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Sima Porten, MD, MPH, is an associate professor at the University of California San Francisco. 

Sima Porten, MD, MPH, discusses the rationale for the phase 3 SunRISe-5 study of TAR-200 in non-muscle invasive bladder cancer and unmet needs in this patient population. 

About the Phase 3 SunRISe-5 Study of TAR-200

ASH 2024 Preview for Community Oncologists: The Show and After Show

The American Society of Hematology (ASH) Annual Meeting and Exposition aims to educate oncology providers across an array of hematologic malignancies, with a focus on novel agents, drugs across the FDA pipeline, and more.

, co-hosts Kristie L. Kahl and Andrew Svonavec offer a glimpse at some of the presentations guaranteed to spark one’s curiosity, spur debate, and enhance the field even further. Some key highlights include:

 Continued advancements in CAR T-cell therapy are expected to revolutionize the treatment of hematologic malignancies.

 Bispecific antibodies, such as Epcoritamab (Epkinly), offer a novel approach to target multiple antigens on cancer cells.

 The assessment of MRD is becoming increasingly important in predicting treatment response and overall survival.

Advances in Acute Lymphoblastic Leukemia (ALL)

Blinatumomab (Blincyto) in pediatric ALL:

 The addition of blinatumomab to chemotherapy has shown promise in improving disease-free survival in high-risk pediatric ALL. This combination therapy may offer a more effective treatment option for young patients.

Acalabrutinib (Calquence) in mantle cell lymphoma (MCL):

 The FDA is set to review the approval of acalabrutinib with bendamustine or rituximab (Rituxan) for previously untreated MCL, based on data from the phase 3 ECHO trial (NCT02972840).

Asciminib (Scemblix) in chronic phase chronic myelogenous leukemia (CML-CP):

 The FDA recently granted accelerated approval to asciminib for newly diagnosed CML-CP. This tyrosine kinase inhibitor has shown favorable safety and tolerability profiles.

 isn't just about data, as the duo also offers food recommendations, tourist attractions and fun activities to partake in, as well as interesting facts about San Diego.

This is just a taste of the wealth of information and inspiration waiting at the 2024 ASH Annual Meeting. Check back for future meeting previews with 

Targeted Oncology co-hosts Kristie L. Kahl and Andrew Svonavec highlight abstracts for community oncologists to look out for at the upcoming ASH Annual Meeting in San Diego, with some additional tidbits to round out the main event.

News

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A man, aged 61 years with an active lifestyle, had a history of metastatic renal cell carcinoma (mRCC), and was post‒left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) with metastases in the adrenal​ gland. Four years later, he had a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, they had been present on scans for at least 2 years prior​. Based on low volume, indolency of disease, and patient preference​, he underwent observation. Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis (2.0 x 1.5 cm). His ECOG performance score was 0.

Vote in the polls below on what you would have chosen if this was your patient.

 This is where we stand with regards to the National Comprehensive Cancer Network [NCCN] guidelines for kidney cancer for favorable-risk disease: we have category 1 data for all 3 immuno-oncology [IO] plus VEGF–tyrosine kinase inhibitor [TKI] combinations that have demonstrated improvements in overall survival [OS].

 These include axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab. Then under other recommendations axitinib/avelumab [Bavencio] is listed, cabozantinib alone is listed with a category 2B designation, nivolumab plus ipilimumab [Yervoy], and then single-agent TKI.

 These can be options for patients with favorable-risk disease.

With checkpoint inhibitor combinations like nivolumab/ipilimumab, the data there support the long-term durability of the regimen with long-term PFS at five years at around 30%.

 The Achilles heel of the CheckMate 214 [NCT02231749] data is that the primary progressive disease rate is 18%.

 At the present time we don’t have biomarkers to help us with the selection between IO/IO versus IO/VEGF-TKI.

In that context it seems like no [participants at this roundtable event would] select single-agent TKI. More individuals selected nivolumab/ipilimumab as a potential option, and then some continuing to select the IO/VEGF-TKI combination.

 I changed my treatment from single TKI to a TKI/IO because of the more aggressive presentation likely in the liver as well as the lung. The cancer now is progressing more and likely it's going to progress [even] more. We’ll gain more control of it. Patients need a more active treatment.

 I selected nivolumab/ipilimumab because of the liver involvement and a clear cell morphology. All options, TKI plus nivolumab or pembrolizumab are absolutely acceptable options, but I chose this particular combination because of the aggressive pattern of metastases and liver involvement, which in this setting of RCC, tends to be a much more aggressive disease compared with pulmonary involvement.

 That’s absolutely correct that those with liver metastases can behave more aggressively than those without those sites of metastases.

 I picked lenvatinib plus pembrolizumab based on data from the CLEAR trial [NCT02811861]. I know that it has the longest response seen for any of the mRCC trials with a 71% objective response rate [ORR].

 The reason I didn’t go with cabozantinib plus nivolumab is that this patient did not have any bone metastases and we know cabozantinib/nivolumab is especially good in that subset of patients.

 I picked the pembrolizumab/lenvatinib based on the complete response rate, quicker response, and personal experience. I have a few patients that did really well on this combination and having the disease in the liver, it's probably more aggressive. Also, if the patient is symptomatic, doing TKI with immunotherapy probably reasonable.

A Black woman, aged 59 years, was diagnosed with a left renal mass ​and underwent left radical nephrectomy in December 2019​. Her diagnosis was ccRCC, T3aN0Mx, Fuhrman Grade 3​. Nine months later, she developed metastatic disease to the liver and retroperitoneal lymph nodes. Her radiographic diagnosis was stage IV RCC, with metastases to liver and retroperitoneum​. Her Karnofsky performance status was 90%. Her hemoglobin level was 11.1 g/dL​, and corrected calcium, neutrophils, and platelets were within normal limits.

A fair bit of participants would choose nivolumab/ipilimumab, some lenvatinib/pembrolizumab, some nivolumab/cabozantinib. There were not many people selecting pembrolizumab/axitinib or single-agent cabozantinib.

In the updated NCCN guidelines for treatment for patients with poor- and intermediate-risk disease, all the IO/VEGF-TKI combinations are fair game and so is nivolumab/ipilimumab.

[We can compare] the granular data regarding OS, progression-free survival, and ORR for the intermediate- and poor-risk population compared with the intent-to-treat population across these trials. I would keep in mind the number of patients with poor-risk disease that were enrolled across all of these trials, but based on topline data, every single one of these regimens is effective for patients with intermediate- and poor-risk disease.

Looking at the hazard ratio [HR] for OS, with the long-term follow-up of 67.7 months for nivolumab/ipilimumab is holding steady at 0.68 and for pembrolizumab/axitinib, 0.63.

 For cabozantinib/nivolumab, the HR for the intermediate-risk patients is 0.74; for the poor-risk patients it is 0.45.

 Then similarly for lenvatinib/pembrolizumab, the HR for intermediate-risk patients is 0.72 and for poor-risk patients is 0.39, so these are highly effective regimens.

 The ORR in the intermediate- and poor- risk patients, range from over 50% with the IO/VEGF combinations and 72% with lenvatinib/pembrolizumab, whereas for nivolumab/ipilimumab it's 42%.

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, 2.2023. Accessed August 23, 2022. https://bit.ly/2TAx1m3

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab vs sunitinib in patients with advanced renal cell carcinoma. 

. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

4. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

5. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib vs sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. 

 Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib vs sunitinib for patients with advanced renal cell carcinoma. 

2022;40(suppl 6):350. doi: 10.1200/JCO.2022.40.6_suppl.350

7. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab vs sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021; October 7-8, 2021; Philadelphia, PA. Abstract E41. Accessed August 23th, 2022. https://bit.ly/3yRcxMx

Participants of a live, virtual case-based event discussed different scenarios for treatment of a patient with previously untreated clear cell renal cell carcinoma. Vote in the polls on what you would have chosen if this was your patient.

POLL: What Frontline Treatment Would You Choose for Favorable- and Intermediate-Risk RCC?

A 78-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago; his lymph node dissection (LND) was positive for nodal involvement. The patient declined complete LND and adjuvant systemic therapy. He remained active since his surgery and maintained regular follow-up appointments.

On routine follow-up, the patient presented with moderate asthenia that limited his daily activities. His ECOG performance status was 1, and his physical examination was unremarkable. Notable laboratory findings included lactate dehydrogenase (LDH) level of 380 U/L (reference range, 110-240 U/L). A full-body CT scan revealed pulmonary and hepatic nodules but no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma.

 If this patient was in your clinic with previously untreated metastatic melanoma, we have lots of choices. It’s a good problem to have as an oncologist treating melanoma these days. Based on the factors, this is a patient without brain metastases, but with distant visceral disease. I’m curious to see what you would offer this 78-year-old patient. It seems the choices were primarily split between the dual checkpoint inhibitor therapies, with some PD-1 inhibitor monotherapy.

 I would probably use nivolumab [Opdivo] plus ipilimumab [Yervoy]. I think that’s still the preferred regimen, but I may consider, from his age, using low-dose ipilimumab with higher-dose nivolumab.

 There are some data now that show you can use nivolumab/relatlimab [Opdualag] once they fail nivolumab/ipilimumab.

 It gives you a second-line option. That’s the way I would probably approach it. I’ve used more of the alternate dosing because of age, but I still think nivolumab/ipilimumab is the preferred [regimen].

 I [would choose] nivolumab/relatlimab because the data are similar compared with nivolumab/ipilimumab and the tolerability is slightly better.

During a Targeted Oncology™ Case-Based Roundtable™ event, April K.S. Salama, MD, discussed treatment approaches for a 78-year-old patient with metastatic melanoma discovered 12 years after surgical resection. 

Sima Porten, MD, MPH

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