Reid Merryman, MD, of the Dana-Farber Cancer Institute, spoke with 

 about the significance of dividing cohorts of patients with diffuse large B-cell lymphoma (DLBCL) into by pre- and post-transplantation groups and the questions that need to be asked from an oral presentation at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.

So, I think it’s kind of 2 different questions. Looking at samples before transplant, you’re asking, “could we use information that we have to determine if transplant is the right treatment approach for patients?” And [What’s] different from 5 or 10 years ago, I think [is that] we have novel treatments. The obvious one would be CAR [chimeric antigen receptor] T-cell therapies that could potentially be used with curative intent in this setting for patients who we think might do poorly with autologous stem cell transplant.

We’re asking a little bit of a different question for the serial samples after autologous stem cell transplant. In that setting, obviously, the patient has undergone transplantation. The question would be, “are there things that we could do in terms of maintenance or consolidation therapies that might improve outcomes for high-risk patients who are likely to relapse?”

Videos

Merryman explains the value of evaluating separate transplant-related questions for patients with relapsed or refractory diffuse large B-cell lymphoma.

Reid Merryman, MD, on Pre- and Post-Transplant Data for Patients with DLBCL

A diagnostic tool that uses noninvasive optoacoustic ultrasound (OA/US) technology to differentiate between benign and malignant breast lesions was granted premarket approval by the FDA, according to the system developer, Seno Medical.

Imagio provides real-time information on suspicious breast lesions and helps physicians characterize and determine which masses require more invasive diagnostic assessment. The system is indicated to evaluate both palpable and nonpalpable breast abnormalities presenting during clinical presentation or mammography in adults who are referred for diagnostic imaging and work-up.

“Optimizing the diagnosis of breast masses requires a combination of very high sensitivity (≥98%) while simultaneously maximizing specificity and minimizing false positives and biopsies of benign masses,” A. Thomas Stavros, MD, FACR, FSBI, Seno’s chief medical officer, said in a statement. “Other modalities have reported improvements in specificity, but these have often come at the expense of the desired high ≥98% sensitivity. The data from the PMA study shows that OA/US successfully achieved improved specificity at a fixed sensitivity of 98%, the part of the [receiver operating characteristic] curve where clinical decisions about whether or not to biopsy a mass are actually made.”

False-positive diagnostic evaluations are attributable to about $2 billion in wasted health care spending on breast biopsy procedures.

 The makers of Imagio assert that the diagnostic system may help mitigate some of this waste by providing clinicians with real-time information about breast masses and increasing confidence in decision making.

The system technology uses OA/US, which combines laser optics and grayscale ultrasound, to provide functional and anatomical breast imaging. The optoacoustic component provides a “blood map” of the breast mass that is coupled with traditional anatomical imaging from the ultrasound. Its unique ability to assess angiogenesis and deoxygenation, 2 key characteristics of cancerous lesions, offers radiologists an opportunity to more accurately identify malignancy without the patient needing additional radiographs or contrast agents.

Along with the system, the SenoGram artificial intelligence support tool will aid physicians to interpret the images and provide training and certification to support transition from traditional imaging to OA/US.

“We are thrilled to have reached this milestone and are looking forward to moving our technology platform forward in the [United States] with this FDA approval,” Tom Umbrel, Seno’s chief executive officer, said in a press release. “Our internal team and our faithful investigators and clinical trial sites have worked diligently to bring Imagio to market and improve care for patients and providers with the precise diagnostic capabilities and enhanced decision-making support that our novel OA/US imaging provides.”

PMA is a is the process by which the FDA reviews the safety and value of Class III medical devices—which are those that sustain or support human life, are instrumental in preventing human health impairment, or present a potentially significant risk of harm or morbidity—and is the most stringent type of device marketing application required.

1. FDA approves Seno Medical’s ground-breaking breast cancer diagnostic technology. News release. January 19, 2021. January 20, 2021. https://bit.ly/2XVor6f

2. Vlahiotis A, Griffin B, Stavros AT, Margolis J. Analysis of utilization patterns and associated costs of the breast imaging and diagnostic procedures after screening mammography. 

. 2018;10:157-167. doi: 10.2147/CEOR.S150260

Articles

Imagio, a diagnostic tool that uses novel technology to provide real-time information on suspicious lesions in the breast, is OK’d by the FDA.

Optoacoustic Ultrasound Device for Assessing Breast Lesions Gets Premarket Approval

Responses to neoadjuvant systemic therapy in patients with high-risk retroperitoneal sarcoma (RPS) led to clinical benefit in roughly three-quarters of patients and varied according to disease histology and the number of treatment cycles, according to a retrospective study whose results were published in 

These data suggest that disease progression on neoadjuvant therapy could potentially be used to predict patient survival post-surgery, while subtype-specific regimens still need further validation in this area.

“In this series of patients with RPS treated with neoadjuvant systemic therapy over a 10-year time span, partial responses were possible in almost a quarter of the cases, whereas most tumors demonstrated stable disease,” wrote the investigators who were led by William W. Tseng, MD. “Disease progression on systemic therapy was clearly associated with worse outcomes. The current analysis provides data to begin defining the role of neoadjuvant systemic therapy in RPS and help to optimize the design of an upcoming prospective trial.”

According to the RECIST 1.1 criteria, none of the patients analyzed (n = 158) demonstrated a complete response, but 37 patients (23%) experienced a partial response (PR), 88 (56%) had stable disease (SD), and 33 (21%) demonstrated progressive disease (PD). Regardless of the analyzed tumor response, all patients underwent complete resection.

Of the patients who demonstrated progressive disease before surgery, their overall survival was significantly worse than other patients (

 = .005). In regard to clinical outcomes, more positive outcomes were seen with specific regimens intended to treat grade 3 dedifferentiated liposarcoma and leiomyosarcoma.

“Our findings show that neoadjuvant systemic therapy can result in a radiographic tumor response in almost a quarter of patients with RPS,” the investigators wrote. “The majority of patients (79%), in fact, can experience a clinical benefit (PR + SD) with this approach. Therefore, our results suggest that in clinical practice, neoadjuvant systemic therapy may be helpful in the management of RPS.”

Overall, patients with a median of 3 cycles of neoadjuvant therapy (interquartile range, 2-4 cycles) administered for high-risk RPS were analyzed. While the regimens were mostly anthracycline based, the investigators emphasized that there was significant heterogeneity in chosen therapy.

Eligible patients were treated for high-risk RPS at 13 different referral centers between 2008 and 2018. The investigators compared overall survival and “cumulative incidences of local recurrence and distant metastasis” with the goal of determining predictors of radiologic tumor responses and to assess clinical outcomes.

The investigators recognized the retrospective design and “relatively low numbers of events, particularly for histologic subtype analyses,” as limiting factors of the data. Moreover, they explained that bias was present because there were a limited number of referral centers who treated the targeted cohort.

“In daily practice, the decision making to initiate and continue with neoadjuvant systemic therapy should be multidisciplinary with continual input from the surgical oncologist to assess for the risk of unresectability with PD,” wrote the researchers.

Tseng WW, Barretta F, Conti L, et al. Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: a multi-institutional study from the transatlantic Australasian retroperitoneal sarcoma working group. 

. Published November 18, 2020. doi: 10.1002/cncr.33323.

Data published in Cancer the journal found that the response to neoadjuvant therapy in patients with retroperitoneal sarcoma following surgery was fair overall, with data suggesting the potential for disease progression as a predictive tool for patient survival.

Neoadjuvant Systemic Therapy Induces Fair Response Rate for High-Risk Retroperitoneal Sarcoma

, Deepu Madduri, MD, assistant professor of Medicine (Hematology and Medical Oncology), associate director of Cellular Therapy Service, and director of Clinical Operations with the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, discussed the most influential multiple myeloma research that came out of 2020.

At the ASH [Annual Meeting & Exposition] this year, the most influential research, as you saw, were [about] bispecific [agents] or CAR T-cell therapies, right? We’re seeing a lot of changes in immune regulation [regarding] how the immune cells are working and understanding how to use those to target and attack the myeloma cells. There’s going to be a combination of trials and combination therapies that are really going to come up [to the front-line setting to determine] if that will benefit the patients.

The expert in multiple myeloma spoke about the research that she believes will be most influential for patients with multiple myeloma.

Deepu Madduri, MD, on Research in Multiple Myeloma This Past Year

The FDA has granted approval to the supplemental biologics license application for the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) as therapy for patients with advanced renal cell carcinoma (RCC) in the frontline setting, according to Exelixis, the developer of cabozantinib.

 that was granted in October, and comes ahead of the assigned a Prescription Drug User Fee Act (PDUFA) goal date of February 20, 2021.

Efficacy of the combination was verified in the pivotal phase 3 CheckMate 9ER trial (NCT03141177), which compared the combination versus standard-of-care therapy with sunitinib (Sutent) in patients with previously untreated RCC

“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib–progression-free survival [PFS], overall survival [OS], and objective response rate [ORR]–while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate 9ER and quality-of-life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, said in a press release. “With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer.”

Data from the trial presented at the European Society for Medical Oncology 2020 Virtual Congress demonstrated statistically significant improvement in OS with the experimental combination versus sunitinib, with medians not reached in either arm (HR, 0.60; 98.89% CI, 0.40-0.89; 

 = .001). The median PFS was also improved, at 16.6 months in the cabozantinib and nivolumab arm versus 8.3 months with sunitinib, and this association was found to be statistically significant (HR, 0.51; 95% CI, 0.41-0.64; 

 <.0001). ORR was almost doubled in the experimental arm, at 56% versus 27% with sunitinib.

The combination was generally well tolerated and mimicked the known safety profiles of both agents. The most common adverse reactions that were noted in 20% of patients or more in the cabozantinib/nivolumab arm included diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough and upper respiratory tract infection. The discontinuation rate from all causes was around 20%.

“While significant progress has been made in the treatment landscape for advanced kidney cancer over the last several years, patients still need more therapeutic options to treat this disease as we search for a possible cure,” Bryan Lewis, President and Co-founder of KidneyCAN, said in a press release. “As patients are living longer with advanced kidney cancer, focusing on the safety and effectiveness of new treatments has become even more important. The findings for the combination of cabozantinib and nivolumab in the CheckMate 9ER trial make the FDA approval of this combination a notable development for the patient community.”

In total, 651 patients with untreated advanced or metastatic RCC with a clear cell component were randomized to cabozantinib at 4 mg daily plus nivolumab at 240 mg intravenously every 2 weeks (n = 323) or oral sunitinib administered at 50 mg daily on a 4-weeks-on/2-weeks-off cycle (n = 328). PFS was the primary end point with secondary end points of OS, ORR, and safety.

Both nivolumab and cabozantinib are already approved for separate indications in RCC. This combination is currently under review for approval by other global agencies.

Exelixis Announces U.S. FDA approval of Cabometyx (cabozantinib) in Combination with Opdivo (nivolumab) as a First-Line Treatment for Patients with Advanced Renal Cell Carcinoma. News release. January 22, 2021. Accessed January 22, 2021. 

https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-fda-approval-cabometyxr-cabozantinib-2

The FDA granted approval to the combination use of cabozantinib plus nivolumab ahead of its February PDUFA date as therapy for the first-line treatment of patients with advanced renal cell carcinoma.

Cabozantinib Plus Nivolumab Is Granted Full Approval for Frontline RCC Indication

Data from the phase 1/2 TRANSCEND-CLL-004 study (NCT03331198) established feasibility for the combination of the investigational CD-19–directed chimeric antigen receptor (CAR) T-cell product lisocabtagene maraleucel (liso-cel) with ibrutinib (Imbruvica) for patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The phase 1, dose-escalation portion of the trial examining the CAR T-cell product plus a BTK inhibitor in patients with relapsed/refractory disease were presented at the American Society of Hematology Annual (ASH) Meeting & Exposition and showed that the combination was well tolerated and achieved high rates of response and undetectable minimal residual disease (MRD).

“Despite highly active targeted therapy, most patients with high-risk CLL will eventually relapse or progress on treatment and many develop refractory disease,” William G. Wierda, MD, PhD, executive medical director of The University of Texas MD Anderson Cancer Center, said in a presentation of the data. “Notably responses [to ibrutinib and liso-cel therapy] were seen among these heavily pretreated patients. Liso-cel expansion and function were seen in vivo in the presence of concurrent ibrutinib therapy.”

Liso-cel—a CD-19­–targeting, defined composition, 4-1BB CAR T-cell product administered at equal doses of CD8+ and CD4+ CAR-positive T cells—was examined at 2 dose levels of 50 or 100 × 106 CAR T-cells with or without ibrutinib at 420 mg daily. Eligible patients had progressed on prior ibrutinib therapy at enrollment, high-risk features and received ibrutinib for 6 months or more with less than a complete remission (CR), 

 mutations, or prior ibrutinib with no contraindications to reinitiating therapy.

Patients in the current analysis (n = 19) were either restarted or continued on ibrutinib therapy at initiation, then underwent leukapheresis for T-cell collection and production. Bridging therapy was allowed. Lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 30 mg/m2 was followed by liso-cel administration. Patients remained on daily ibrutinib at least 90 days after receiving liso-cel and could be continued beyond the 90 days per investigator preference. The primary end point of the phase 1 combination therapy arm was safety and laboratory abnormalities with exploratory objectives of antitumor activity.

Among all treated patients, 12 (63%) had a CR or CR with incomplete blood count recovery (CRi) and 6 had a partial response (PR), resulting in an overall response rate (ORR) of 95% (95% CI, 74.0%-99.9%). For those treated at the lower liso-cel dose (n = 4), those rates were 50% and 25%, respectively, with an ORR of 75% (95% CI, 19.4%-99.9%). With the highest dose level of liso-cel (n = 15), the ORR was 100% (95% CI, 78.2%-100.0%), with a 67% CR/Cri rate and a 33% PR rate.

Among all patients, 89% had undetectable MRD (≤10-4 at 10-month follow-up) in the blood and 79% on the bone marrow. In the lower-dose group, undetectable MRD occurred at a rate of 75% in both the blood and marrow. For the higher-dose group, rates of undetectable MRD were 93% and 80%, respectively.

“There was a high undetectable MRD concordance between blood and bone marrow,” Wierda said. “Complete remission and undetectable MRD rates were high, demonstrating therapeutic activity for this combination.”

Most patients remained in remission at follow-up and most responses occurred by day 30. Liso-cel peak expansion occurred by day 11 and long-term persistence was noted in 38% of patients at 6 months and 20% at 12 months.

Grade 3/4 treatment-emergent adverse events (AEs) occurred in 95% of patients, with neutropenia/decreased neutrophil count (89%), anemia (47%), and febrile neutropenia (26%) occurring most frequently. Notably, cytokine release syndrome was observed in three-quarters of patients (74%), but only 1 experienced a grade 3 event and none had grade 4 complications. Neurological events were observed in 32%, with 16% being grade 3 and none at grade 4. Managements of CRS and neurological events included tocilizumab alone (11%), corticosteroids alone (16%), or a combination of both therapies (16%).

Baseline characteristics revealed that patients were mostly men (63%) with a median age of 61 years (range, 50-77). About a third (32%) had bulky disease, defined as at least 1 lesion measuring 5 cm or more, and most had high risk features including deletion 17 p (42%), a 

 mutation (32%), and/or a complex karyotype (42%).

“Research continues with this combination at dose level 2 [100 × 106 CAR-positive T-cells] in a cohort expansion,” Weirda concluded.

Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 

. 2020;136(suppl 1):39-40. Abstract 644. doi:10.1182/blood-2020-14062.

Findings from a phase 1/2 trial indicate that lisocabtagene maraleucel plus ibrutinib may represent a viable treatment option for patients with heavily pretreated chronic lymphocytic leukemia or small lymphocytic lymphoma and high-risk disease features.

Promising Efficacy Data for Heavily Pretreated CLL/SLL Indicate Potential Benefit for Liso-cel Combination With Ibrutinib

Compared with concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A), total neoadjuvant therapy for patients with locally advanced rectal cancer was associated with better pathological complete response (PCR) rates and a potential advantage for disease-free survival (DFS), according to data published in 

While the data suggest total neoadjuvant therapy is a promising strategy, the long-term effects this treatment has on disease recurrence and overall survival rates need further exploration.

“Total neoadjuvant therapy appears to be a promising treatment strategy that has been reported in several trials,” wrote the investigators who were led by Anup Kasi, MD, MPH. “Total neoadjuvant therapy enhances one’s chances of attaining a PCR, which traditionally has been shown to correspond to higher overall and disease-free survival. Our meta-analysis suggests an improved disease-free survival, although the true effect of (total neoadjuvant therapy) on overall and disease-free survival is unclear and requires further evaluation in a prospective randomized manner.”

Overall, the use of total neoadjuvant therapy was associated with an increased chance of achieving PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98) for patients with locally advanced rectal cancer. Pooled prevalence of PCR was recorded at 29.9% (range, 17.2%-38.5%) for patients in the total neoadjuvant therapy group and 14.9% (range, 4.2%-21.3%) for those in the CRT-plus-A group.

The investigators did not find a statistically significant difference for the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between the total neoadjuvant therapy and CRT-plus-A groups.

Only 3 out of 7 total studies examined data on DFS. A pooled analysis of these results showed that patients undergoing total neoadjuvant therapy saw significantly higher odds of improved DFS (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%).

This systematic review and meta-analysis examined 2416 patients from 7 unique studies in which 1206 patients received total neoadjuvant therapy. Median age for patients receiving total neoadjuvant therapy ranged from 57 to 69 years, with 58% to 73% of patients being male.

“The pooled analysis demonstrated a significantly higher chance of achieving a PCR as well as improved disease-free survival [with total neoadjuvant therapy],” wrote the investigators. “Surgical outcomes, including rates of sphincter-preserving surgery and ileostomy, did not significantly differ among the 2 populations.”

The investigators explained that a significant limitation of the data is that none of the end points were consistently reported across the 7 unique studies analyzed. Specifically, while all 7 included PCR, only 4 studies reported the rates of sphincter-preserving surgery, 2 reported specific ileostomy requirements, and 3 reported DFS.

Moreover, there was not enough data to accurately calculate a pooled overall survival rate for patients across the 7 studies. Therefore, the investigators were limited by the data they could report in their systematic review and meta-analysis.

“Total neoadjuvant therapy theoretically offers multiple surgical advantages, such as improved odds of receiving a sphincter-sparing surgery and lower odds of requiring an ileostomy; however, neither of these outcomes was evident in our meta-analysis, suggesting that the benefit is primarily in disease control and decreased recurrence rates,” the investigators concluded.

Kasi A, Abbasi S, Handa S, et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer. 

. 2020;3(12):e2030097. doi:10.1001/jamanetworkopen.2020.30097.

Research published in JAMA Network Open found that total neoadjuvant therapy enhanced pathological complete response rates for patients with locally advanced rectal cancer.

Total Neoadjuvant Therapy Improves Rates of Pathological Complete Response in Rectal Cancer

The FDA has accepted and granted priority review to the biologics license application (BLA) for the intravenous PD-1 inhibitor retifanlimab as a possible treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on, or who are refractory to, platinum-based chemotherapy, according to the drugs developer, Incyte.

A prescription drug user fee act (PDUFA) target action was set by the FDA for July 25, 2021.

“Patients with SCAC who have progressed after first-line chemotherapy treatment currently have no approved treatments available, and we are encouraged that the FDA’s acceptance of this BLA for priority review brings us one step closer to addressing this historically neglected, yet important, tumor,” Lance Leopold, MD, group vice president of Immuno-Oncology Clinical Development at Incyte, said in a press release. “Despite SCAC being a rare disease, its incidence is increasing, and its impact is profound. We look forward to working with the FDA to potentially fill an unmet need and advance progress in SCAC for patients.”

The BLA submission is based on data observed in the open-label, single-arm, multicenter, phase 2 POD1UM-202 (NCT03597295) trial, which evaluated retifanlimab in the indicated patient population. Results from this trial were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Patients enrolled in the trial were given retifanlimab intravenously at a dose of 500 mg every 4 weeks. The trial enrolled a total of 94 patients, including several with well-controlled HIV infection.

The primary end point of the study is objective response rate (ORR) as determined by independent central review using RECIST v1.1. Key secondary end points include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), safety, and pharmacokinetics.

The study results presented at ESMO 2020 showed an ORR of 13.8% with retifanlimab monotherapy, including 1 complete response and 12 partial responses; 33 patients (35.1%) had stable disease. Responses were observed regardless of PD-L1 status, presence of liver metastases, age, or HIV-positive status and were also durable, with a median DOR of 9.5 months (5.6-not estimable).

Median PFS and OS were 2.3 (95% CI, 1.9-3.6) and 10.1 (95% CI, 7.9-NE) months, respectively. Importantly, responses were associated correlated with longer PFS and OS.

Treatment-related adverse events (AEs) of grade 3 or higher were reported in 11.7% of patients. Moreover, immune-related AEs of grade 3 or higher occurred in 6.4% of patients and treatment discontinuation due to immune-related AEs occurred in 2.1% of patients. The most common AEs observed (incidence ≥20%) were fatigue and diarrhea.

Retifanlimab was previously granted orphan drug designation by the FDA for the treatment of anal cancer. The investigational intravenous anti-PD1 agent is currently under evaluation in registration-directed trials as a monotherapy for patients with microsatellite instability–-high endometrial cancer, Merkel cell carcinoma, and SCAC as well as part of a combination regimen with platinum-based chemotherapy for patients with non–-small cell lung cancer and SCAC.

The phase 3 POD1UM-303/InterAACT 2 (NCT04472429) trial of retifanlimab in combination with carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic SCAC is now open and actively recruiting patients.

1. Incyte announces acceptance and priority review of BLA for retifanlimab as a potential treatment for patients with squamous cell carcinoma of the anal canal (SCAC). News release. Incyte. Published January 21, 2021. Accessed January 22, 2021. https://investor.incyte.com/press-releases/press-releases/2021/Incyte-Announces-Acceptance-and-Priority-Review-of-BLA-for-Retifanlimab-as-a-Potential-Treatment-for-Patients-with-Squamous-Cell-Carcinoma-of-the-Anal-Canal-SCAC/default.aspx

2. Rao S, Capdevila J, Gilbert D, et al. POD1UM-202: Phase II study of retifanlimab in patients (pts) with squamous carcinoma of the anal canal (SCAC) who progressed following platinum-based chemotherapy. 

. 2020;31(suppl 4):S1142-S1215. doi: 10.1016/annonc/annonc325

The BLA submission is based on data observed in the phase 2 POD1UM-202 trial of retifanlimab in previously treated patients with locally advanced or metastatic squamous cell carcinoma of the anal canal who had progressed on, or were intolerant of, standard platinum-based chemotherapy.

FDA Grants Priority Review to BLA for Retifanlimab as Possible Treatment for SCAC

The FDA has granted orphan drug designation to the novel viral immunotherapy PVSRIPO for the treatment of patients with advanced stage IIB through IV melanoma, according to Istari Oncology, the developer of the agent.

PVSRIPO is designed to stimulate a patient’s innate and adaptive immune system to promote an anti-tumor response and establish long-term immunologic memory to help prevent the cancer’s return.

Istari is currently recruiting for the open-label, randomized, phase 2 LUMINOS-102 (NCT04577807) trial of PVSRIPO in patients with PD-1 refractory melanoma. The study plans to characterize the safety, tolerability, and initial efficacy of PVSRIPO intratumoral injection alone and in combination with a PD-1 inhibitor.

The company plans to dose the first patient this quarter.

“We are happy to kick off the new year with the announcement that our request for an orphan drug designation has been granted to PVSRIPO for the treatment of advanced melanoma,” Matt Stober, president and chief executive officer at Istari Oncology, said in a press release. “This is just one of many milestones to come in 2021 as we continue to drive the clinical development of PVSRIPO across multiple indications.”

LUMINOS-102 will follow the successful phase 1 monotherapy study (NCT03712358) of PVSRIPO in anti–-PD-1 refractory advanced melanoma, results of which were previously presented at the 2020 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

In this study, PVSRIPO injections were well tolerated with no serious adverse events (AEs) or dose-limiting toxicities reported. Moreover, all treatment-emergent AEs were grade 1 or 2, with grade 1 pruritus being the most common at 58%. All but 2 PVSRIPO-related, treatment-emergent AEs were localized to the injected or adjacent lesions (1 event each of grade 1 hot flash and grade 1 fatigue).

In spite of the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients >5 lesions), 4 of 12 patients (33%) achieved an objective response per independent radiologic review committee, including 4 of 6 (66%) who received the maximum administered dose of 3 injections. Pathologic complete response was also reported in 2 of 4 (50%) patients with in-transit disease.

Following treatment with PVSRIPO therapy, 10 of 12 patients (83%) again received immune checkpoint inhibitor (ICI)–-based therapy and 6 of 12 patients (50%) remained progression-free at the data cutoff.

“We are encouraged by the data from our phase 1 trial presented at last year’s Society for Immunotherapy of Cancer (SITC) 2020 Annual Meeting” Garrett Nichols, MD, MS, chief medical officer at Istari Oncology, said in the release. “We plan to build upon that success with LUMINOS-102. As those data and the data from our other solid tumor trials emerge, we will continue to work closely with the FDA toward the goal of bringing PVSRIPO to market.”

1. Istari Oncology announces FDA grants orphan drug designation for PVSRIPO for the treatment of advanced melanoma. News release. Durham, NC. Published January 10, 2021. Accessed January 19, 2021. https://istarioncology.com/press-release-fda-grants-orphan-drug-designation-for-pvsripo-for-the-treatment-of-advanced-melanoma/

2. Beasley G, Farrow N, Landa K, et al. A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma.

 2020;8(suppl 2):A185. Abstract 302. doi:10.1136/jitc-2020-SITC2020.0302

The novel viral immunotherapy PVSRIPO is designed to stimulate a patient’s innate and adaptive immune system to promote an antitumor response and establish long-term immunologic memory to help keep their cancer at bay.

FDA Grants Orphan Drug Designation to PVSRIPO for Treatment of Advanced Melanoma

 suggest that assays determining intratumor heterogeneity (ITH) could be helpful in determining which patients with renal cell carcinoma (RCC) are more likely to respond to PD-1 blockade.

Moving forward, the investigators suggested that understanding the mechanism by which ITH impacts response to PD-1 inhibitors may provide insights into how ITH could affect cancer therapy and patient survival, and aid in the development of predictive biomarkers for response to immune checkpoint therapy (ICT).

“A key unanswered question in RCC is whether and which genomic metrics are correlated with clinical benefit of ICT,” wrote the study authors who were led by Xia Ran. “Our results suggest that low ITH is associated with increased response to anti–PD-1 immunotherapy in RCC through increased immune activity involving more neoantigens and less frequent immune evasion.”

Among patients with clear cell RCC (ccRCC; n = 336) and papillary RCC (pRCC; n = 280) taken from The Cancer Genome Atlas, investigators quantified ITH using mutant-allele tumor heterogeneity (MATH). An independent cohort of 152 patients with ccRCC was used to validate the findings. Additionally, to assess the relationship between ITH and response to anti–PD-1 immunotherapy, 35 patients with metastatic ccRCC from a clinical trial of anti­–PD-1 therapy were evaluated with results validated across 3 equal-size simulated data sets (n = 60) generated by random sampling with replacement based on the trial cohort.

Of those with ccRCC, low ITH was found to be associated with response to anti­–PD-1 immunotherapy through increased immune activity involving more neoantigens, elevated expression of human lymphocyte antigen class 1 genes, and greater abundance of dendritic cells. Moreover, the investigators also revealed that among patients with ccRCC, the association between the level of ITH and response to PD-1 blockade was independent of 

 mutation status and that taking both factors into consideration resulted in better performance when compared with the individual predictors in determining prognosis with anti–PD-1 immunotherapy.

In patients with pRCC, increased immune activity was greater in patient with low-ITH status, which included greater neoantigen counts, increased amounts of monocytes, and decreased expression of PD-L1 and PD-L2.

“In this study, we quantified ITH using MATH based on the allele frequencies of somatic mutations,” the authors noted. “Admittedly, there are other well-designed tools (eg PyClone, EXPANDS, and ABSOLUTE) quantifying ITH based on not only somatic mutations, but also other metrics such as copy number estimates and loss of heterozygosity. While taking more parameters into account may improve the accuracy of ITH quantification, it also means more complex analyses and longer run time, which is not conducive to large-scale clinical application.”

Ultimately, based on their findings, the investigators indicated MATH may be a quick and accurate measurement of ITH in RCC. However, it was also suggested that the cutpoint of MATH scores for ccRCC and pRCC will need further preclinical and prospective clinical validation in order to be used for large-scale clinical application.

Ran X, Xiao J, Zhang Y, et al. Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma. 

. 2020;12:1-17. doi:10.1177/1758835920977117

“Our results suggest that low [intertumoral heterogeneity] is associated with increased response to anti–PD-1 immunotherapy in renal cell carcinoma through increased immune activity involving more neoantigens and less frequent immune evasion,” wrote the study authors, led by Xia Ran.