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Nicolas Ferreyros is the managing director of policy, advocacy, and communications at Community Oncology Alliance.

Nicolas Ferreyros discusses the Community Oncology Alliance’s position statements on biomarker testing and physician autonomy.

Ferreyros on Biomarker Access and Physician Autonomy in Community Oncology

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

: What trial led to the use of quadruplet therapy in newly-diagnosed multiple myeloma?

One of the initial studies that led to the wide incorporation of quadruplet therapy was the GRIFFIN study [NCT02874742]. This study was looking at transplant preferred—some studies now are saying transplant preferred so you can include or not include patients on the preference of the physician and the patient, rather than just being eligible or not. These were transplant-preferred, newly-diagnosed patients with ECOG [performance status of] 0 to 2. Patients had to have adequate renal function, and there were some stratification factors.

This was a 1:1 randomization of VRd [bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone] vs daratumumab [Darzalex] plus VRd. Then patients went on to [autologous stem cell] transplant [ASCT]. They then had consolidation consistent with their initial randomization. Maintenance was also different in the 2 arms. In the quadruplet arm, it was daratumumab/lenalidomide maintenance. In the other arm, it was lenalidomide maintenance, and the primary end point was stringent complete response [CR] rate, because we know the depth of response seems to matter in multiple myeloma.

What were the final outcomes of the GRIFFIN trial?

In terms of the final analysis, there was a progression-free survival [PFS] benefit with the addition of the daratumumab [HR, 0.45; 95% CI, 0.21-0.95; 

 There was not an overall survival benefit [HR, 0.90; 95% CI, 0.31-2.56; 

 = .84]. It is important to note that more and more like we are with a lot of our diseases in oncology, PFS is what we're trying to achieve, because in a cancer like multiple myeloma, patients are living longer. It can be very difficult to show overall survival benefit.

Then in terms of the response rates, one thing that was interesting that's come out across a bunch of studies is that the depth of response seemed to increase over time, and more so in the Dara-VRd group compared with the VRd group. There were very high rates of CR or better, of 83% at the final analysis vs 60% [respectively]. Lastly, with the GRIFFIN study, there was also improvement in MRD [minimal residual disease] negativity. There were higher rates of MRD negativity with the addition of daratumumab, which is a common theme throughout the studies that we look at.

How was Dara-VRd investigated in a larger patient population?

The PERSEUS study [NCT03710603], similarly, was looking at quadruplet vs triplet therapy; the randomizations were a little bit different. These were patients with intent for transplant, not preferred. It excluded patients who had neuropathy greater than or equal to grade 2. We found neuropathy can be a big barrier to enrollment of patients on trials, so a lot of studies are trying to relax this a little bit.

Essentially, after the initial Dara-VRd or VRd, patients had their ASCT, they then had consolidation of Dara-VRd or VRd. After that, the patients in the triplet arm went on to receive lenalidomide alone, and in the quadruplet arm, they then had daratumumab/lenalidomide maintenance, similar to the GRIFFIN study. Then, patients who had achieved MRD negativity for 12 months after their initial maintenance were then able to discontinue daratumumab and continue lenalidomide until progression vs continued daratumumab/lenalidomide if they were not MRD negative. It’s more of a complicated randomization at the second juncture, but similarly, PFS was statistically significantly improved with the addition of the daratumumab to the triplet [HR, 42; 95% CI, 0.30-0.59; 

MRD was also improved when adding daratumumab; sustained MRD negativity was higher with the quadruplet vs the triplet [64.8% vs 29.7%, respectively]. These look very similar to the GRIFFIN graphs. For response over time, it shows that in myeloma, there is a deepening of response over time. At the end of the daratumumab/lenalidomide maintenance, which would be at the 24-month time point, CR or better was achieved in 87.9% of patients in the quadruplet arm, and then in the triplet arm, it was 70%.

As I mentioned, part of the randomization was based on sustained MRD negativity. A good proportion of patients did maintain their MRD negativity for 12 months or longer in the quadruplet arm, certainly much higher numbers than in the VRd arm. There was a good proportion of patients who even sustained their MRD negativity for greater than or equal to 18 months [59.4% vs 25.1%, respectively]. This shows the benefit of adding a CD38 monoclonal antibody to upfront treatment.

What did the subgroup analyses and toxicity profile show in the PERSEUS trial?

I don't think this would be surprising, but the analysis showed that when you compare different risk groups of patients, when you're comparing Dara-VRd to in a standard-risk patient to VRd with standard-risk patient, Dara-VRd did better.

 When you look at high-risk patients, even though the high-risk patients did poorer than the standard-risk patients who received VRd, they still did better than high-risk patients who received the triplet.

In terms of adverse events, the main things we see with the quadruplets are higher rates of cytopenias, thrombocytopenia, neutropenia, and infection.

 This has been shown throughout these different studies of quadruplets.

: Dorritie previously disclosed research support from Kite Pharma-Gilead, Janssen, Bristol Myers Squibb, Genmab, Hoffman-LaRoche, and an advisory board member role for Janssen.

1. Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. 

. 2023;10(10):e825-e837. doi:10.1016/S2352-3026(23)00217-X

2. Rodríguez-Otero P, Moreau P, Dimopoulos MA, et al. Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial

. 2024;42(suppl 16):7502. doi:10.1200/JCO.2024.42.16_suppl.7502

3. Dimopoulos MA, Sonneveld P, Rodríguez-Otero P, et al. Daratumumab (dara)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance (maint) in transplant-eligible (TE) newly diagnosed myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P974.

4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. 

. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054

During a live event, Kathleen A. Dorritie, MD, discussed updated outcomes from the GRIFFIN and PERSEUS clinical trials of quadruplet therapy in multiple myeloma.

Dara-VRd Leads to Sustained MRD Negativity in Newly Diagnosed Myeloma

A 65-year-old man presented with back pain for past 6 months and hematuria for 1 week.

Physical examination: palpable mass in epigastric and left hypochondriac region, firm and not tender

Laboratory results: hemoglobin, 11.4 g/dL; lactate dehydrogenase, 980 U/L; all others within normal limits

Chest x-ray: widened mediastinum with bilateral hilar enlargement

Ultrasound of abdomen/pelvis showed a left renal mass, 8 cm, with multiple enlarged para-aortic nodes

CT scan of chest, abdomen, and pelvis showed multiple mediastinal and hilar nodes, deposits in left lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium

Fine needle aspiration of renal mass and bone biopsy confirmed metastatic clear cell renal cell carcinoma (ccRCC).

There is not one right answer here, but let's say a decision was made to initiate IO [immunotherapy] plus TKI [tyrosine kinase inhibitor], whether it's for patient preference, your preference, because you were looking for a higher and quicker response rate, whatever that may be. If you chose to do IO/TKI, what first-line regimen are you most likely to choose for this patient? Is that axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], lenvatinib [Lenvima] plus pembrolizumab, or something else?

Nobody is choosing other, which I think is very appropriate, because there is no other approved IO/TKI regimen. There are others studied, but, but none approved. Since we're divided equally, can somebody tell me why they chose axitinib/pembrolizumab? There are no clearly right answers.

 I chose the one with axitinib because it's easier to use and discontinue when needed, because it's only a 3-day period in which, if they have to have procedures or [other treatments], you don't have to be off of it for a whole 2 weeks before and after. It makes it easier to utilize. That's the main reason I tend to gravitate to that regimen more than the others.

I chose cabozantinib/nivolumab. In patients who have bone metastases, there are data that support using cabozantinib as opposed to other [TKI].

 For somebody has sarcomatoid pathology, or papillary renal cell carcinoma, I would choose cabozantinib.

With bony disease, you like cabozantinib. Remember, cabozantinib in a combination, is a dose of 40 mg, not 60 mg, which is the way it's approved for single-agent use.

During a live event, Daniel M. Geynisman, MD, and participants discussed their answers to a poll on which combination to use for a patient with advanced renal cell carcinoma. 

Nicolas Ferreyros

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