%] of 187). Further, of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were considered probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count (26 episodes in 14 participants).

SIOPEL 6 was a multi-center, open-label, randomized phase III trial of the efficacy of sodium thiosulphate in reducing ototoxicity in patients receiving cisplatin monotherapy for standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter).

 In total, 109 children were randomly assigned to receive either cisplatin plus sodium thiosulfate (n = 57) or cisplatin alone (n = 52). The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. The main secondary end points were overall survival (OS) and event-free survival (EFS) at 3 years.

The absolute hearing threshold was assessed in 101 children and sodium thiosulfate was found to be associated with few high-grade toxic effects. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, compared to 29 of 46 (63%) in the cisplatin-alone group, demonstrating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% CI, 0.33-0.81; 

 = 0.002). At a median of 52 months of follow-up, the 3-year rates of EFS were 82% (95% CI, 69-90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65-88) in the cisplatin-alone group, and the 3-year rates of OS were 98% (95% CI, 88-100) and 92% (95% CI, 81-97), respectively.

Currently, there is no approved preventative agent for platinum-based therapy-induced ototoxicity, and only expensive, technically difficult and sub-optimal cochlear implants have been shown to provide some benefit. Moreover, infants and young children that suffer ototoxicity at critical stages of development generally lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

1. Fennec Pharmaceutical Announces FDA Filing Acceptance and Priority Review of New Drug Application for PEDMARK [news release]. Research Triangle Park, NC. Published April 13, 2020. globenewswire.com/news-release/2020/04/13/2014977/0/en/Fennec-Pharmaceuticals-Announces-FDA-Filing-Acceptance-and-Priority-Review-of-New-Drug-Application-for-PEDMARK.html. Accessed April 14, 2020.

2. Freyer DR, Chen L, Krailo MD, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicenter, randomized, controlled, open-label, phase 3 trial. 

3. Brock PR, Maibach R, Childs M, et al. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. 

The FDA granted priority review to the new drug application for sodium thiosulfate for the prevention of ototoxicity induced by cisplatin chemotherapy in patients 1 month to 

FDA Grants Priority Review to Sodium Thiosulfate for Ototoxicity Prevention

The FDA granted priority review to a new supplemental biologics license application (sNDA) for pembrolizumab (Keytruda), according to Merck, the agent’s developer.

The sNDA is seeking accelerated approval of pembrolizumab monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) ≥10 mutations/megabase, as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options.

The FDA set a prescription drug user fee act (PDUFA) date of June 16, 2020.

“From the start, biomarker research has been a critical aspect of our clinical program evaluating Keytruda monotherapy,” Scott Ebbinghaus, MD, vice president of clinical research at Merck, said in a press release.

 “TMB has been an area of scientific interest to help identify patients most likely to benefit from Keytruda. We look forward to working with the FDA throughout the review process to help bring Keytruda monotherapy to patients with cancer in the second-line or higher treatment setting, where options remain limited.”

The application was based, in part, on results from the phase II KEYNOTE-158 trial, which evaluated pembrolizumab in patients with solid tumors. The trial also supported the 2017 FDA approval of pembrolizumab as the first cancer treatment based on a biomarker, regardless of cancer type, in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors.

Data from the KEYNOTE-158 trial on the TMB-H patient population were presented at the European Society for Medical Oncology (ESMO) 2019 Congress.

In the study, tissue TMB was assessed using the FoundationOne CDx assay.

 Moreover, TMB-H status was defined as at least 10 mutations/megabase and all patients received 200 mg of intravenous pembrolizumab every 3 weeks.

Of the patients who were evaluable for tissue TMB status in the trial, 99 (13.2%) had TMB-high tumors. These patients were then followed for a median of 11.7 months (range, 0.5-33.0), and their outcomes were compared with 652 patients with non-TMB-H tumors who were followed for a median of 13.1 months (range, 0.4-34.3).

In the TMB-H group, 65.7% of patients had positive PD-L1 expression, and 14.1% had microsatellite instability—high (MSI-H) tumors. Further, all but 1 patient had received prior therapy in the recurrent or metastatic setting, and 12 patients had received at least 4 prior regimens.

The most common tumor types identified in the TMB-H group were small cell lung cancer (34.3%), cervical (16.2%), endometrial (15.2%), and anal (14.1%). Comparably, the most common tumor types found in the non-TMB-H group were mesothelioma (12.7%), neuroendocrine (12.3%), salivary (12.0%), and endometrial (10.3%).

An overall response rate (ORR) of 30.3% (95% CI, 21.5%-40.4%) was achieved in the TMB-H group, which included complete responses in 4.0% and partial responses in 26.3%. Stable disease was also observed in 14.1%. When patients with MSI-H tumors were excluded, the ORR was 27.1%, and in the non-TMB-H group, the ORR was 6.7%. However, the median duration of response was not reached in either group. 

Median progression-free survival (PFS) in both groups was 2.1 months. At 1 year, the PFS rates were 26.4% and 14.1% in the TMB-H and non—TMB-H groups, respectively, and at 2 years the rates were 18.9% and 6.5%.

Additionally, the median overall survival (OS) was found to be higher in the non-TMB-H group at 13.0 months (95% CI, 11.5-14.6) compared with 11.7 months (95% CI, 8.2-19.1) in the TMB-H group. At 1 year, the OS rates were 49.1% for the TMB-H population and 52.5% for the non-TMB-H patients, and at 2 years the OS rates were 34.5% and 31.1%, respectively.

The safety findings in this study population were consistent with previously observed toxicity profiles for pembrolizumab.

1. Merck Receives Priority Review from FDA for Second Application for KEYTRUDA (pembrolizumab) Based on Biomarker, Regardless of Tumor Type [news release]. Kenilworth, NJ. Published April 7, 2020. mrknewsroom.com/news-release/oncology-newsroom/merck-receives-priority-review-fda-second-application-keytruda-pembro. Accessed April 7, 2020.

2. Marabelle A., Fakih M, Lopez J, et al. Association of Tumor Mutational Burden with Outcomes in Patients with Select Advanced Solid Tumors Treated with Pembrolizumab in KEYNOTE-158. 

The FDA granted priority review to pembrolizumab monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic TMB-high solid tumors who have progressed following prior treatment and who have no satisfactory alternative treatment options.
 

FDA Grants Priority Review to Pembrolizumab Monotherapy for TMB-High Tumors

The FDA granted priority review to a biologics license application (BLA) for tafasitamab in combination with lenalidomide (Revlimid) for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to MorphoSys, the developer of the anti-CD19 antibody.

A Prescription Drug User Fee Act (PDUFA) goal date was set for August 30, 2020. Additionally, the FDA has notified the company that they are not currently planning to hold an advisory committee meeting to discuss the application.

“We are extremely pleased that the FDA has accepted filing of our application and granted priority review, as we believe that the combination of tafasitamab and lenalidomide may provide an additional treatment option for patients suffering from DLBCL, who have relapsed after or are refractory to the current standard of care,” Malte Peters, MD, chief development officer of MorphoSys, said in a press release. “We would like to thank all patients participating in our clinical studies and we will continue to work relentlessly towards making tafasitamab available to patients.”

The submission was based on the primary analysis data from the L-MIND trial of tafasitamab in combination with lenalidomide in patients with relapsed or refractory DLBCL and the retrospective observational matched control cohort Re-MIND evaluating efficacy outcomes of relapsed or refractory DLBCL patients with received lenalidomide monotherapy.

L-MIND is a single arm, open-label phase II study evaluating the combination in patients with relapsed or refractory DLBCL after up to 2 prior lines of therapy who are not eligible for high-dose chemotherapy and subsequent autologous stem cell transplantation. Primary analysis data, with a cut-off date of November 30, 2018, included 80 participants enrolled in the trial who had received tafasitamab and lenalidomide with a follow-up of at least 1 year. The primary endpoint, defined as best objective response rate (ORR) compared to published data on the respective monotherapies, was met.

As of May 2019, the study had reached its primary completion. The ORR was 60%, and the complete response (CR) rate was 43%. Moreover, 81% of the CRs were PET (positron-emission tomography)-confirmed, and the median progression-free survival was 12.1 months with a median follow-up of 17.3 months. Responses were durable with a median duration of response of 21.7 months, though median overall survival was not reached (95% CI, 18.3 months — not reached) with a median follow-up time of 19.6 months. The 12-month overall survival (OS) rate was 73.3%.

Re-MIND, an observational retrospective study, was designed to isolate the contribution of tafasitamab in the combination with lenalidomide to prove the combinatorial effect. Collecting efficacy data from 490 relapsed or refractory DLBCL patients in the US and Europe, the study compared this data with efficacy outcomes from the L-MIND trial. This resulted in 76 eligible Re-MIND patients being matched 1:1 to 76 of 80 L-MIND patients based on specified baseline characteristics.

The primary endpoint of the study was met and showed a statistically significant superior best ORR of the combination compared to lenalidomide monotherapy.

 ORR was 67.1% (95% CI, 55.4-77.5) for the combination of tafasitamab and lenalidomide, compared to 34.2% (CI: 23.7-46.0) for the lenalidomide monotherapy (

 < 0.0001). Furthermore, superiority was consistently observed across all secondary endpoints, including CR rate (tafasitamab/lenalidomide combination 39.5%; CI: 28.4-51.4 vs lenalidomide monotherapy 11.8%; CI: 5.6-21.3; 

< 0.0001), as well as in pre-specified statistical sensitivity analyses. There was also a significant difference observed in OS, which was not reached in the combination as compared to 9.3 months in the lenalidomide monotherapy (hazard ratio 0.47; CI: 0.30-0.73; 

The submission of the BLA was announced by MorphoSys in December 2019. The FDA granted Breakthrough Therapy Designation for the combination of tafasitamab and lenalidomide in relapsed or refractory DLBCL in 2017.

1. FDA Accepts MorphoSys’ Biologics License Application (BLA) and Grants Priority Review for Tafasitamab and Lenalidomide for the Treatment of Relapsed/Refractory DLBCL (news with additional features) [news release]. Planegg/Munich, Germany. Published March 2, 2020. morphosys.com/media-investors/media-center/fda-accepts-morphosys-biologics-license-application-bla-and-grants. Accessed March 2, 2020.

2. MorphoSys Presents Primary Analysis Data from L-MIND Study of Tafasitamab (MOR208) in combination with Lenalidomide in r/r DLBCL at ICML 2019 [news release]. Planegg/Munich, Germany. Published June 22, 2019. morphosys.com/media-investors/media-center/morphosys-presents-primary-analysis-data-from-l-mind-study-of. Accessed March 2, 2020.

3. MorphoSys AG: Primary Endpoint met in Real-World Data Study Demonstrating Clinical Superiority of the Combination of Tafasitamab and Lenalidomide compared to Lenalidomide alone. Planegg/Munich, Germany. Published October 29, 2019. morphosys.com/media-investors/media-center/morphosys-ag-primary-endpoint-met-in-real-world-data-study. Accessed March 2, 2020.

The FDA granted priority review to a biologics license application for tafasitamab in combination with lenalidomide for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma.
 

Hannah Slater