Authors of a paper recently published in 

 suggest that as health care providers increasingly use minimal residual disease (MRD) assessment to influence real-world clinical decisions, then investigators should seek to establish MRD negativity as a surrogate endpoint for patient outcomes in multiple myeloma trials.

The integration of novel therapies and combinations for the treatment of patients with multiple myeloma has led to more durable responses, translating to improved survival. However, it has also shed light on shortcomings with current residual disease testing modalities that have been used to defined complete responses (CRs) in this patient population. Nearly all patients who achieved CRs with such testing experience relapse, suggesting that the standard immunofixation techniques and morphological evaluation of bone marrow provided a “false sense of disease control,” lead study author Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School and program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, and co-authors wrote.

As such, MRD assessment was incorporated into the International Myeloma Working Group uniform response criteria based on available data demonstrating the prognostic value of MRD negativity in patients with multiple myeloma.

 In January 2016, a white paper collaboration of minds across the myeloma field updated the status of MRD and highlighted that a study-based definition of MRD as a surrogate end point was needed to inform clinical decisions in multiple myeloma.

Subsequently, more research has emerged establishing MRD as a potential regulatory end point for clinical trials and MRD negativity had routinely been incorporated into clinical trial designs. Moreover, these efforts are providing additional insight into the value of MRD assessment at various stages of multiple myeloma.

“Many of these designs have now been implemented, and almost 50 phase 3 trials are currently actively enrolling, using MRD-directed treatment assignment or MRD as an end point,” Anderson, who is a 2014 Giants of Cancer Care® winner in multiple myeloma, and co-authors wrote.1

Multiple MRD assessment technologies are emerging as potentially employable strategies for clinical trials, drug development, and real-world utility, including next-generation flow (NGF), next-generation sequencing (NGS), blood-based MRD assessment, circulating cell-free DNA assessment, single-cell RNA-sequencing, imaging, and mass spectrometry-based paraprotein analyses. Although these technologies differ, any measurement of tumor burden can “provide consistency when comparing treatment arms or stratifying patient populations into different arms of therapeutic intervention and ultimately in the future in choosing treatment options in real-world practice,” Anderson and co-authors wrote.

However, factors such as prior treatments, other diagnostic tests and risk markers, and patient-related factors, such as symptoms, comorbidities, and quality of life, should be considered when determining how much value MRD assessment holds for an individual patient.

“Determination of MRD at a single point in time may have prognostic significance, but quantitative, accurate, standardized, and sensitive MRD determinations may provide greater information relevant to tumor biology and likelihood of relapse when performed in a sequential fashion over multiple time points during a continuum of care to establish the trend and pace of the change in tumor burden,” wrote Anderson and co-authors.

Despite the estimate that MRD assessment can open opportunities for potential regulatory and clinical uses as a biomarker, factors such as underlying disease, patient heterogeneity, therapeutic context, target of therapy, or a combination of disease parameters must be considered before wide implementation of MRD assessment can be used in the clinical and regulatory settings.

Moreover, with so many ongoing trials incorporating MRD negativity as end points, it is critical to ensure that emerging data regarding MRD is interpretable. The FDA has highlighted issues such as inadequate data, data not proposed for inclusion because of missing or disparate data points, high rates of test failures, incomplete test characteristics, and incomplete planned statistical analysis with MRD assessment in past regulatory submissions. Notably, although NGF and NGS are the most widely utilized MRD technologies currently, the FDA does not have a preference in terms of technology platforms used in clinical trials assessing MRD, stating only that the test must be analytically validated for its context of use in the trial.

The role of MRD assessment as a clinical end point in trials is an important facet of the biomarker’s development in multiple myeloma. With the significant advances that have been made in therapeutics in recent years, the time to reach progression-free survival and overall survival has become very long, which prevents therapies from moving into clinical use in a timely manner, particularly with regard to frontline regimens. Because MRD-negativity status has demonstrated improved survival outcomes, incorporation of MRD negativity as a surrogate end point could expedite therapeutic development for patients with multiple myeloma.

“It would be beneficial for regulatory agencies to use existing data from completed [multiple myeloma] trials to provide industry with guidance on specific timepoints that can be used in prospective [multiple myeloma] trials for evaluating MRD status. Such guidance will of course evolve, but if we wait for future clinical trials to provide definitive validation of MRD as a surrogate end point, valuable years will be lost as we wait for these studies to progress and these data to mature,” Anderson and co-authors wrote.

Ultimately, MRD assessment stands to benefit patients across the spectrum of multiple myeloma, including smoldering, transplant-eligible and -ineligible newly diagnosed, and relapsed/refractory disease states. MRD assessment also appears to have utility in patients with extramedullary disease.

“The pace of advances in targeted and immune therapies in [multiple myeloma] is unprecedented, and this collaborative effort, inspired by a shared commitment to patients, will assure that these advances translate to clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes,” Anderson and co-authors concluded.

Anderson KC, Auclair D, Adam SJ, et al. Minimal residual disease in myeloma: application for clinical care and new drug registration. 

Published online July 28, 2021. Accessed August 17, 2021. doi:10.1158/1078-0432.CCR-21-1059

Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. 

. 2016;17(8):e328-e346. doi:10.1016/S1470-2045(16)30206-6

This article was originally published on OncLive as “MRD Negativity Moves Into the Spotlight as a Potential Surrogate End Point in Multiple Myeloma”

Articles

The prognostic value of minimal residual disease negativity in multiple myeloma may make it a suitable surrogate endpoint in clinical trials, according to a group of researchers. 

Could MRD Negativity Become A Suitable Surrogate Endpoint in Multiple Myeloma Trials?

Minimal residual disease (MRD) has the potential to be a useful prognostic tool in personalizing early lines of treatment for patients with non-small cell lung cancer, according to David R. Gandara, MD, in a presentation during the 

 International Lung Cancer Congress® (ILCC), a program hosted by the Physicians’ Education Resource®, LLC.

“Looking at what is happening, not only in lung cancer but in multiple other tumor types, [the integration of predictive MRD] has the most promise of anything we will talk about at ILCC,” said Gandara, a professor, director of the Thoracic Oncology Program, and senior advisor to the director at the University of California Davis Comprehensive Cancer Center.

Establishing the Utility of Liquid Biopsy in Advanced NSCLC

MRD has an established prognostic role in the treatment of patients with advanced NSCLC, Gandara said. However, before this, liquid biopsy with circulating tumor DNA (ctDNA), for example, demonstrated potential applications throughout the management of patients with NSCLC, from screening to diagnosis to disease monitoring to determining mechanisms of resistance to therapy.

However, like many technologies that have been used in later-line settings, the field of NSCLC is hoping to incorporate liquid biopsy, and, in particular, MRD testing, into earlier lines of treatment, explained Gandara.

“Doing [liquid biopsy] in the advanced-stage setting, means that we can possibly apply it to early-stage disease if we have assays that are sensitive and specific enough,” said Gandara.

, demonstrated that ctDNA analysis can identify post-treatment MRD in patients with localized lung cancer and do so earlier than radiologic imaging, which was standard at the time.

 The findings from the study showed that 94% of patients had detectable ctDNA in the first post-treatment blood sample as assessed by cancer personalized profiling by deep sequencing (CAPP-seq).

“We have already established to some extent that we can use MRD detection and that this correlates with prognosis,” Gandara added.

Findings from another study (NCT03004755), published in 

 in 2017, demonstrated that phylogenetic ctDNA profiling can predict disease recurrence; however, the technology was limited at the time in terms of universal application to an MRD setting, Gandara explained.

Subsequently, findings from a large, retrospective study of 21,807 patients with treated, late-stage cancer, including NSCLC, showed that cell-free DNA sequencing was able to identify subclonal structures and emerging resistance mechanisms.

An 85% detection rate with the Guardant360 plasma next-generation sequencing assay was reported from the analysis. In thoracic cancers, the detection rates were 93% in small cell lung cancer and 87% in NSCLC. Notably, the median variant allele frequency (VAF) rate was 0.41% (range, 0.03%-97.6%).

“Remember in blood, when we talk about VAF, we are talking about comparison to all the DNA that is in the blood, not just the tumor DNA,” Gandara said.

Now, with positive data emerging from studies conducted in the adjuvant setting, such as the phase 3 ADAURA (NCT02511106) and IMpower010 (NCT02486718) trials, the question remains as to whether MRD will predict for which patients should receive adjuvant therapy vs who is effectively cured after surgery, Gandara explained.

Definitive Data and Ongoing Research Efforts

Studies are ongoing with the goal of addressing the question of whether MRD assessment has utility in the adjuvant setting, Gandara said.

For example, the ongoing phase 3 MERMAID-1 trial (NCT04385368) is evaluating MRD assessment in patients with surgically resected stage II/III NSCLC.5 After surgery, patients will undergo plasma collection for MRD status testing. Then, patients will be randomized 1:1 to receive durvalumab (Imfinzi) plus chemotherapy followed by durvalumab or placebo plus chemotherapy followed by placebo for up to 12 months. The primary end point of the study is investigator-assessed disease-free survival in the MRD-positive analysis set with MRD status serving as a stratification factor.

The study investigators will use whole-exome sequencing to identify tumor-specific variants within a patient’s surgical specimen. Then tumor-specific DNA in the plasma can be detected in the adjuvant setting.

Additionally, the phase 3 MERMAID-2 trial (NCT04642469) has recently begun enrollment of patients with stage II/III NSCLC who underwent curative-intent therapy.6 The study is evaluating the efficacy of durvalumab vs placebo in patients with MRD-positive disease; patients with MRD-negative disease will receive surveillance instead of durvalumab or placebo for up to 96 weeks.

“[The MERMAID-2 trial] is relevant and will give us information in a new way. Both [the MERMAID-1 and MERMAID-2 trials] will be important studies,” Gandara concluded.

Gandara DR. Minimal residual disease in non-small cell lung cancer (NSCLC): emerging role in therapeutic decision making. Presented at: 

 International Lung Cancer Congress®; July 29-31, 2021; hybrid interactive conference.

Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. 

2017;7(12):1394-1403. doi:10.1158/2159-8290.CD-17-0716

Abbosh C, Birkbak NJ, Wilson GA, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. 

. 2017;545(7655):446-451. doi:10.1038/nature22364

Zill OA, Banks KC, Fairclough SR, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. 

2018;24(15):3528-3538. doi:10.1158/1078-0432.CCR-17-3837

Peters S, Spigel D, Ahn M, et al. MERMAID-1: a phase III study of adjuvant durvalumab plus chemotherapy in resected NSCLC patients with MRD+ post-surgery. 

. 2021;16(3):S258-S259. doi:10.1016/j.jtho.2021.01.376

Phase III study to determine efficacy of durvalumab in stage II-III non-small cell lung cancer (NSCLC) after curative intent therapy. ClinicalTrials.gov. Updated July 15, 2021. Accessed July 29, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04642469

This article was originally published on OncLive as 

“MRD Offers a Potential Predictive Strategy to Further Personalize Treatment in NSCLC”

Early lines of treatment for non-small cell lung cancer treatment might be effectively guided by minimal residual disease. 

MRD Might Aid in Efforts to Personalize Early Non-Small Cell Lung Cancer Treatment

Plinabulin, an investigational, first-in-class, selective immunomodulating microtube binding agent (SIMBA), has demonstrated a potential capability to prevent chemotherapy-induced neutropenia (CIN) as well as serve as an anticancer agent in treating non-small cell lung cancer (NSCLC). 

 The drug’s status as a potential preventative and active drug is based on its highly differentiated mechanism of action.

Plinabulin binds to the vicinity of the colchicine binding domain of the ß-tubulin in αβ-tubulin heterodimers. The binding occurs at a site and with kinetics that is unique from other tubulin targeting agents.

Moreover, by binding to tubulin, GEF-H1, an immune defense protein, is released by plinabulin. This activates a signaling transduction pathway that leads to dendritic cell (DC) maturation. In turn, DC maturation elicits innate and adaptive immune activity. DC maturation also results in increased antigen presentation and T-cell activation, which appears to contribute to plinabulin’s anticancer activity.

On June 1, 2021, the FDA granted a priority review designation to a new drug application for plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of CIN.2 The regulatory designation is based on findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), as well as 5 supportive trials that enrolled over 1200 patients.

In PROTECTIVE-2, the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN vs pegfilgrastim alone in patients with early-stage or stage III breast cancer receiving high–febrile neutropenia risk chemotherapy (n = 221).

The final results of the study, which were presented during the 2021 ASCO Annual Meeting, confirmed that the combination elicited superior CIN protection compared with pegfilgrastim alone.5 The addition of plinabulin also reduced adverse clinical sequalae, did not add toxicity, reduced the severity of grade 4 treatment-emergent adverse effects (AEs), and significantly reduced bone pain (

“We think that the combination protects [patients] throughout the chemotherapy cycle. We know from a long experience that there is a vulnerability or lack of protection within the first week after chemotherapy with pegfilgrastim. Adding plinabulin to pegfilgrastim seems to mitigate that vulnerability or increase the protection in the first week after chemotherapy,” said lead study author of the PROTECTIVE-2 study Douglas W. Blayney, MD, a medical oncologist at Stanford Health Care and a professor of medicine at Stanford Medicine, in an interview during an episode of 

“This will help oncologists and their patients receive more chemotherapy during both weeks of the chemotherapy cycle before the bone marrow recovers normally,” Blayney added.

Plinabulin’s activity has also been evaluated in lung cancer. The agent is currently being evaluated in combination with docetaxel for patients with advanced NSCLC who have measurable lung lesions in the phase 3 DUBLIN-3 trial (Study 103; NCT02504489).

The anticancer results for overall survival are expected in the final quarter of 2021, according to Blayney.

Plinabulin is also being evaluated in combination with the PD-1 inhibitor nivolumab (Opdivo) with the rationale that adding the agent will elicit synergistic immune-enhancing effects.1 Historically, cumulative toxicity has been a concern with nivolumab in combination with other checkpoint inhibitors; however, it is thought that plinabulin/nivolumab may demonstrate improved antitumor activity vs nivolumab alone without significantly increased toxicity. An ongoing phase 1/2 study (NCT02812667) is evaluating the combination in patients with metastatic NSCLC.

Triplet combinations are also under study with plinabulin.

 The combination of plinabulin, nivolumab, and ipilimumab (Yervoy) is being evaluated in a phase 1/2 study (NCT03575793) in patients with recurrent small cell lung cancer to determine whether plinabulin will be synergistic with nivolumab and ipilimumab while limiting immune-related AEs associated with the agents.

Finally, research is ongoing to test the potential benefits of adding plinabulin to PD-1 inhibitors and radiation therapy.

“Given the high incidence of progression with PD-1/PD-L1 antibody therapies in the majority of cancers, we believe this novel triplet approach will restore or enable the immune targeting of cancer in patients that have progressed on checkpoint [inhibitor] therapy,” according to BeyondSpring Pharmaceuticals.

Plinabulin. BeyondSpring Pharmaceuticals. 2021. Accessed July 14, 2021. https://bit.ly/3rjFXPu.

BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring. June 1, 2021. Accessed July 14, 2021. https://bit.ly/2SQVl8U.

Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PS13-53-01.

BeyondSpring announces new positive PROTECTIVE-2 phase 3 registrational trial results at the 2020 San Antonio Breast Cancer Symposium. News release. BeyondSpring. December 10, 2020. Accessed July 14, 2021. 

Blayney DW, Shi Y, Adamchuk H, et al. Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention. 

. 2021;39(suppl 15):533. doi:10.1200/JCO.2021.39.15_suppl.533

Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC. ClinicalTrials.gov. Updated May 21, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02504489

Nivolumab in combination with plinabulin in patients with metastatic non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02812667

A phase I/II study of nivolumab, ipilimumab and plinabulin in patients with recurrent small cell lung cancer. ClinicalTrials.gov. Updated May 28, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03575793

This article was originally published on OncLive as “

Unique Mechanism of Action Positions Plinabulin as a Preventive and Active Therapy in Breast Cancer, NSCLC”


Study results have posited plinabulin as a potentially effective preventative and active therapy due to its unique mechanism of action.


Distinct Mechanism of Action Makes Plinabulin a Potentially Powerful Therapy in Treating Breast Cancer

Presented findings from the 36th Annual European Association of Urology (EAU) Congress showed that urologic care experienced a significant decline throughout the peak of the COVID-19 pandemic. Despite varying stay-at-home order mandates, all demographic groups and practice settings in the United States reported similar findings.

Notably, declines of more than 40% were observed among outpatient visits from March 2020 to April 2020. Although outpatient visits recovered through May 2020 and early June 2020, they began to fall again in July 2020 in the overall population.

“This study provides timely, real-world evidence on the magnitude of decline in the provision of urological care across demographic groups and practice settings, and demonstrates a differential impact on the utilization of urologic health services by sociodemographic strata and specific diagnoses,” Daniel J. Lee, MD, MS, an assistant professor of urologic oncology in the Department of Surgery at the Perelman School of Medicine at the University of Pennsylvania, and co-authors wrote.

Non-urgent visits, including visits for microscopic hematuria, overactive bladder, elevated prostate-specific antigen, erectile dysfunction, and benign prostatic hyperplasia, also declined, as did procedure visits.

Non-urgent visits declined by 39% to 47% from March 2020 to April 2020, whereas visits for urgent diagnoses declined by 29% to 43%. Surgical procedures for non-urgent conditions declined by 37% to 53% compared with surgical procedures for potentially urgent matters, which declined by 13% to 21% during the evaluated time period.

The COVID-19 pandemic affected facets of health care access and delivery, including hospital admissions and outpatient care for certain conditions, throughout the United States, wrote Lee and co-authors. However, the significance of the pandemic with regard to specialty care had not been fully realized, which provided the clinical rationale to conduct the analysis.

The specialty-wide, community-based cohort study evaluated trends in outpatient urologic care visits, as well as procedural volume from February 2020 to July 2020. The study utilized the American Urological Association Quality (AQUA) Registry, which automatically extracts patient data from electronic health records.

AQUA collects data from 157 urology practices, which comprise 3,165 providers. Notably, these providers account for approximately one-fourth of all urologists in the United States, wrote Lee and co-authors. The practices are spread across 48 states and territories in the United States.

The trends were evaluated based on patient, practice, and local or regional demographic and pandemic response features.

Primary outcomes included mean visit volume and procedure volume-per-week, which were compared with the respective weeks in 2019.

Overall, 2,750,001 patients were included in the cohort, which comprised 8,953,832 outpatient visits and 1,570,161 procedures.

The decrease in visits was smaller among African American and Hispanic patients compared with Asian and Caucasian patients; however, African American and Hispanic patients experienced a slower recovery in visits to baseline.

Patients insured by Medicare, most of whom were over the age of 65, observed the steepest reduction in visits at 50%. Additionally, 84.4% of patients insured by Medicaid, most of whom were low-income patients, did not recover to the baseline number of weekly visits before the COVID-19 pandemic.

Finally, among practices located in areas with lower median incomes, higher poverty levels, and lower urologist-to-population rations experienced smaller decreases in outpatient visits.

Lee DJ, Shelton JB, Brendel P, et al. Impact of the COVID-19 pandemic on urologic care delivery in the United States. Presented at: 36th Annual EAU Congress; July 8-12, 2021; Virtual. Abstract P0183.

“Urologic Care Rates Decline Across US Demographics During Height of COVID-19 Pandemic”

The impact of the pandemic in regard to specialty care remains to be fully realized. 

Urologic Care Rates Decrease Throughout Climax of COVID-19 Pandemic   

Findings from an exposure-response (ER) analysis of the phase 3 CheckMate 9ER trial (NCT03141177) showed that Cabozantinib (Cabometyx) did not result with an improved progression-free survival (PFS) but instead was associated with higher rates of plantar erythrodysesthesia (PPE) and diarrhea in patients with advanced renal cell carcinoma (RCC). 

“ER modeling predicts that appropriate dose modification of the 40-mg cabozantinib starting dose to manage AEs [adverse effects] will not adversely affect the efficacy of nivolumab plus cabozantinib in first-line advanced RCC,” lead study author Amishi Y. Shah, MD, an assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and co-authors wrote in a poster of the data.

The CheckMate 9ER trial revealed that the frontline combination of nivolumab plus cabozantinib significantly improved PFS (HR, 0.51; 95% CI, 0.41-0.64; 

 < .001), overall survival (OS; HR, 0.60; 95% CI, 0.40-0.89; 

 < .001) compared with sunitinib (Sutent) in patients with advanced RCC.

In the study, patients with previously untreated RCC received 40 mg of cabozantinib daily in combination with 240 mg of nivolumab every 2 weeks.

The regimen was generally well tolerated among patients, with low rates of treatment-related discontinuations. Dose modifications appeared to successfully manage AEs and allow patients to tolerate the regimen.

Patients (n = 320) received a median average daily dose of 29.4 mg of cabozantinib in the CheckMate 9ER trial. First-level dose reductions of cabozantinib to 20 mg daily because of AEs were observed in 50% (n = 161) of patients after a median time of 98 days (range, 9-506). Second-level dose reductions of cabozantinib to 20 mg every 2 days were observed in 8.1% of patients (n = 26) after a median time of 173 days (range, 65-613).

Because of AEs, 7.5% of patients (n = 24) discontinued cabozantinib, 6.6% of patients (n = 21) discontinued nivolumab, and 5.6% of patients (n = 18) discontinued both agents.

With a database lock date of March 30, 2020, investigators sought to understand the relationship between cabozantinib exposure, and the efficacy and safety outcomes observed in the CheckMate 9ER trial utilizing time-to-event Cox proportional hazard ER models.

The models evaluated specified end points, including PFS, dose modifications (holds or reductions), and select AEs, such as grade 1 or greater PPE, grade 3 or greater diarrhea, grade 3 or greater hypertension, grade 3 or greater fatigue/asthenia, and grade 3 or greater alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase.

“Cabozantinib exposure was defined as the overall average concentration from time zero to time of event or censoring [CAVG0T] for each end point and estimated by population pharmacokinetic modeling,” Shah and co-authors wrote.

As of the database lock date, survival data were immature, so the relationship between OS and cabozantinib exposure was not assessed.

Regarding end points, the number of patients at risk receiving 1 or more doses of cabozantinib were 311 for PFS, 318 for dose modification, 320 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 317 for ALT/AST elevation. Of these, the number of patients with 1 or more measurable cabozantinib concentration was 303 for PFS, 306 for dose modification, 308 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 307 for ALT/AST elevation.

Regarding the number of events by end point, the number of patients receiving at least 1 dose of cabozantinib was 144 for PFS, 285 for dose modification, 128 for PPE, 22 for diarrhea, 44 for hypertension, 24 for fatigue/asthenia, and 35 for ALT/AST elevation. Of these, patients with at least 1 measurable cabozantinib concentration included 139 for PFS, 279 for dose modification, 128 for PPE, 21 for diarrhea, 44 for hypertension, 23 for fatigue/asthenia, and 34 for ALT/AST elevation.

In evaluable populations, patients were a median age of 62 years (range, 29-90), with a median body weight of 80.3 kg (range, 36.0-159.3), and the majority of patients (77%) were male with high Karnofsky Performance Statuses (≥90, 79%) and low lactase dehydrogenase (≤1.5 x upper limit of normal, 94%). The median nivolumab clearance was 0.009 L/h (range, 16.0-53.4).

The target lesions were a median of 69 mm (range, 10-330). Most patients did not have prior radiotherapy (86%) but underwent prior nephrectomy (69%).

Most patients (65%) were randomized to treatment in the CheckMate 9ER trial less than 1 year from initial diagnosis.

The majority of patients (74%) had a baseline PD-L1 status of less than 1% or an indeterminate status and International Metastatic RCC Database Consortium (IMDC) scores of 1 or 2 (58%).

In the PFS analysis population (n = 303), more favorable IMDC scores were observed in patients in higher exposure quartiles. However, baseline characteristics were generally similar otherwise.

Further results revealed that cabozantinib exhibited higher interpatient variability in apparent clearance (n = 306; median 1.93 L/h; range, 0.64-10.3) and average exposure (n = 303; median 564.6 ng/mL; range, 29.3-1995).

With regard to PFS, the median exposure in quartile 4 was 848.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 302.3 ng/mL (HR, 0.99; 95% CI, 0.71-1.40) in quartile 1, 485 ng/mL (HR, 1.00; 95% CI, 0.79-1.25) in quartile 2, and 641.2 ng/mL (HR, 1.00; 95% CI, 0.88-1.14) in quartile 3. Overall, this suggested that PFS was not different between cabozantinib exposure quartiles.

Regarding the development of grade 1 or greater PPE, the median exposure in quartile 4 was 872.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 318.9 ng/mL (HR, 0.51; 95% CI, 0.37-0.70) in quartile 1, 512.5 ng/mL (HR, 0.65; 95% CI, 0.53-0.80) in quartile 2, and 658.6 ng/mL (HR, 0.77; 95% CI, 0.68-0.87) in quartile 3.

Regarding the development of grade 3 or higher diarrhea, the median exposure in quartile 4 was 825.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 312.2 ng/mL (HR, 0.38; 95% CI, 0.19-0.75) in quartile 1, 471.2 ng/mL (HR, 0.51; 95% CI, 0.32-0.82) in quartile 2, and 606.9 ng/mL (HR, 0.66; 95% CI, 0.49-0.88) in quartile 3.

“The risk of developing PPE or diarrhea was greater at higher cabozantinib exposure quartiles; there was not association for hypertension, fatigue/asthenia, or AST/ALT elevation,” wrote Shah and co-authors.

Regarding dose modifications, the median exposure was 2.96 L/h in clearance quartile 4 (HR relative to CL/F, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 1.32 L/h (HR, 1.20; 95% CI, 0.91-1.57) in quartile 1, 1.74 L/h (HR, 1.13; 95% CI, 0.94-1.35) in quartile 2, and 2.19 L/h (HR, 1.07; 95% CI, 0.97-1.18) in quartile 3.

“The risk of cabozantinib dose modification increased with decreasing cabozantinib clearance but was not significantly different between cabozantinib clearance quartiles,” Shah and co-authors wrote.

Additionally, cabozantinib exposure was not found to be a statistically significant predictor of PFS, and the rate of progression or death was not significantly associated with daily cabozantinib exposure (20 mg vs 40 mg). CAVG0T was 386 ng/mL at the 20 mg daily dose vs 772 ng/mL at the 40 mg daily dose (HR, 1.00; 95% CI, 0.78-1.27).

Increased cabozantinib exposure was significantly associated with an increased risk of PPE (HR, 0.63; 95% CI, 0.50-0.78) and diarrhea (HR, 0.48; 95% CI, 0.29-0.80), but no significant exposure-response relationships were identified for hypertension, fatigue/asthenia, or ALT/AST elevation.

Although not statistically significant, higher cabozantinib clearance was associated with a lower rate of cabozantinib dose modification (2.2 L/h vs 1.2 L/h; HR, 0.87; 95% CI, 0.71-1.07; 3.2 L/h vs 1.2 L/h; HR, 0.80; 95% CI, 0.57-1.12).

A multivariable analysis with backward elimination showed that certain baseline patient characteristics, including sex, nivolumab clearance, and baseline albumin, were significant covariates. Patients with higher baseline nivolumab clearance or lower baseline albumin levels were predicted to have higher rates of disease progression or death.

Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. 

 2021;39(suppl 15):4561. doi:10.1200/JCO.2021.39.15_suppl.4561

This article was originally published as 

“Cabozantinib Exposure Not Associated With PFS, But Is Linked With Higher AEs With Cabozantinib/Nivolumab in RCC”

A presentation from the 2021 ASCO Annual Meeting highlights the current limitations of Cabozantinib as a treatment for RCC. 

Cabozantinib Did Not Improve PFS in CheckMate -9ER Exposure-Response Analysis and Results in More AEs in Patients with RCC 

While merkel cell carcinoma (MCC) tends to have poor prognoses and limited treatment options, promising response rates with checkpoint inhibitors may pave the way for better treatment for the rare skin cancer, according to James A. DeCaprio, MD. 

“Within the medical community there has been awareness raised for MCC because of the success [seen] with checkpoint blockade therapy,” said DeCaprio. “Now, more people know about MCC, and even people who are not involved in skin cancer [treatment] are aware of it. We’re never going to see an ad on TV for MCC treatment because it is rare, but there are certainly opportunities to build on the really spectacular responses to checkpoint blockade [we’ve seen].”

For example, the novel, oral, MDM2 small molecule inhibitor KRT-232 is being evaluated in a phase 2 study (NCT03787602) for patients with 

 wild-type MCC who have failed treatment with a PD-1/PD-L1 inhibitor.

 Initial results of the study demonstrated early efficacy signals and good tolerability with KRT-232 monotherapy in this patient population.

, DeCaprio, a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, discussed the incidence of MCC, risk factors for the disease, established treatment options, and investigational regimens on the horizon.

: MCC is a very interesting cancer. It is among the rarer skin cancers; it is 40 times less common compared with melanoma and many times less common compared with squamous cell carcinoma and basal cell carcinoma. MCC is highly aggressive, so we can’t fool around with [diagnosing] it. It shows up as an innocuous little skin bump but can grow very quickly. Usually, just the speed of growth has a patient coming to their doctor.

Many patients with MCC already have a dermatologist because they have a history of skin cancer, such as squamous cell carcinoma or basal cell carcinoma. A few patients with melanoma have also gone on to develop MCC.

[The incidence of MCC] is about 1 per 100,000 in the United States. The incidence is going up, however. Part of that increase in incidence is because MCC is a rare cancer. It was only first described in 1972 by [the late] Cyril Toker, [MBBCh, FRCS, MS, JD, of the University of Maryland]. MCC is rarely suspected when a patient shows up with a skin bump. Most pathology specimens do not have [the ability to] rule out MCC on the clinical diagnosis. In fact, I’ve only seen one pathology report even suggest that [a patient] could have MCC. Usually, MCC is thought to be a benign cyst that [can be resected]. Then, the pathologist will call back and let [the patient] know it is MCC.

Sunlight exposure, as well as age, are contributing to the rising incidence of MCC. MCC can show up in younger people in their 20s with tanning bed exposure, as well as in people in their 30s and 40s. The incidence starts taking off in [individuals between the ages of] 60 years to 90 years.

What are some of the risk factors for MCC?

One risk factor for MCC is sunlight exposure or intense ultraviolet (UV) exposure. Often sun-exposed areas, such as the face, neck, arms, and legs, are where many MCC [nodules] show up.

Maybe as much as 10% of all patients with MCC are immunocompromised in some way. Solid organ transplantation is another risk factor, as well as the treatments of some autoimmune diseases, such as rheumatoid arthritis, and psoriatic arthritis. Therefore, there is an immune component to this disease, both in its risk factors and treatment. We have had a few patients have some genetic predisposition to immunosuppression as well.

MCC is rare even under all of those circumstances. Most people with psoriatic arthritis do not develop MCC, but it is definitely a risk factor.

How do you categorize some of the unique challenges in MCC?

There are 2 unique challenges with MCC: one is on the biologic side and the other is on the clinical side.

On the biologic side, MCC can be caused by excessive UV damage to the tumor genome [that causes] lots of mutations. The other form of MCC is caused by the Merkel cell polyomavirus. This virus is very common; everyone has it living on the skin. On the wrong day, the virus can get into the wrong place and become integrated into a normal cell to transform it into MCC.

The tumors of [both forms] of MCC look and act identically. They are almost indistinguishable in where they show up on a patient, who is at risk, and how they respond to treatment; it’s quite striking. The similar phenotypes, presentations, histologies, and biologies, but completely unique etiologies are why I study MCC. How does this [polyomavirus] trick a normal cell into becoming this highly aggressive cancer? [The UV-exposure form] helps us to decipher thousands, if not millions, of mutations that UV light [can] introduce into the tumor genome. What driver mutations are really causing the cancer?

On the clinical side, MCC is a solid tumor with the highest response rate to checkpoint inhibitor therapy. PD-1/PD-L1 antibodies have dramatic activity in [patients with] MCC [inducing response rates of] 50% to 60%, often for quite a long time.

It’s great news that MCC responds, but why does it do that? Conversely, why do some patients with MCC not respond to checkpoint blockade? There are a lot of very important questions [being asked] related to that. Of course, we use the biology of this virus to understand this phenotype as well as why [a patient’s disease] would be sensitive [to checkpoint inhibitors] or not.

The other unique thing about MCC is that it shows up commonly on the head and neck area [where] a lot of important and complicated structures [are], but it can also show up in the hands. Because MCC is a rare cancer, there is not much experience in treatment. However, it is very clear that we need skilled teams of physicians that can take care of these patients. These tumors are very sensitive to radiation therapy; radiation can cure MCC without the need for disfiguring surgery to remove the entire tumor. How much of the tumor do we need to remove? How much do we need to radiate? Is there need for additional therapy, such as checkpoint blockade? Often, a lot of morbidity related to surgery or chemotherapy could be spared if the team has experience and knows how to best take care of these patients [with a good] treatment plan.

How have checkpoint inhibitors improved upon historical treatment, such as chemotherapy? How can the field improve upon responses with checkpoint inhibitors?

The world is completely different since 2016 with the first report of checkpoint blockade response in MCC. Up until 2016, we were commonly giving chemotherapy with cisplatin or carboplatin plus etoposide for advanced cases of MCC. This is very toxic chemotherapy but very effective in MCC. Most patients would respond rapidly to that form of therapy.

Chemotherapy itself is immunosuppressive so we were inhibiting the body’s own immune system in trying to protect against MCC by using a cytotoxic therapy. It was also recognized that the responses to chemotherapy did not last that long—maybe 2 to 3 months on average.

When checkpoint inhibitors became available and showed efficacy in MCC, it changed practice dramatically. Pembrolizumab [Keytruda] and avelumab [Bavencio] were both FDA approved rapidly with very small case numbers because responses were so dramatic and there wasn’t an FDA-approved alternative. [The treatment landscape] is completely different now since 2016.

In melanoma, we know that checkpoint inhibitors are also very effective, but [they don’t elicit] response rates as high as 50%. Often in melanoma, the response duration is quite long, [meaning] up to several years. I think of [former president] Jimmy Carter [who has melanoma with brain metastases] and how well he has responded to checkpoint inhibitors for years now.

In MCC, the responses to checkpoint inhibitors may not last as long [as they do in melanoma], so physicians are forced to adapt their checkpoint blockade by changing the dosing schedule, drug, or combining drugs. Because the response durations are not as long, there are significant challenges and opportunities to improve what is already a success story.

Can we extend the responses for patients who do respond? Can we improve the response? Can we find something to help patients who don’t respond at all, either up front or later on? A lot of key challenges [exist].

We study the biology of the virus, which has definitely given us clues about how to go after virus-positive MCC. One of the opportunities [to improve upon responses] is [to use] p53 and MDM2 inhibitors. As it turns out, the polyomavirus goes after 

 susceptible to MDM2 inhibition; it is a unique virus in that sense. It gives us the perfect opportunity to activate 

 by inhibiting MDM2. Papillomavirus, for example, goes after 

 very well, but it eliminates our opportunity to activate it. We haven’t been able to get in the middle of papillomavirus and 

. In MCC, polyomavirus leaves itself exposed to 

 activation. There is a phase 2 clinical trial [NCT03787602] from Kartos using KRT-232, a small molecule inhibitor for MDM2, that is showing very promising activity. We are excited about that and hopefully we will hear more about it in the coming months.

Are there other research efforts ongoing that you would like to highlight?

There is a great [clinical] opportunity with MDM2 [inhibitors] but related to that are MDM4 [inhibitors]. 

 work collaboratively with each other to get rid of 

. Our lab has found that we can independently inhibit MDM2 and MDM4, and that combination will synergistically activate 

. There is a golden opportunity to target 

 together, so with some luck, we will have an [FDA] approval for MDM2 inhibitors [, and potentially MDM4 inhibitors, in the future]. This can also be expanded for drugs that inhibit both [MDM2 and MDM4].

Another pathway we’ve uncovered is LSD1. There is an opportunity for LSD1 inhibitors in MCC and we have talked to a few companies [about trials to that end]. Because MCC is rare, it makes it challenging to put together a study. The MCC that we have studied has been very sensitive to LSD1 inhibitors.

Because the virus is driving a normal cell [to turn into a cancer cell], we’ve found several other targets that could be opportunities for therapy. We are just getting started and there is certainly a really interesting possibility that one of the drug targets could synergize with checkpoint inhibitors. We could have a rational strategy to inhibit checkpoint blockade but then work with the virus to activate the immune response. We will look at some inhibitors in that regard too. Hopefully, we will all be reading about that soon.

How can the community raise awareness for MCC?

In Australia, MCC is a household word and is well understood because of [Australians’] increased risk for all skin cancers. MCC is of a higher incidence [in Australia]—though it is still rare—so it is well understood.

Although melanoma, for example, is a terrible disease, patients can often live a long time with it, particularly when it is caught early before metastasizing. Now, because of certain therapies, even patients with metastatic disease live long to tell their story. MCC is so aggressive that patients don’t often live to tell their story. Patients with stage I or II disease with just a lump and no lymph node [involvement] can mostly be cured.

[Advanced-stage disease] is highly aggressive. Those are the patients we are trying to learn from so that some of them will be able to tell their stories. We are getting some success in this disease. Encouraging patients to tell their stories is one way to get the word out.

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with (p53WT) Merkel cell carcinoma who have failed anti-PD-1/PD-L1 immunotherapy. ClinicalTrials.gov. Updated December 20, 2019. Accessed June 1, 2021. https://clinicaltrials.gov/ct2/show/NCT03787602.

Wong MKK, Kelly CM, Burgess MA, et al. KRT-232, a first-in-class, murine double minute 2 inhibitor (MDM2i), for TP53 wild-type (p53WT) Merkel cell carcinoma (MCC) after anti–PD-1/L1 immunotherapy. 

. 2020;38(suppl 15):10072. doi:10.1200/JCO.2020.38.15_suppl.10072


This article was originally published on OncLive as, "

Novel Targets Set to Add to Checkpoint Blockade Success in Merkel Cell Carcinoma

While merkel cell carcinoma (MCC) tends to have poor prognoses and limited treatment options, promising response rates with checkpoint inhibitors may pave the way for better treatment for the rare skin cancer. 

Jessica Hergert

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