Alana Hippensteele, Senior Editor

The landscape of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) has changed significantly over the past several years, explained Jennifer Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, during a session at the Society of Hematologic Oncology 2021 conference.

For example, patients relapsing after minimal therapy are now considered to be essentially like frontline, which is a significant shift in practice, Brown explained. Most of the data demonstrating this shift in practice pertain to patients relapsing after chemoimmunotherapy with targeted agents. In this way, patients relapsing have been previously treated with targeted agents, and there is not yet enough data available on how to approach this when it occurs.

Brown noted that she generally divides patients with R/R CLL into the following categories: patients exposed to Bruton's tyrosine kinase (BTK) inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 (BCL-2) inhibitors.

“In terms of patients exposed to BTKi, in data from Ohio State, the most common reason for discontinuation was adverse events (AEs), and then over the long term, progression was the other main reason for discontinuation,” Brown said during the session.

In the study from Ohio State, investigators assessed toxicities and outcomes from ibrutinib-treated patients. The results showed that the most common AEs that led to discontinuation of therapy in patients with frontline CLL were arthralgia (42%), atrial fibrillation (25%), and rash (17%). For patients with R/R CLL, the most common AEs were atrial fibrillation (12%), infection (11%), pneumonitis (10%), bleeding (9%), and diarrhea (7%).

“Unfortunately, this does result in a reduced progression free survival compared to what we’ve seen in patients who stay on therapy in randomized trials,” Brown said during the session. “Those who come off for AEs have a better prognosis than those who progress and can still respond to other kinase inhibitors, such as phosphoinositide 3-kinases (PI3Ks) kinase inhibitors. However, in these real-world data, the best outcomes were with venetoclax.”

In addition to PI3Ks kinase inhibitors, data have demonstrated that patients who stop ibrutinib or another BTK inhibitor for an intolerance can respond with a relatively low rate of recurrence to acalabrutinib and zanubritinib, which demonstrates these are viable options for patients who stop BTKi due to the occurrence of AEs.

Additionally, patients who have stopped BTKi are at an increased risk of progression, Brown explained. Progression among these patients is most commonly due to mutations in BTK, with a subset of patients also having a mutation in phospholipase C gamma 2 (PLCG2).

“We now have data that similar mechanisms of resistance with mutations of C481 in BTK apply to acalabrutinib, in data from Ohio State, and also zanubritinib, in data from Australia. Our only prospective data specifically in this population are from a trial of venetoclax, in which the overall response rate (ORR) was 65%, which is really quite good,” Brown said during the session.

However, Brown noted that the complete response rate of 9% and the undetectable minimal residual disease (uMRD) of 42% are both lower than expected in patients who have not progressed after BTKi. Specifically, progressing after BTKi is associated with a lower response rate to venetoclax in combined analyses of outcomes.

To manage this lower response rate to venetoclax, some groups have responded by adding PI3Ks to venetoclax. In a study assessing umbralisib, ublituximab, and venetoclax, half the patients were R/R prior to BTKi, and the ORR to umbralisib and ublituximab in the first 3 cycles was 64% in patients with R/R CLL, Brown explained.

“This is rather encouraging,” Brown said during the session. “And then, of course, venetoclax was added, with very high rates of uMRD. Our study of duvelisib and venetoclax had similar results. So, there are opportunities for combinations in this space that can potentially enhance the efficacy of venetoclax.”

Brown J. Managing CLL Patients Relapsed or Refractory to Targeted Therapy. Presented at: Society of Hematologic Oncology 2021 Virtual Meeting. September 8, 2021. Accessed September 28, 2021.

Articles

Patients with relapsed or refractory chronic lymphocytic leukemia are generally divided by those exposed to Bruton's tyrosine kinase inhibitors (BTKi), patients relapsing after venetoclax, and patients relapsing after BTKi and B-cell lymphoma-2 inhibitors.

The Changing Landscape of Relapsed/Refractory Chronic Lymphocytic Leukemia Treatment

Alterations in the amino acid profile of children with attention-deficit hyperactivity disorder (ADHD) were observed by investigators in a recent study published in 

. The results may support further research into potential new treatment strategies for ADHD, according to the investigators.

Generally, ADHD manifests in childhood, resulting in children diagnosed with the disorder having difficulty with concentration and issues around impulsivity. Additionally, ADHD is understood to manifest at the neurochemical level, such as by disrupting dopamine and norepinephrine pathways.

However, the amino acids in the brain that may cause these profile changes in children with ADHD is still not fully understood, despite most of the treatments for the disorder consisting of amino acids. Because of these lack of data on the exact amino acid profile that may lead to the positive response from common ADHD treatments among this population, the investigators looked to identify the alterations present in the amino acid profile in the blood serum of children with ADHD in comparison to neurotypical children.

"Amino acids serve a significant role in brain development and functioning. In particular, certain amino acids or their precursors are well-established to be involved in neuronal signaling as neurotransmitters,” said Anatoly Skalny, DSc, head of RUDN University’s Department of Medical Elements Studies—where the study was conducted—in a press release. “Correspondingly, disruption of amino acid metabolism results in significant neurological disorders, particularly in children. Therefore, unraveling the potential underlying mechanisms implicated in ADHD pathogenesis is essential for improving our understanding of the disorder and further development of management strategies."

During the study, the investigators included 102 children aged 7 to 14 years, 71 of whom had been diagnosed with ADHD and 31 of whom were neurotypical. Using liquid chromatography, the investigators assessed the levels of amino acids in the blood serum of the study participants. The investigators then compared the data from the children with ADHD to the neurotypical children using statistical methods.

The results from the study demonstrated that the amino acid profile in children with ADHD differed from that of neurotypical children, with histidine, glutamine, and proline levels found to be lower by 29%, 10%, and 20%, respectively. Conversely, aspartic acid and glutamate were found to be 7% higher, whereas hydroxyproline was 42% higher.

The investigators found based on these data, the ratio of glutamine to glutamate (Gln/Glu) among children with ADHD was 28% lower than it was among neurotypical children, whereas the ratio of proline to hydroxyproline was 29% lower. The Gln/Glu ratio is known to be one of the indicators of the transmission of nerve impulses, whereas the second ratio of proline to hydroxyproline (Pro/Hypro) is known as a marker of disorders of collagen metabolism and connective tissue.

“The observed alterations in Pro/Hypro and Gln/Glu levels and ratios are likely associated with the coexisting connective tissue pathology and alterations in glutamatergic neurotransmission in ADHD, respectively,” Skalny said in the press release. “However, further in vivo and in vitro studies are required in order to investigate the detailed mechanisms linking amino acid metabolism with ADHD.”

RUDN University medics detect alterations in amino acid profiles in children with ADHD. 

https://www.eurekalert.org/news-releases/797064

Alterations in the amino acid profile of children with attention-deficit hyperactivity disorder may support further research into potential new treatment strategies.

Amino Acid Profile Differentiation Detected Among Children With ADHD

Non–small cell lung cancer (NSCLC) has become the most heterogeneous, molecularly driven cancer in therapeutics, explained R. Donald Harvey, PharmD, BCOP, FCCP, during a session at the virtual 2021 American Society of Clinical Oncology Annual Meeting. The agents that have been evaluated and approved, and those that are coming in the pipeline, make for an exciting time to consider directed therapies in NSCLC.

"Oral MET, RET, and KRAS inhibitors certainly have unique pharmacologic principles that we need to think of when these agents are selected for use, and certainly during and after use as well, as we consider mechanisms of resistance and other aspects of adverse events (AEs), drug interactions, etc," Harvey said during the session.

Before 2020, significant expansion occurred in the field of non–small cell small molecule therapeutics around the agents being used in clinics today, Harvey explained. Epidermal growth factor receptor (EGFR) inhibition, anaplastic lymphoma kinase (ALK) inhibition, and others provided the foundation for the start to the molecularly derived and molecularly selected population of patients who may be able to be treated with small molecules.

Harvey explained that in this space, over 2020 and 2021, there were FDA approvals of 3 RET inhibitors and 2 MET inhibitors, with more potentially on the horizon in the second half of 2021. Similarly, the first KRAS G12C inhibitor was submitted to the FDA for a new drug application in late 2020, with more potentially to follow.

In terms of the clinical pharmacology characteristics of some of the small molecules, Harvey explained that it is important to note certain valuable points for both patients and practitioners to understand around these agents. For example, in the case of 

 skipping variants in the exon 14 region, capmatinib (Tabrecta; Novartis) has some areas worth considering for patients and practitioners alike.

"First, it's a twice-daily agent with or without food. It has no food effects for absorption. It is a [cytochrome P450 family 3 subfamily A (CYP3A) member 4] and P-glycoprotein substrate, and so should patients be on agents that inhibit those pathways? You need to consider capmatinib exposure and, ideally, avoid moderate and strong inducers of CYP3A as well," Harvey said during the session.

Additionally, there are some AEs associated with capmatinib. Although it is generally well tolerated, Harvey explained that there can be some rare and serious pneumonitis and transaminitis. Although these are issues that should be monitored closely, pneumonitis and transaminitis are not considered overt or common AEs for capmatinib.

"Each of these agents does have a dose reduction and discontinuation rate. I think it's important, when we counsel patients and think about therapy initiations, that we consider this in the background, that we may have to dose reduce in certain areas," Harvey said during the session. "Only about 1 out of 5 patients needed to discontinue these agents within the licensing trials submitted for approval. Specifically, with capmatinib, there's no effect o age or weight on pharmacokinetics, and so the dose and exposure are linearly related within each of those areas."

Additionally, Harvey noted that with tepotinib (Tepmetko, EMD Serono), an important drug interaction that practitioners should stay aware of is with dabigatran (Pradaxa; Boehringer Ingelheim), which is a P-glycoprotein substrate. Since tepotinib is a strong P-glycoprotein inhibitor, it has the potential to significantly increase dabigatran's Cmax value, Harvey explained. Specifically, clinicians would preferably avoid concurrent use of dabigatran with tepotinib for this reason.

In the RET inhibition space, selpercatinib (Retevmo; Eli Lilly and Company) is the first agent that was approved in this class. For dosing, although selpercatinib has weight-based dosing as an option, most adults will be dosed at 160 milligrams. Additionally, although it is a CYP3A4 substrate, it may also have other CYP and transport protein substrate and interacting potential as well.

For patients treated with selpercatinib, acid-reducing agents should be avoided, Harvey noted. However, if, for example, a proton pump inhibitor is unavoidable, then selpercatinib can be taken by patients with food at least 2 hours before other antacids, outside proton pump inhibitors.

Additionally, selpercatinib has a good tolerability profile in terms of AEs. Although there are some rare but serious occurrences of transaminitis and hemorrhage, overall, the AE profile is reasonable and manageable.

Both selpercatinib and the RET inhibitor pralsetinib (Gavreto; Blueprint Medicines and Genentech) should be held for at least 7 days before elective surgery, and for about 2 weeks after surgery, so healing can occur. This healing period is necessary since RET fusion inhibitors can impair wound healing for many patients, Harvey explained.

For the RET inhibitor pralsetinib, the dosing for patients should be 400 milligrams on an empty stomach. Pralsetinib is also a CYP3A4 substrate with a good tolerability profile and low discontinuation rates. However, approximately 1 in 3 patients were found to need a dose reduction during the licensing trials that were conducted.

For the first KRAS G12C inhibitor sotorasib (Lumakras; Amgen), there is currently not much known, Harvey explained. However, it is known based on the data available that the recommended phase 2 dose and the licensing dose is 960 milligrams.

“It comes in 120 milligram sizes and so it’s 8 tablets that need to be used within that,” Harvey said. “There are ongoing questions of dosing of 240 mg vs 960 mg in a comparison trial that’s been recommended by FDA to be performed.”

For sotorasib, AEs such as diarrhea, fatigue, and nausea are known to occur, with a discontinuation rate of 7%. However, dose reduction data have not been reported.

Additionally, Harvey noted that there are resistance mechanisms that should be considered for patients who are receiving small molecule inhibitors. One resistance mechanism is within the kinase domain itself, whether that be RET, MET, or other aspects of the kinase, while another is the activation of escape alternative pathways.

“When we look specifically at MET, there’s laboratory data suggesting that EGFR activation and/or PI3 kinase upregulation may be responsible for those who develop resistance to the MET inhibitors that are approved,” Harvey said during the session. “RET inhibition, as well, has resistance pathways that need to be considered. There may be new RET mutations within the domain of the gene itself, and there may be MET gene amplifications or KRAS mutations that may lead to RET resistance clinically.”

The occurrence of KRAS G12C resistance shows how these agents work, Harvey explained. The active G12C binding of the KRAS compound to an overarching tumor cell demonstrates the active proliferation and conversion of GDP to GTP, which can go unchecked. With the addition of an inhibitor of the G12C molecule, inhibition of KRAS G12C can lead to growth arrest and subsequent cell death as the GDP-bound cells go into quiescence.

“One mechanism of resistance that’s been identified is that KRAS G12C cells may then undergo an increase in epidermal growth factor, as well as aurora kinase A expression,” Harvey said during the session. “Though those pathways may reactivate in an escape mechanism, the G12C can become once again GTP-bound, rather than GDP-bound, and allow for proliferation to occur. This is one mechanism of resistance that’s been identified and there may be others that come forward.”

Harvey RD. TKIs, MAbs, PROTACs, and more: the pharmacology of cutting-edge cancer therapies. Presented at: ASCO 2021 Annual Meeting; June 12, 2021. Accessed July 20, 2021. 

https://meetinglibrary.asco.org/record/193789/video

The agents that have been evaluated and approved, and those that are coming in the pipeline, make for an exciting time to consider directed therapies.

The Pharmacology of Cutting-Edge Non-Small Cell Lung Cancer Therapies in 2021

Advances in the lung cancer space are all about biomarkers, explained Alexander Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute at The US Oncology Network; and assistant professor of oncology at Johns Hopkins School of Medicine, during a session at the 2021 virtual Community Oncology Alliance Conference.

In the United States, non–small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancers, with most patients (66%) initially receiving a diagnosis of advanced or metastatic disease. One of the most common driver mutations in patients with NSCLC is KRAS G12C, a subset of oncogenic drivers specifically in the KRAS gene.

KRAS has been one of the primary targets posing a challenge in the lung cancer space. Spira explained that KRAS has been described as an “undruggable target,” which specifically relates to how intricate KRAS is in the signaling pathways for lung cancer.

Recent data have shown both a high unmet need and poor outcomes associated with the second-line treatment of KRAS G12C–driven NSCLC. Each year, approximately 25,000 new patients diagnosed are with KRAS G12C–mutated NSCLC across the country.

Spira noted that KRAS has specifically been referred to in the field as “undruggable” for many years; however, it is not for a lack of trying by investigators, as numerous therapies have been thoroughly assessed for potential benefit.

“They all have failed. So it’s been a very frustrating area,” Spira said during the session. “So how do we target it right now?”

One drug was recently FDA approved for adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC who have received at least 1 prior systemic therapy, and another has received a breakthrough therapy designation from the agency.

The accelerated approval of sotorasib (Lumakras; Amgen) follows it being granted priority review by the FDA in February.3 A first-in-class, highly selective, irreversible KRAS G12C inhibitor, sotorasib works by binding KRAS in the inactive state in order to hinder downstream signaling effects.

The FDA’s decision to approve sotorasib was based on the single-arm, open-label, multicenter study CodeBreaK 100 (NCT03600883).

 During this study, the investigators enrolled 124 patients with KRAS G12C–mutant solid tumors, with the study’s primary end point set as centrally reviewed objective response rate (ORR). To be eligible, patients needed to have received a prior line of systemic anticancer therapy that was consistent with both tumor type and disease stage.

The top-line results from the phase 2 trial demonstrated that 80% of patients achieved disease control, including 3 complete responses (CRs) and 43 partial responses (PRs). The best ORR was approximately 2% CRs, 34% PRs, and 40% stable disease.

“There’s a pretty deep response that was seen in many of our patients,” Spira said during the session. “It works, and in many of our patients it works very well. [Keep in mind] that many of these patients have multiple lines of therapy, making it of course less likely that you can have a deeper response to tumor volume, so pretty impressive results.”

The recommended sotorasib dose is 960 mg orally once daily with or without food.

The most common adverse reactions (≥ 20%) reported in the CodeBreaK 100 trial were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. According to the FDA, the most common laboratory abnormalities (≥ 25%) were decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

A similar drug that will potentially receive approval from the FDA this year is adagrasib (MRTX849; Mirati Therapeutics, Inc), according to Spira.

 The drug received a breakthrough therapy designation from the FDA in June for the potential treatment of patients with NSCLC who harbor the KRAS G12C mutation following prior systemic therapy.

Adagrasib was specifically designed to be a differentiated selective inhibitor of KRAS G12C, and Spira noted that this drug was intended to be even more specific than sotorasib, as it is a very potent inhibitor with a very high selectivity for the KRAS G12C protein. Additionally, adagrasib was designed to have a very long half-life, oral bioavailability, and tissue distribution.

The new designation was based on the phase 1/1b/2 KRYSTAL-1 study (NCT03785249).4 Results from the study demonstrated adagrasib yielded durable responses and broad disease control while also providing extensive coverage throughout the dosing interval.

At a dose of 600 mg given twice daily, adagrasib yielded an ORR of 43% in the phase 1/1b cohort (n = 14) and 45% in the pooled population of the phase 1/1b and 2 cohorts (n = 51).

Furthermore, the results demonstrated a disease control rate of 100% in the phase 1/1b cohort and 96% in the phase 1/1b and 2 cohort, with 57% and 51% of patients having stable disease, respectively. Additionally, in the phase 1/1b cohort, disease progression did not occur, and in the phase 1/1b and 2 cohort, it occurred in 2% of patients.

“Almost never seen before in this phase 1/1b cohort [is] a 100% disease control rate,” Spira said during the session. “I don’t think I’ve ever seen that in a study before. It did drop down to 96% in the pooled population, but it’s pretty remarkable numbers here.”

1. Spira A. New advances in lung cancer therapies coming in 2021. Presented at: 2021 Community Oncology Alliance Conference. Accessed April 9, 2021.

2. FDA grants sotorasib priority review designation for the treatment of patients with KRAS G12C-mutated locally advanced or metastatic non–small cell lung cancer. News release. Amgen. February 16, 2021. Accessed April 9, 2021. https://www.prnewswire.com/news-releases/fda-grants-sotorasib-priority-review-designation-for-the-treatmentof-patients-with-kras-g12c-mutated-locally-advanced-or-metastatic-non-small-cell-lung-cancer-301229256.html

3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. Updated May 28, 2021; FDA. Accessed July 16, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc

4. Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from US Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics Inc. June 24, 2021. Accessed July 16, 2021. https://ir.mirati.com/press-releases/press-release-details/2021/Mirati-Therapeutics-Adagrasib-Receives-Breakthrough-Therapy-Designation-from-U.S.-Food-and-Drug-Administration-for-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-Harboring-the-KRAS-G12C-Mutation/default.aspx

5. Virgil H. Adagrasib demonstrates favorable efficacy, pharmacokinetic profile in advanced KRAS G12C+ NSCLC. OncLive . March 25, 2021. Accessed April 9, 2021. https://www.onclive.com/view/adagrasib-demonstrates-favorable-efficacy-pharmacokinetic-profile-in-advanced-kras-g12c-nsclc

New treatments show promise for patients with KRAS G12C–mutated disease.

Advances in Non–Small Cell Lung Cancer Therapies

The FDA has approved the combination of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) plus the orally available multiple receptor tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai) for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

The approval was based on the results of the phase 3 CLEAR/KEYNOTE-581 trial. During the trial, the efficacy outcome measures of pembrolizumab plus lenvatinib demonstrated statistically significant improvements in comparison to sunitinib for progression-free survival (PFS), overall survival (OS), and confirmed objective response rate (ORR).

“This approval is based in part on data demonstrating that Keytruda plus Lenvima significantly reduced the risk of disease progression or death versus sunitinib,” said Robert Motzer, MD, Jack and Dorothy Byrne chair in clinical oncology, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, in a press release. “This is a significant milestone for newly diagnosed patients with advanced renal cell carcinoma and introduces a promising combination option in the first-line setting.”

Data regarding the PFS for pembrolizumab plus lenvatinib demonstrated that the combination therapy was able to reduce disease progression or mortality risk by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months compared with sunitinib at 9.2 months. For OS, the combination therapy was found to reduce mortality risk by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.0049) compared with sunitinib.

Additionally, the investigators found that patients who received pembrolizumab plus lenvatinib had a confirmed ORR of 71% (95% CI: 66-76) (n=252) compared with patients who received sunitinib at 36% (95% CI: 31-41) (n=129). The combination therapy also achieved a complete response (CR) rate of 16% and partial response (PR) rate of 55%, whereas patients administered sunitinib had a CR rate of 4% and a PR rate of 32%.

“This FDA approval reinforces the potential of Keytruda plus Lenvima, which is now approved for two different types of cancer. In the study, Keytruda plus Lenvima demonstrated a survival benefit for patients with advanced renal cell carcinoma, supporting the importance of this combination as a new first-line treatment option for these patients,” said Gregory Lubiniecki, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, in the press release.

During or after treatment with pembrolizumab, immune-mediated adverse effects (AEs) can occur, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Such immune-mediated AEs can be severe or fatal, result from any organ system or tissue, and affect more than a single system in the body at any given time.

To ensure the safe use of pembrolizumab, early identification and management of immune-mediated AEs are critical. Dependent on the severity of the AEs, treatment with pembrolizumab may need to be disrupted or permanently discontinued, with corticosteroids administered as necessary.

Furthermore, treatment with pembrolizumab can result in severe or life-threatening infusion-related reactions. When administered to pregnant women, pembrolizumab is also capable of causing fetal harm. Because lenvatinib can cause fetal harm as well when administered to pregnant woman, patients with reproductive potential may be advised to use effective contraception while being administered this combination therapy.

With lenvatinib, serious or fatal AEs can also occur, such as hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing, osteonecrosis of the jaw, and embryo-fetal toxicity.

Based on the severity of the AE, lenvatinib may need to be interrupted, reduced, and/or discontinued.

“This FDA approval is truly significant for the advanced renal cell carcinoma community. The CLEAR/KEYNOTE-581 trial shows treatment with Keytruda plus Lenvima resulted in superior outcomes across progression-free survival, overall survival and objective response rate versus sunitinib in patients with advanced renal cell carcinoma,” said Takashi Owa, MD, chief medicine creation and chief discovery officer, Oncology Business Group at Eisai, in the press release.

The FDA approved the application for the pembrolizumab plus lenvatinib combination therapy as a part of its Real-Time Oncology Review pilot program. This program was established to improve the efficiency of the review process for applications to ensure that treatments are accessible as early as possible.

Prior to this approval for pembrolizumab plus lenvatinib as the first-line treatment for RCC, the 

FDA granted priority review to pembrolizumab

 (Keytruda, Merck) as an adjuvant therapy for RCC. If approved, pembrolizumab would become the first adjuvant immunotherapy option for this patient population.

FDA Approves KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination for First-Line Treatment of Adult Patients With Advanced Renal Cell Carcinoma (RCC). Kenilworth, NJ: Merck; August 11, 2021. 

https://www.businesswire.com/news/home/20210811005902/en

The FDA approved pembrolizumab plus lenvatinib for the first-line treatment of adult patients with advanced RCC.

FDA Approves Pembrolizumab Plus Lenvatinib Combination as First-Line Treatment for Advanced Renal Cell Carcinoma

In patients with episodic migraine who did not successfully respond to 2 to 4 prior preventive treatments, erenumab (Aimovig; Amgen, Novartis) was found to have a sustained efficacy as a monotherapy treatment during a period of up to 64 weeks, according to results from the LIBERTY study.

Additionally, the investigators observed that the safety of erenumab was consistent with the safety profile found during previous clinical trials.

During the study, investigators enrolled 240 patients with episodic migraine who had previously completed the double-blind treatment trial phase (DBTP). In DBTP, patients received either a placebo or erenumab at 140 mg as a monotherapy administered through subcutaneous injections every 4 weeks.

In the current open-label extension phase (OLEP) of the LIBERTY study, the investigators assigned patients at random to the once-monthly subcutaneous injections of erenumab monotherapy dosed at 140 mg over a period of 3 years. The investigators also allowed patients who were in the placebo arm of the DBTP to move to erenumab during the OLEP.

In total, the week 52 visit in the OLEP was completed by 85% patients, with 36 patients discontinuing treatment in the OLEP either before or at week 64. The reasons patients discontinued the treatment included lack of efficacy (7.9%), subject or guardian decision (4.6%), and the occurrence of adverse events (1.7%).

Among patients who continued erenumab during the trial, the 50% responder rate increased from 29.9% during weeks 9 through 12 and up to 44.3% during weeks 61 through 64. In patients who initiated erenumab in the OLEP, the 50% responder rate was greater in the OLEP at 50.0% during weeks 61 through 64 than during DBTP at 14.2% during weeks 9 through 12, compared with the results from patients in the continuous erenumab arm.

Among the overall population, the 50% responder rate in the OLEP increased from weeks 13 through 16 up to weeks 37 through 40, and then remained stable during weeks 61 through 64.

Additionally, patients who were treated with erenumab in the DBTP demonstrated sustained efficacy across all measured efficacy outcomes, whereas those who initiated erenumab in the OLEP demonstrated ongoing improvement starting at week 13 and thereafter.

Overall, the investigators found that approximately 80.8% of patients experienced adverse events (AEs), whereas serious AEs occurred in 6.7% of patients; however, no deaths occurred among this patient population.

Goadsby PJ, Reuter U, Lanteri-Minet M, et al. Long-term Efficacy and Safety of Erenumab: Results From 64 Weeks of the LIBERTY Study. 

. April 28, 2021. doi: 10.1212/WNL.0000000000012029.

Erenumab was found to have a sustained efficacy as a monotherapy treatment for  episodic migraine that was found to not respond to 2 to 4 prior preventive treatments.