Ryan McDonald

Findings from an analysis of peripheral blood samples taken from patients with advanced or metastatic urothelial carcinoma enrolled onto the JAVELIN Bladder 100 trial (NCT02603432) may indicate that there are multiple biomarkers that are predictive of disease response to maintenance avelumab (Bavencio).

In fact, the exploratory analysis—the findings of which were presented at the European Society for Medical Oncology (ESMO) Congress 2022—may have showcased the benefit of testing for tertiary lymphoid structures (TLSs).

Ectopic lymphoid tissue that arises in inflamed tissues including cancer, TLSs have been generating quite a bit of interest, according to Thomas B. Powles, MBBS, MRCP, MD, director, Barts Cancer Centre at St. Bartholomew's Hospital in London.

“They’re characterized by B-cell and T-cell zones and are attracting attention in urothelial cancer,” Powles said while presenting the data. “They’re essentially balls of active immune cells … And (the) characterization of these tertiary lymphoid structures is an area of interest.”

To determine whether blood-based biomarkers could potentially provide insight into which patient populations may best benefit from immune checkpoint inhibitors such as avelumab, the investigators used the EpiSwitch platform to analyze white blood cell chromatin loops associated with tumor immune activity.

This analysis was conducted using peripheral blood samples that were collected from 496 patients enrolled onto the trial after non-progression with first-line chemotherapy and before patients were randomized to either avelumab plus best supportive care or best supportive care only.

“So we looked at whole blood, we looked at PBMCs and we looked at the structure of chromatin,” Powles explained. “Chromatin has a really important role in DNA packaging. And it also therefore has a really important role in transcriptome extender and gene expression. The chromatin allows loops, these loops are associated with activation of transcription. And these loops can result in dynamic changes, of course, to protein expression.”

The EpiSwitch platform, Powles continued, can identify whether the chromatin loops are present or absent in a patient’s blood.

What the investigators found was that the absence of 

, a transcription factor with known roles in B-cell maturation and participation in T-cell dependent humoral immunity, was most strongly associated with the T-effector signature, according to Powles.

 is a gene we don't know a huge amount about,” he said during the presentation. “Nevertheless, it does seem to be important regulation of B cells and may or may not be involved in TLSs.”

One of the main questions posed by the researchers, according to Powles, was what role does 

play in determining patient outcomes. So, they looked for the chromatin loop in the blood as well as the genetic expression of the tumor.

expression in the tumor was linked to a survival benefit with maintenance avelumab. The benefit was highest in patients who had 

 and a tumor mutation burden (TMB) above the median threshold of 7.66 non-synonymous SNVs per Mb (HR = 0.69; 95% CI, 0.51-0.93).

loop in the blood samples was also associated with a better survival benefit associated with maintenance avelumab (HR = 0.62; 95% CI, 0.36-1.08).

Of note, Powles highlighted that the absence of the 

loop may pinpoint a benefit in patients who have a low TMB.

“Remember, these low TMB patients aren't supposed to be responding to therapy,” he said. “But indeed, if you have 

 low, which is high gene expression, and low TMB, we can pick out a group of patients who are supposed to be the TMB low non-responders, and we can identify them as responders. And we can do this from blood tests, not from tissue, which I think is cool.”

The median survival probability for the 22 patients who received avelumab and did not have 

 but a low TMB was 36.99 months versus 13.6 months in the 18 patients who only received best supportive care.

However, Powles stressed that there are several limitations with the trial, including that the analysis was exploratory in nature. Additionally, the investigators still need to validate the findings to confirm its feasibility to be used in the clinic.

Nonetheless, Powles concluded the presentation explaining the significance of the findings of the exploratory analysis of the peripheral blood samples.

“I think it's reasonable to say that we showed TLS appear relevant in terms of outcome in the JAVELIN 100 trial,” he stated. “And these TLSs, along with the immuno signature helped us identify from the circulating white cells, 

 as a key chromatin loop, and indeed gene expression, which may be relevant in predicting outcome for the future. … I think it's also reasonable to say that moving forward, the predisposition to form TLS in response to inflammatory stimuli may be a host factor influencing response to immune checkpoint inhibition, and therefore bringing the circulating and tumor-based biomarkers together is a really exciting area for the future.”

1. Powles T, Sridhar SS, Bellmunt J, et al. Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC). 

. 2022;33(suppl 7):LBA74. doi:10.1016/annonc/annonc1089

Articles

The exploratory analysis may have showcased the benefit of testing for tertiary lymphoid structures.

Exploratory analysis identifies blood-based biomarkers that may predict treatment outcomes in urothelial carcinoma 

Study results shared ahead of the 2022 ASCO Annual Meeting suggest that despite the surge in telemedicine use for cancer care during the pandemic, inequities in its usage remain.

“The COVID-19 pandemic was associated with disruptions in healthcare delivery, including substantial declines in personal clinical visits,” lead study author Jenny S. Guadamuz, PhD, a postdoctoral research fellow, USC Program on Medicines and Public Health, USC School of Pharmacy, said during a presentation of the data. “And as a result, many clinicians shifted to telemedicine services, and this was facilitated by federal and state regulations enacted early in the pandemic that expanded coverage and reimbursement for these services. And while there's some evidence suggesting that telemedicine uptake varied by social demographic factors such as age and region, there has been limited evaluation of inequities.”

To investigate the inequities associated with telemedicine use by race, ethnicity and social determinants of health, the study authors analyzed electronic health records from a Flatiron Health database.

They reviewed the records of 26,788 people aged 18 years and older who started their first-line of cancer treatment between March 2020 and November 2021. The patients included in the analysis had to have had received follow-up care within 90 days and been treated at a community-based oncology practice.

The findings were adjusted using patient clinical characteristics including age, sex, performance status and the stage of their disease.

Of the patients included in the analysis, 16.0% used telemedicine services.

The investigators identified that telemedicine use was notably lower in Black patients when compared with their White counterparts (13.2% versus 15.6%, respectively). Additionally, patients without documented insurance were less likely than patients who had private insurance or were insured through Medicare to use telemedicine services during the same time period (11.8% versus 16.4%).

The largest disparity in telemedicine use was in people based on socioeconomic status —10.6% of patients living in the lowest socioeconomic status areas partook in telemedicine care compared with 23.6% of patients in areas with the highest socioeconomic status.

Guadamuz stressed that the inequities remained after the investigators adjusted for clinical characteristics.

“We found that black patients had lower odds of using telemedicine services in both unadjusted and adjusted models,” she said. “In other words, clinical characteristics do not account for these differences.”

And although their findings demonstrated that telemedicine use waned as the pandemic progressed (25% from March to May 2020 versus 12% from Sept. to Nov. 2021), the inequities persisted.

“These findings are critically important considering recent efforts to make coverage for telemedicine services permanent instead of being tied to the HHS public health emergency declaration,” she said. “There (are) also efforts to increase reimbursement rates for telemedicine services by Medicare, several Medicaid programs and private insurers.”

The most important conclusion from these findings, according to Guadamuz, is that this disparity access and use to telemedicine services may further widen the inequity gap in cancer care.

For instance, she explained, it should not be assumed that every patient has equitable access to the necessary infrastructure — such as high-speed internet — to utilize telemedicine services.

Guadamuz noted that there are several things to keep in mind for future research. One thing she said was to see if there’s any differences in the timely receipt of necessary treatment between patients who received telemedicine care and those who received in-person care. Moreover, it is important to learn from the centers that have successfully utilized telehealth services.

“It'll be important to determine what types of practices are providing telemedicine more equitably to their patients, because we can learn from these clinics and bring it back to the rest of the of our network of clinics, therefore supporting more affordable care at community-based oncology clinics,” Guadamuz concluded.

1. Use of Telemedicine for Cancer Care Increased, but Varied by Race, Socioeconomic Status, and Other Factors During the COVID-19 Pandemic. News Release. ASCO. May 26, 2022. Accessed May 26, 2022. https://bit.ly/3wPFVD9

“We found that black patients had lower odds of using telemedicine services,” said lead study author Jenny S. Guadamuz, PhD. 

Disparities persist in use of telemedicine for cancer care

Results from an exploratory analysis of the KEYNOTE-146/study 111 trial shared during the 2022 ASCO Genitourinary Cancers Symposium showed the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) was effective in patients with advanced renal cell carcinoma (RCC), regardless of their biomarker status.

Although the study results were “disappointing from a biomarker development standpoint,” according to lead study author Chung-Han Lee, MD, PhD, assistant attending physician, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, the results confirm the effectiveness of the regimen across various lines of treatment.

“We know that even without biomarker stratification, this regimen already has high response rates and a fairly long progression-free survival,” see Lee. “[Providers] don't necessarily need to do extra steps in order to make a decision about whether or not they would offer this type of treatment to their patients.”

The primary objective of the analysis was to identify if there was an association between patient outcomes and gene expression signatures generated via RNA sequencing and DNA variants for individual genes of interest via whole exome sequencing. As of now, Lee explained, the field is in its infancy stages in learning if there are good predictive biomarkers to stratify patients to different treatment modalities.

“What we’ve done already is we’ve looked at various genomic and gene expression biomarkers in various settings. A lot of this comes from analysis of both phase 2 and phase 3 studies. Perhaps the most informative (data) recently has been looking within the first-line space,” he said. “And what they've demonstrated is there are specific gene expression patterns that have correlated with superior outcomes. However, where we really are lacking is the ability to translate this into clinical practice and having this type of information guide some of the clinical choices that we're making.”

In the past, providers have been able to analyze the genomics of patients who were naive to immunotherapy and identify those high levels of HLA diversity were linked to an increased odds of response to lenvatinib plus pembrolizumab.

In this exploratory analysis, Lee said, the study authors were interested in seeing if this could be translated in patients who have been pretreated with immunotherapy.

“We're trying to understand whether or not treatment-naive tissue, can be predictive of outcomes for people who've already had multiple lines of systemic therapy,” he explained. “So, we're trying to answer … whether or not there were good predictive biomarkers in the space and whether or not we could use older tissue? Or do the treatments that people have, potentially have an impact on whether or not some of the things that have worked can still continue to work?”

The phase 1b/2 KEYNOTE-146/study 111 trial comprised 147 patients (median age, 60 years; 78.2% male; 86.5% White), of which 80 (median age, 62 years; 75% male; 92.5% White) had available RNA sequencing and 60 had available whole exome sequencing (median age, 63.5 years; 78.3% male; 90% White).

A significant proportion of patients (71.4%) in the overall population had received prior anti–PD-1/PD-L1 therapy, as did patients in the RNA-sequencing population (87.5%) and whole exome sequencing population (88.3%). Few patients in the overall population, RNA-sequencing and whole exome sequencing population were treatment naïve (15.6%; 12.5%; 11.7%, respectively).

The findings showed that the objective response rate was similar among the 3 patient subgroups — 63.9% in the overall population, 66.2% in those with evaluable RNA sequencing and 68.3% in those with evaluable whole exome sequencing.

Moreover, the median PFS was also similar across the 3 groups. The median PFS in the overall population was 14.1 months (95% CI, 11.7-18.6), and 17.7 months in both the RNA-sequencing evaluable group (95% CI, 11.1-19.8) and the whole exome sequencing-evaluable group (95% CI, 11.7-22.1). The data also showed similar objective response rates across selected DNA variants including 

As for next steps, Lee noted that more analyses are warranted.

“It really is going to be looking to see whether or not we can get tissue that is closer to the time of systemic therapy and doing an analysis to see whether or not that is going to end up being predictive,” he concluded. “We certainly also want to see our ability to understand what are the changes that happened to the tumor as (a patient) gets treatment, because that may be very informative in terms of what the subsequent therapies you should think about.

1. Lee CH, Rasco DW, Rao A, et al. Association between biomarkers and clinical outcomes of lenvatinib + pembrolizumab in advanced renal cell carcinoma (RCC): Results from Study 111/KEYNOTE-146. 

. 2022;40(suppl 6):375. doi: 10.1200/JCO.2022.40.6_suppl.375.

Lead study author Chung-Han Lee, MD, PhD, said that while the findings were “disappointing from a biomarker development standpoint,” the results confirm the effectiveness of the regimen across various lines of treatment.

Lenvatinib/pembrolizumab effective in all-comer RCC population, independent of biomarker status

Combination therapy with the PARP inhibitor rucaparib (Rubraca) and the immunotherapy nivolumab (Opdivo) demonstrated clinical activity in patients with homologous recombination deficiency–positive metastatic castration-resistant prostate cancer (mCRPC) who had no prior chemotherapy, according to findings shared during the 2021 ESMO Congress.

The findings from the CheckMate 9KD trial also showed noteworthy activity in individuals whose tumors harbored 

mutations. However, as study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and co-director of the Cancer Signaling Networks Research Program at Yale Cancer Center in New Haven, Connecticut, noted in his presentation of data, there was limited clinical activity with the combination in patients with HRD-negative tumors.

Among all cohorts of the phase 2 CheckMate 9KD trial (NCT03338790), patients had to have mCRPC, documented disease progression, an ECOG performance status of 0-1, available tumor tissue for HRD testing and no prior treatment with drugs that targeted T-cell co-stimulation or immune checkpoint pathways.

Here, Petrylak presented data from the final analysis of cohort A2 — which comprised 71 patients (median age, 73 years; range, 51-87 years) who had received 1 to 2 prior new hormonal therapies in the pre-chemotherapy setting. Patients in this cohort also did not receive any prior treatments with PARP inhibitors. Additionally, patients who made up the study population were ineligible for (or refused) immediate chemotherapy.

Nivolumab was administered at a 480-mg dose every 4 weeks (Q4W) and rucaparib was given at a 600-mg dose twice per day (BID). Treatment was given until a patient’s disease progressed or unacceptable toxicity was reached. Of note, nivolumab dosing was limited to a maximum of 2 years.

The primary endpoints assessed in this cohort were overall response rate (ORR) and PSA response rate (PSA-RR). Additional secondary endpoints included overall survival (OS), time to and duration of objective response, time to PSA progression, safety and radiographic progression-free survival (rPFS).

More than half (57.7%) of the patient population in the cohort had an ECOG performance status of 1. All other patients had an ECOG status of 0. HRD status was almost evenly split in the cohort:

47.9% of patients had HRD-positive tumors;

50.7% of patients had HRD-negative tumors, and

1.4% of patients had an undetermined HRD status.

In terms of prior treatment with new hormonal therapies, 60.6% of patients had received abiraterone monotherapy, 23.9% received enzalutamide monotherapy and 14.1% received a combination of those two.

The median treatment duration of nivolumab was 4.6 months and 5.5 months for rucaparib.

After a median follow-up of 17.5 months, the ORR among all evaluable patients (n = 39) was 15.4% (95% CI, 5.9-30.5). Confirmed ORR among the 20 patients with HRD-positive tumors was 25% (95% CI, 8.7-49.1). Moreover, the 9 patients whose disease harbored 

-positive mutations achieved an ORR of 33.3% (95% CI, 7.5-70.1). However, ORR was unfavorable in the 19 patients who had HRD-negative or not evaluable tumors (5.3%; 95% CI, 0.1-26.0).

The trend of noteworthy clinical activity in patients with HRD-positive tumors and 

-positive mutations continued in confirmed PSA-RRs. Among 66 evaluable patients, confirmed PSA-RR reached 27.3% (95% CI, 17.0-39.6). The confirmed PSA-RR rate among patients with HRD-positive tumors (n = 31) was 41.9% (95% CI, 24.5-60.9). And the 13 patients with 

-positive mutations achieved a confirmed PSA-RR of 84.6% (95% CI, 54.6-98.1).

Petrylak also noted that the results showed survival outcomes favored patients with HRD-positive tumors. Among the overall population (n = 71), the median rPFS was 8.1 months (95% CI, 5.6-10.9). The median rPFS in those with HRD-negative tumors (n = 37) was 5.6 months (95% CI, 3.7-9.1) compared to 10.9 months (95% CI, 6.7-12.0) in those with HRD-positive tumors (n = 34).

Treatment with the combination was also associated with favorable OS results. The median OS among all patients was 20.2 months (95% CI, 14.1-22.8). The median OS in the 34 patients with HRD-positive tumors was 22.7 months (95% CI, 14.1 months-NE). Patients in the HRD-negative group (n = 37) had the least favorable median OS at 19.0 months (95% CI, 8.2-22.1).

Most of the study participants (n = 64) experienced a treatment-related adverse event (TRAE) of any grade. And, approximately half (n = 36) experienced a TRAE that was classified as grade 3 or 4.

Petrylak noted that the most common TRAEs included nausea, anemia, fatigue and increased liver enzymes. He also highlighted that there were no study deaths related to treatment.

Although the results showed favorable outcomes associated with the use of nivolumab and rucaparib in these patients, Petrylak expressed that more research is needed.

“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer,” he concluded.

1. Petrylak DP, et al. CheckMate 9KD cohort A2 final analysis: Nivolumab (NIVO) + rucaparib for chemotherapy (CT)-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 ESMO Annual Congress. September 16-21, 2021. Abstract 579MO.

There was limited clinical activity with the combination in patients with HRD-negative tumors. 

Ryan McDonald

Articles

Exploratory analysis identifies blood-based biomarkers that may predict treatment outcomes in urothelial carcinoma

Disparities persist in use of telemedicine for cancer care

Lenvatinib/pembrolizumab effective in all-comer RCC population, independent of biomarker status

Rucaparib/nivolumab combo shows clinical activity in HRD-positive mCRPC