Medical World News: Clinical, Regulatory, and Managed Care Updates – AJMC.com Managed Markets Network

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The phase 3 POLLUX study compared daratumumab, lenalidomide, and dexamethasone (D-Rd) with lenalidomide and dexamethasone (Rd) in RRMM. CASTOR, also a phase 3 study, compared daratumumab, bortezomib, and dexamethasone (D-Vd) with bortezomib and dexamethasone (Vd) in RRMM. Overall, 569 patients in POLLUX and 498 in CASTOR were included in the new analysis.

Both studies assessed MRD, a known sensitive measure of disease control, with next-generation sequencing based on the International Myeloma Working Group guidelines, which recommend a sensitivity threshold of 10-5 (1 tumor cell in 100,000). Patients were assessed at numerous time points: at suspected complete response (CR); at 3 and 6 months after confirmed CR in the POLLUX study; at 6 and 12 months after the first dose in the CASTOR study; and every 12 months following CR in both studies.

The combined analysis included 537 patients on daratumumab-containing regimens and 530 patients given the standard of care (Rd or Vd). Researchers assessed MRD in both the intention-to-treat (ITT) population and in patients who achieved CR or better. Sustained MRD negativity of at least at least 6 months in the ITT population and at least 12 months in the CR population. Median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR.

For POLLUX, MRD negativity rates in the ITT population were 32.5% in the D-Rd group and 6.7% in the Rd cohort. Patients who achieved CR or better had higher MRD rates, with 57.4% of those patients on the D-Rd regimen and 29.2% on the Rd regimen showing MRD negativity (P = .0001). In the CASTOR study, MRD negativity rates in the ITT population were 15.1% in the D-Vd group vs 1.6% in the Vd group. In the CR-or-better population, 52.8% of patients on the D-Vd regimen and 17.4% on the Vd regimen achieved MRD negativity (P = .0035).

In both studies, the daratumumab combination treatment saw higher percentages of patients in the ITT and CR-or-better cohorts achieve sustained MRD negativity compared with those receiving the standard of care. In the D-Rd group in POLLUX, 20.3% of patients achieved sustained MRD negativity of at least 6 months vs 2.1% in the Rd cohort (P< .0001). At 12 or more months, combination-group patients still had higher rates of sustained negativity (16.1% vs 1.4%; P< .0001).

In CASTOR, the D-Vd and Vd groups achieved 6 months or longer sustained negativity at rates of 10.4% and 1.2%, respectively (P< .0001). More D-Vd patients also achieved sustained MRD negativity for 12 or more months (6.8%) compared with Vd patients (0%).

MRD negativity was also associated with longer progression-free survival (PFS). In patients who achieved sustained MRD negativity for 6 or more months, PFS was prolonged in both studies, regardless of treatment arm. Patients who achieved sustained MRD negativity for 12 or more months on a daratumumab combination regimen also had longer PFS compared with those who were MRD positive. Overall survival data will be assessed at the end of both studies. “Achieving durable MRD negativity may predict long-term outcomes, as durable MRD negativity improves PFS and increases the time between treatment relapses for RRMM,” the authors wrote. “This supports the concept that sustained MRD negativity may serve as a surrogate end point for PFS in ongoing and future clinical trials.”

The authors point out that although findings suggest that MRD monitoring may be predictive of long-term outcomes in RRMM, there is no consensus on how or when to use it. “Prospectively gathered clinical data will be useful in developing future paradigms for MRD analysis as a clinical practice decision tool,” they wrote.

Reference
Avet-Loiseau H, San-Miguel J, Casneuf T, et al. Evaluation of sustained minimal residual disease negativity with daratumumab-combination regimens in relapsed and/or refractory multiple myeloma: analysis of POLLUX and CASTOR. J Clin Oncol. Published online January 29, 2021. doi:10.1200/JCO.20.01814

Cosela Is Approved for Protection Against Myelosuppression From SCLC Treatment

The FDA approved trilaciclib (Cosela; G1 Therapeutics) to be used as a protective agent against bone marrow loss among adults before chemotherapy regimens that contain a platinum agent/etoposide or topotecan for extensive-stage small cell lung cancer (SCLC). This is the first and only such approval for a cyclin-dependent kinase 4/6 inhibitor.

Bone marrow loss and myelosuppression are well-documented adverse effects (AEs) of chemotherapy, which leave the immune system without some of its most potent fighters: red blood cells, which contain hemoglobin; white blood cells, which help to fight infection; and platelets, which assist in clotting. These losses, in turn, can cause fatigue and increase risk of infection, bleeding, anemia, and thrombocytopenia.

Previous treatments that address bone marrow injury have only attempted to remedy it after the fact. “To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed,” stated Jeffrey Crawford, MD, George Barth Geller Distinguished Professor for Research
in Cancer in the Department of Medicine, Duke University School of Medicine, and a member of the Duke Cancer Institute, in G1 Therapeutics’ news release. “By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect
the bone marrow from damage by chemotherapy.”

G1 Therapeutics’ application was backed by data from 3 double-blind, placebo-controlled studies of 245 patients randomized to intravenous (IV) trilaciclib or placebo, with dual primary outcomes of severe neutropenia and its length during the first chemotherapy cycle. The effectiveness of trilaciclib plus carboplatin/etoposide (with or without atezolizumab) or topotecan was
evaluated in these trials. Severe neutropenia was a less likely outcome, and lasted for a shorter time among those for whom it did occur, following treatment with trilaciclib. These findings were deemed clinically meaningful and statistically significant.

Most common AEs (≥10%) of the treatment are fatigue, headache, high aspartate aminotransferase levels, pneumonia, and low calcium, potassium, and phosphate levels. Injection-site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity are also possible. Serious AEs that occurred (>3%) wererespiratory failure, hemorrhage, and
thrombosis; fatal AEs were seen in 5% (pneumonia, 2%; respiratory failure, 2%; acute respiratory failure, <1%; hemoptysis, <1%; and cerebrovascular accident, <1%); and 9% permanently discontinued the preventive measure for reasons that included asthenia, ischemic stroke, and myositis.

“For patients with extensive-stage SCLC, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” said Albert Deisseroth, MD, PhD, supervisory medical officer in the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research, in a statement from the FDA. “Cosela will give patients a treatment option that can reduce the occurrence of a common, harmful [adverse] effect of chemotherapy.”

Cosela received a Breakthrough Therapy designation in 2019 and a Priority Review in 2020; a postapproval clinical trial is currently scheduled for 2022. The treatment is administered as a 30-minute IV infusion within 4 hours of the start of chemotherapy.

Reference

FDA approves G1 Therapeutics’ Cosela (trilaciclib): the first and only myeloprotection therapy to decrease the incidence of chemotherapy-induced myelosuppression. News release. G1 Therapeutics; February 12, 2021. Accessed February 17, 2021. http://investor.g1therapeutics.com/news-releases/news-release-details/fda-approves-g1-therapeutics-coselatm-trilaciclib-first-and-only

Combination Treatment Maintains Quality of Life in Relapsed/Refractory MM

Results from patient reports indicate that health-related quality of life (HRQOL) was maintained when treating relapsed/refractory multiple myeloma (RRMM) with daratumumab (Darzalex) in combination with bortezomib (Velcade) and dexamethasone, according to a new study.

Previously reported results from the phase 3 CASTOR trial had demonstrated that adding daratumumab to the combination of bortezomib and dexamethasone extended progression-free survival when compared with the use of the chemotherapy and steroid alone. The additional data on patient-reported outcomes (PROs) from the CASTOR trial, published this month in the British
Journal of Haematology
, amplify the clinical findings on the benefits of the 3-drug combination.

Daratumumab is an anti-CD38 monoclonal antibody with a direct on-tumor and immunomodulatory mechanism of action.

Patients in the group taking daratumumab, bortezomib, and dexamethasone (D-Vd group) reported similar HRQOL changes from baseline in comparison with those taking only bortezomib and dexamethasone (Vd group). Patients received 8 cycles of treatment for the comparative study.

Patients in both groups indicated they experienced long-term improvements in quality of health and pain levels. A total of 498 patients with RRMM participated. The researchers explained that they conducted the study because, first, treatment of MM is recommended for an undetermined amount of time (until the disease progresses), and second, the introduction of novel agents has extended
progression-free survival. The study was also intended to provide clinicians with further insight into treating older patients who may have comorbidities such as diabetes or cardiovascular disease.

Study results showed no clinically meaningful changes from baseline in PROs through the 8 cycles. Some patients in the Vd group saw clinically significant improvements in fatigue, pain, or sleep disturbance, but the mean changes for each group were not clinically meaningful.

The authors suggested that the lack of significant differences between the 2 groups may have been due to the benefit of bortezomib treatment, leaving little room for improvement from the daratumumab.

Reports continued to be collected from the D-Vd group for a maximum of 49 weeks. Improvement in QOL and pain continued past the eighth cycle. The authors speculated that those findings may have been due to a change in patients’ expectations after prolonged experience with RRMM. Less frequent visits to the clinic might have improved mood as well. Other possible reasons for the improvement included organ and skeletal recovery, which can lag behind other clinical responses; reduced toxicity from halting dexamethasone; and the fact that adverse effects from daratumumab, unlike those of bortezomib, aren’t cumulative and stay steady over time.

PROs were measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system questionnaire (EQ-5D-5L). The EORTC QLQ-C30 is a cancer-specific questionnaire with 30items on 5 functional scales (physical, role, emotional, cognitive, and social).
The EQ-5D-5L is a generic measure of health status assessing mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. An additional scale rated “health today.”

Reference

Hungria V, Beksac M, Weisel KC, et al. Health¨related quality of life maintained over time in patients with relapsed or refractory multiple myeloma treated with daratumumab in combination with bortezomib and dexamethasone: results
from the phase III CASTOR trial. Br J Haematol. Published online February 8, 2021. doi:10.1111/bjh.17321

Study Explores Costs Linked With Adverse Events in Mantle Cell Lymphoma

A study examining the economic burden of mantle cell lymphoma (MCL) treatment found that hypertension, anemia, and infection were the most common adverse events (AEs), while the costliest AEs were hepatotoxicity, stroke, and renal failure.

The retrospective study, using data from the Optum Research Database and the Social Security Administration to examine the financial implications of the rare form of non-Hodgkin lymphoma, also found that the most common therapy by far for MCL was the combination of the chemotherapy drug bendamustine and the biologic rituximab (Rituxan).

The authors said the study was undertaken in part because the real-world data available on MCL have been limited, with the number of novel agents arriving on the scene affecting researchers’ ability to keep up with developments. In one other recent study, the data were slightly older; in another, the patients included did not represent an older cohort.

“This study shows that AEs are common during treatment, and [they are] expensive,” the authors wrote in the February issue of Anticancer Research. “Therefore, as new treatments and combinations are being developed and recommended, there must also be focus on management of AEs to achieve the best outcomes for patients.”

AEs and health care costs were significant overall, varying by treatment regimen. Anemia was the only AE that appeared on lists of most frequent AEs and costliest ones: It was the second-most frequent AE, and the fifth costliest, according to the study.

Hypertension (40.5%) was the most commonly developed AE in treatment of MCL, followed by anemia (37.7%), infection (36.1%), neutropenia (36.1%), and thrombocytopenia (13.4%).

Due largely to inpatient care, hepatotoxicity ($19,645) had the highest cost per patient per month (PPPM), followed by stroke ($18,893), renal failure ($9037), atrial fibrillation ($5751), and anemia ($5097), according to the study results. Inpatient costs for nonhematologic AEs were higher than previous studies had indicated.

The study used data from 395 patients (69% male) with a median age of 72 years; 69% were enrolled in Medicare Advantage plans. The data were for patients with multiple claims for MCL whose initial claim was submitted between July 2012 and May 2017.

Chemoimmunotherapy remained the most common treatment regimen throughout the study period. Ibrutinib (Imbruvica) was the most common treatment for patients in their second or third line of therapy. Patients started therapy a mean of 72 days after diagnosis. Nearly all (95%)
underwent systemic therapy within the first year.

The most common regimens administered at initiation of the patient follow-up period (at least 1 month after the initial claim) were bendamustine HCl/rituximab (52%); cyclophosphamide, doxorubicin, vincristine, and rituximab with or without prednisone (R-CHOP; 13%); and ibrutinib (3%). The majority received rituximab (92%) during the study period either alone or in combination with other drugs. The next most common agents, used either alone or in combination, were bendamustine (62%), cyclophosphamide (26%), vincristine (26%), doxorubicin (22%), ibrutinib (17%), and bortezomib (Velcade; 11%).

The study was funded by AstraZeneca and written in cooperation with Optum.­

Reference

Kabadi SM, Dacosta Byfield S, Le L, Olufade T. Adverse events and economic burden among patients receiving systemic treatment for mantle cell lymphoma: a real-world retrospective cohort study. Anticancer Res. 2021;41(2):927-936. doi:10.21873/anticanres.14846

Humana, IBM Watson Health Collaborate to Improve Health Benefit Transparency

Humana and IBM Watson Health announced a collaboration that will deploy IBM’s artificial intelligence (AI) solution, known as IBM Watson Assistant for Health Benefits, to Humana employer group members, agents, and employers.

Through the AI-enabled virtual assistant built in the IBM Watson Health cloud, members will now have access to transparent and accurate information on benefits, health care costs, and providers. The service will initially be available to Humana’s 1.3 million employer group medical members and 1.8 million of Humana’s employer group dental members.

“At Humana, we strive to use technology to better serve our members with simple and convenient health care experiences,” said Chris Hunter, MBA, segment president of group and military business at Humana. “By harnessing the power of AI fused with embedded analytics in the Watson Health platform, we can help our employer-customers, members, agents, and broker partners enhance their knowledge so they can all make more informed decisions.”

Noted as a conversational AI solution, IBM Watson Assistant for Health Benefits is designed to understand the logic of health plan eligibility and integrate it into member conversation, in which each answer, based on active or future member benefits, coverage, claims, referrals, and health care costs, will be personalized to the Humana member.

“Navigating our health coverage without the right support can potentially serve as a barrier to care. An AI-enabled conversational agent that is trained to understand health plan benefits logic can play a role in helping to simplify complex or possibly confusing plan information,” said Paul Roma, general manager of IBM Watson Health.

The collaboration is designed to improve several aspects of the Humana employer group member benefits experience, including addressing questions directly from members with speed, accuracy, and personalized answers, and assisting Humana employees and call-center personnel in answering questions accurately and quickly. This, in turn, helps to free up more time for customer care representatives to provide concierge-level customer service.

With the goal of creating a cloud native AI platform powered by IBM Watson Assistant for Health Benefits, Humana members will be able to leverage historical claims and provider data to calculate personalized cost estimates for medical services in their health care spending decisions.

“Humana is excited to team up with IBM Watson Health to help our employer-customers and their employees better manage their health care benefits and costs through a more innovative, personalized experience,” said Hunter.

Reference

Humana and IBM Watson Health collaborate to simplify and enhance the member experience for Humana Employer Group customers. News release. Humana; February 11, 2021. Accessed February 22, 2021. https://press.humana.com/
news/news-details/2021/Humana-and-IBM-Watson-Health-Collaborate-to-Simplify-and-Enhance-the-Member-Experience-for-Humana-Employer-Group-Customers/default.aspx#gsc.tab=0

Athenex Receives CRL on Oral Paclitaxel Plus Encequidar for Treatment of Breast Cancer

FDA has sent Athenex, Inc., a complete response letter (CRL) regarding the company’s new drug application (NDA) for oral paclitaxel plus encequidar forthe treatment of metastatic breast cancer. The company announced the CRL in early March and issued a statement along with other developments as part of its financial update for 2020.1

Regulators called for a new “adequate and well-conducted clinical trial,” marking an about-face from the course Athenex seemed to be on when the company’s NDA was accepted for priority review in September 2020. The targeted action date was February 28, 2021.

FDA cited concerns about the risk to patients of increased neutropeniarelated adverse events in the oral paclitaxel arm compared with the intravenous (IV) paclitaxel arm. Regulators also said they were concerned about the uncertainty over results of the primary end point of the objective response rate (ORR) at week 19 conducted by a blinded independent central review (BICR).
In its statement, Athenex said, “The agency stated that the BICR reconciliation and re-read process may have introduced unmeasured bias and influence on the BICR.”

Athenex officials expressed their surprise at the turn of events and said they would request a meeting with FDA to discuss the response and a plan to move forward.

“Our clinical and regulatory teams are disappointed by the complete response letter,” Rudolf Kwan, MD, chief medical officer of Athenex, said in the statement. “We plan to work with the agency to resolve the issues raised in the CRL and to obtain approval for oral paclitaxel plus encequidar in metastatic breast cancer.”

The application was supported by data from a phase 3 trial that showed oral paclitaxel plus encequidar improved ORR compared with IV paclitaxel in patients with metastatic breast cancer; the ORR for the study drug was 36% compared with 24% for the control arm.2 Duration of response among those who responded to treatment was long as well, at 150 days or 2.5 times longer in those given oral paclitaxel with encequidar compared with IV paclitaxel. Rates of neutropenia were comparable between the 2 arms, but more patients who took the study drug had grade 4 neutropenia and were more likely to have gastrointestinal adverse effects.

During the conference call, Athenex officials said the issue of whether the study population was representative of a US population also came up during the review process. The study arm of patients taking the combination drug was 90% Hispanic, 1% Black, and 7% White. According to the US Census Bureau, the nation’s population is 18.5% Hispanic, 13.4% Black, and 60% White.

Johnson Lau, MBBS, MD, FRCP, CEO of Athenex, said, “We remain committed to the breast cancer community and will explore the best path forward to obtain regulatory approval. In the interim, we will identify and undertake the appropriate internal organizational adjustments accordingly.”

References

1. Athenex receives FDA complete response letter for oral paclitaxel plus encequidar for the treatment of metastatic breast cancer. News release. Athenex, Inc. March 1, 2021. Accessed March 4, 2021. https://ir.athenex.com/
news-releases/news-release-details/athenex-receives-fda-complete-response-letter-oral-paclitaxel
2. Athenex announces oral paclitaxel and encequidar had a significantly higher response rate over IV paclitaxel in a phase III pivotal study in metastatic breast cancer. News release. Athenex, Inc. August 7, 2019. Accessed March 4, 2021. https://ir.athenex.com/news-releases/news-release-details/athenex-announces-oral-paclitaxel-andencequidar-
had

FDA Approves Cemiplimab for First-Line Advanced NSCLC With PD-L1 Expression

Regeneron Pharmaceuticals Inc, and Sanofi announced that the PD-1 inhibitor cemiplimab-rwlc (Libtayo) was FDA approved as a monotherapy for patients with first-line advanced non–small cell lung cancer (NSCLC) with PD-L1 expression of at least 50% as determined by an FDA-approved test.1 Patient eligibility criteria also include having either metastatic or locally advanced NSCLC that cannot be resected or treated with definitive chemoradiation, and tumors cannot have EGFR, ALK, or ROS1 aberrations.

The approval is based on an analysis of 710 participants in the phase 3, open-label EMPOWER-Lung 1 trial, which randomized patients 1:1 to receive either cemiplimab or chemotherapy. Patients were intended to have high PD-L1 expression, and the cemiplimab cohort had a 32% lower risk of death than the chemotherapy group in the overall population.

A prespecified analysis was performed on a cohort of 563 patients with confirmed PD-L1–high tumors proven by the PD-L1 immunohistochemistry 22C3 pharmDx kit, and those patients showed a 43% lower risk of death compared with those treated with chemotherapy. The results were published recently in The Lancet.2

“Libtayo has demonstrated an impressive level of efficacy in advanced NSCLC with at least 50% PD-L1 expression in its pivotal trial,” study investigator Ahmet Sezer, MD, professor in the Department of Medical Oncology at Baskent University in Adana, Turkey, said in a statement. “As published in The Lancet, in a prespecified analysis in the subset of patients proven to have PD-L1 expression of at least 50%, Libtayo reduced the risk of death by 43% compared with chemotherapy. This was achieved with a greater than 70% crossover rate to Libtayo following disease progression on chemotherapy, as well as the largest population of patients with pretreated and clinically stable brain metastases among advanced NSCLC pivotal trials to date.”

The approval of cemiplimab for this indication comes after a priority review by the FDA, which is granted when a drug may significantly improve patient outcomes in serious diseases. It is the third cemiplimab approval in the United States and the second in February 2021 alone.

Earlier in the month, the drug was approved for the treatment of advanced basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor (HHI) or in cases when an HHI is not appropriate.3 It was granted full approval for locally advanced BCC and accelerated approval for patients with metastatic BCC. In 2018, cemiplimab was approved for the treatment of locally advanced or metastatic cutaneous squamous cell when curative surgery or radiation is not an option.4

“With this third approval for Libtayo, we are proud to deliver on our ambition to bring our PD-1 inhibitor to patients in need with difficult-to-treat cancers, such as advanced NSCLC,” Peter C. Adamson, MD, global development head of oncology and pediatric innovation at Sanofi, said. “As the leading cause of cancer deaths globally, the need for additional therapeutic options in advanced NSCLC is clear. Libtayo allows physicians to further optimize treatment of these patients whose tumors have high expression of PD-L1. We thank all of the trial investigators, patients and their caregivers who helped make this milestone possible.”

In the trial, 355 patients in the cemiplimab cohort and 342 in the chemotherapy group were included in the safety assessment. In the cemiplimab group, rash and cough occurred more often than in the chemotherapy group and in at least 10% of patients (15% vs 6% and 11% vs 8%, respectively). The most common serious adverse reactions were pneumonia and pneumonitis, which occurred in 5% and 2%, respectively, of cemiplimab patients, and in 6% and 0% of chemotherapy patients. Overall, no new safety signals were found in the cemiplimab cohort.

“Libtayo has already changed the treatment paradigm for certain patients with advanced
cutaneous squamous cell carcinoma and is poised to do the same for advanced basal cell carcinoma,” said Israel Lowy, MD, PhD, senior vice president of clinical sciences, head of translational science, and head of oncology at Regeneron. “Now, Libtayo has the opportunity to make a meaningful difference for the many US patients battling advanced NSCLC. Libtayo is being investigated in a variety of settings, and we hope to share updates later this year on our pivotal trials in cervical cancer and in combination with chemotherapy in advanced NSCLC.”

References
1. FDA approves Libtayo (cemiplimab-rwlc) monotherapy for patients with first-line advanced non-small cell lung cancer with PD-L1 expression of ≥50%. News release. Regeneron Pharmaceuticals, Inc, and Sanofi; February 22, 2021. Accessed February 22, 2021. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-libtayor-cemiplimab-rwlc-monotherapy-patients-first

2. Sezer A, Kilickap S, Gümüs M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;397(10274):592-604. doi:10.1016/S0140-
6736(21)00228-2

3. FDA approves Libtayo (cemiplimab-rwlc) as first immunotherapy indicated for patients with advanced basal cell carcinoma. News release. Regeneron Pharmaceuticals, Inc, and Sanofi; February 9, 2021. Accessed February 22, 2021. https://investor.regeneron.com/news-releases/
news-release-details/fda-approves-libtayor-cemiplimab-rwlc-first-immunotherapy

4. FDA approves Libtayo (cemiplimab-rwlc) as first and only treatment for advanced cutaneous squamous cell carcinoma. News release. Regeneron Pharmaceuticals, Inc, and Sanofi; September 28, 2018. Accessed February 22, 2021. https://investor.regeneron.com/news-releases/
news-release-details/fda-approves-libtayor-cemiplimab-rwlc-first-andonly-
treatment

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