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The diffuse large B-cell lymphoma treatment landscape is evolving with Pola-R-CHP and CAR T-cell therapy moving into the frontline setting.

The New Algorithm for Second-Line Large B-Cell Lymphoma Treatment

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.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A 4-year follow-up of the phase 3 GAIA/CLL13 study (NCT02950051) sought to directly compare venetoclax (Venclexta)-based combinations for the treatment of patients with chronic lymphocytic leukemia (CLL). These included venetoclax with obinutuzumab (Gazvya), venetoclax/obinutuzumab/ibrutinib (Imbruvica), and venetoclax/rituximab (Rituxan). 

patients receiving venetoclax/obinutuzumab

 (85.5%; 97.5% CI, 79.9%-91.1%) or venetoclax/obinutuzumab/ibrutinib (81.8%; 75.8%-87.8%) had significantly longer progression-free survival (PFS) vs patients receiving venetoclax/rituximab (70.1%; 63.0%-77.3%) or chemoimmunotherapy (62.0%; 54.4%-69.7%). While there was no significant PFS difference between venetoclax and obinutuzumab with or without ibrutinib, there were more adverse events associated with the triplet regimen. 

This study suggests that venetoclax combined with obinutuzumab demonstrated a significant advantage in terms of PFS in previously untreated patients with CLL compared with standard chemoimmunotherapy or venetoclax with rituximab. However, the potential benefits of adding ibrutinib need to be weighed against the increased toxicity.

, Moritz Fürstenau, MD, University of Cologne, discussed the findings and implications of this follow-up study.

Targeted Oncology: What is the current standard-of-care in CLL?

The population we looked at were rather young and fit patients with CLL, so fit for chemoimmunotherapy. At the time when we did the study, 1 of the standards of care was still chemoimmunotherapy with with [fludarabine, cyclophosphamide, and rituximab (FCR)] and in Germany, it was [bendamustine and rituximab (BR)] for older patients.

Now, the whole paradigm has shifted a bit 

 with [Bruton tyrosine kinase (BTK)] inhibitors, which is the standard first-line treatment, or venetoclax, or obinutuzumab as a time-limited option for a year. Now, in Europe, we also have venetoclax/ibrutinib available, which is approved by the by the [European Medicines Agency (EMA)] for the first-line treatment of patients with CLL.

What was the original GAIA/CLL13 study evaluating?

The GAIA/CLL13 trial is a phase 3, multicenter trial with approximately 1000 patients included. It was done across Europe and in Israel. We tested different venetoclax-based, time-limited combinations against chemoimmunotherapy in the 

first-line treatment of patients with CLL

. The main primary endpoint analysis was already published about a year ago. What we found in the primary endpoint analysis was that venetoclax/obinitizumab and venetoclax/obinutuzumab/ibrutinib, a triplet treatment that is not approved at the moment, were both superior in terms of progression-free survival compared with chemoimmunotherapy. Now, with a little bit more follow-up, we were able to also compare the venetoclax arms against each other.

Can you summarize the findings of this follow-up?

We had a 4-year follow-up of all the primary efficacy outcomes of the GAIA trial. What we found now was that not only were the venetoclax/obinutuzumab groups, either with or without ibrutinib, associated with longer progression-free survival, compared with the chemoimmunotherapy arm, but they were also superior, in terms of PFS, compared with the third venetoclax arm, which was venetoclax/rituximab.

What we were also looking at was, how does the triplet combination compare with the doublet of venetoclax/obinutuzumab? Does the addition of ibrutinib add something to this combination? In terms of PFS for the whole study population, we did not see a significant difference. However, the curve separated quite clearly. We broke it down a little bit more and looked at the large subgroup of patients, so 60% of all patients in this study who had a nonmutated IGHV [immunoglobulin heavy chain variable], so patients with higher-risk CLL, and in this subgroup, the triplet combination was associated with a significantly longer progression-free survival compared with venetoclax/obinutuzumab. However, what we also found out was that the triplet combination was also associated with more toxicities, infectious adverse events, and cardiac adverse events, which is what we had anticipated by adding ibrutinib.

Could you discuss the safety profiles and adverse events associated with the triplet vs the doublet?

What we saw were mostly hematological toxicities, like neutropenia, thrombocytopenia and so on, and some infectious adverse events that are expected when you add a CD20 antibody. What came as an additional effect of adding ibrutinib, at least when we compare it in this randomized fashion, was a surplus of cardiac adverse events, not all very high grades, but we did see more atrial fibrillation, we did see more bruising, and we did see more hypertension. We also saw more infectious adverse events, and also some atypical infections, like fungal infections. 

Based on these findings, what do you think the implications are? How do you see these findings affecting treatment recommendations going forward?

I think the first conclusion we could draw from this study is that the doublet is safe and efficacious in this patient population and easily beats FCR and BR. For it, it proved that it is a good standard-of-care in this patient population. With regards to the triplet, I would be cautious to recommend it to anyone at this time, because the PFS benefit we see is only in a subgroup, and it is not a big difference compared to venetoclax/obinutuzumab. It is, at the moment, a rather small difference, and it comes with additional toxicities. Adding to that, we did not see any differences in the overall survival, which should be the parameter we look at when it comes to what we recommend in the long run. For the time being, I would say venetoclax/obinutuzumab is a good standard-of-care for this patient population.

Fürstenau M, Kater AP, Robrecht S, et al. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. 

. 2024 Jul;25(7):e284. doi: 10.1016/S1470-2045(24)00329-2]. Lancet Oncol. 2024;25(6):744-759. doi:10.1016/S1470-2045(24)00196-7

Moritz Fürstenau, MD, discussed a follow-up of the GAIA/CLL13 study exploring venetoclax combinations vs chemoimmunotherapy for the treatment of chronic lymphocytic leukemia. 

In 4-Year Follow-Up, Venetoclax Combinations Outperform Chemo in CLL

Ifinatamab deruxtecan (I-DXd; DS-7300), an antibody-drug conjugate (ADC), demonstrated favorable and durable efficacy and manageable toxicity in heavily pretreated patients with small cell lung cancer (SCLC), according to updated results presented at the 2023 World Conference on Lung Cancer.

At median follow-up of 11.7 months for the phase 1/2 study (NCT04145622), there was a 52.4% objective response rate (ORR) in patients with SCLC (95% CI, 29.8%-74.3%), with a median progression-free survival (PFS) of 5.6 months (95% CI, 3.9-8.1). Although I-DXd targets B7 homolog 3 (B7-H3), an analysis showed no correlation between B7-H3 and efficacy parameters in these patients.

“I-DXd, a novel B7-H3–directed DXd-ADC, continues to demonstrate robust and durable efficacy in patients with heavily pretreated SCLC,” investigators stated in their presentation.

B7-H3 is a transmembrane immunoregulatory protein that is overexpressed in cancers, including SCLC, in which 65% of patients have moderate to high expression. This 2-part study investigated I-DXd in patients with advanced solid tumors, including SCLC, using dose-escalation followed by dose-expansion to investigate its safety, tolerability, and antitumor activity.

Investigators presented a subgroup analysis of 22 patients in the dose-escalation portion who had SCLC, 21 of whom received at least 6.4 mg/kg of I-DXd and were evaluable for efficacy. These patients received I-DXd between 3.2 mg/kg and 16.0 mg/kg. They had a median age of 61 (range, 40-84), 14 (63.6%) of them were male, and 15 (68.2%) had an ECOG performance status of 1, with the rest having a performance status of 0. All had received prior platinum-based chemotherapy, with 81.8% having received immunotherapy. Seventeen patients were in the United States and 5 were located in Japan.

Key primary end points for the dose-escalation portion of the trial were dose-limiting toxicities, serious adverse events, treatment-emergent adverse events (TEAEs), and adverse events of special interest. In the dose-expansion portion, ORR, duration of response (DOR), PFS, disease control rate, and overall survival (OS) were evaluated as primary end points. Secondary end points included pharmacokinetics and immunogenicity.

Almost all patients had a reduction in target lesion size in post-baseline scans, with a median time to response of 1.2 months (95% CI, 1.2-1.4). Partial responses were observed in 47.6% and complete responses in 4.8%, confirmed by RECIST v1.1 criteria. The median DOR was 5.9 months (95% CI, 2.8-7.5). At the data cutoff of January 31, 2023, the median OS was 12.2 months (95% CI, 6.4-not applicable).

Patients with SCLC were treated for a median of 3.9 months (range, 0.03-12.5), with a median of 6.5 cycles (range, 1.0-18.0). Two patients remained on treatment after the data cutoff.

The safety profile in the SCLC subgroup was consistent overall with that reported in the overall population. All patients reported at least 1 TEAE, and 8 (36.4%) had a grade 3 or higher TEAE. Five patients (22.7%) had a TEAE associated with discontinuation of I-DXd, whereas 3 each had TEAEs that led to dose delay and dose reduction, respectively. There was 1 TEAE associated with death, which was COVID-19 pneumonia, that was determined to not be treatment-related.

The most common any-grade TEAEs included nausea in 13 (59.1%), fatigue in 11 (50.0%), anemia in 6 (27.3%), vomiting in 6 (27.3%), and decreased appetite in 5 (22.7%). Grade 3 or higher TEAEs included 1 patient with nausea (4.5%), 1 with decreased appetite (4.5%), and 1 with constipation (4.5%). Three patients (13.6%) experienced interstitial lung disease (ILD) or pneumonitis, 2 of which were grade 1 and 1 which was grade 2. The patient with grade 2 ILD received a dose of 8.0 mg/kg, and this was determined to be treatment-related, leading to treatment discontinuation. Patients were not permitted to receive premedication for nausea, vomiting, and infusion-related reaction in cycle 1.

Seventeen patients were retrospectively examined for B7-H3 protein level by immunohistochemistry for correlative analysis. There was no correlation found between B7-H3 combined membrane/cytosol H-score with ORR, PFS, or OS. Patients with above-median H-score had an ORR of 55.6% vs 62.5% for below-median. The median PFS was 5.3 months (1.4- not applicable [NA] in above-median B7-H3 vs 5.8 months (0.7-NA) for those below the median. The median OS was 6.9 months (2.8-NA) in those with above-median B7-HC vs 12.2 months (5.8-NA) in those with below-median B7-H3.

Investigators stated that the correlative relationship between the protein level and efficacy will be evaluated further in future I-DXd studies. These include the IDeate-1 phase 2 trial (NCT05280470) of patients with extensive-stage SCLC which will randomly assign patients to 1 of 2 dose levels (8.0 mg/kg or 12.0 mg/kg) of I-DXd to determine the recommended phase 2 dose.

“These data support further clinical development of I-DXd, including a phase 2 study of patients with extensive stage SCLC following 1-3 prior lines of therapy,” investigators stated in their presentation.

Johnson M, Awad M, Koyama T, et al. Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with refractory SCLC: a subgroup analysis of a phase 1/2 study. Presented at: World Conference on Lung Cancer; September 9-12, 2023; Singapore. Oral abstract OA05.05.

Investigators reported the best objective response, progression-free survival, overall survival, and safety of a B7-H3–directed antibody-drug conjugate at the 2023 World Conference on Lung Cancer.

Conference News

Ifinatamab Deruxtecan Shows Favorable Efficacy and Tolerability in SCLC

A 59-year-old African-American woman presented with a left renal mass​. She underwent left radical nephrectomy in December 2019 revealing clear cell renal cell carcinoma (RCC)​. Nine months later, she developed nodules in both lungs, with mediastinal (35 × 38 mm), and retroperitoneal lymph nodes​. Lung biopsy confirmed stage IV RCC with clear-cell histology​. Her Karnofsky performance status was 90%​. Hemoglobin was 11.1 g/dL and ​corrected calcium, neutrophils, platelets were within normal limits. She was considered to have an International Metastatic RCC Database Consortium (IMDC) intermediate risk status.

: There is a higher rate of patients in the intermediate and poor [risk group] in the [CheckMate 214 trial; NCT02231749] of ipilimumab [Yervoy] plus nivolumab [Opdivo]. So even though the numbers look worse, I think that the population may be a bit different.

 If you look at the CLEAR trial [NCT02811861], the poor prognosis percentage is 9% against 17% in the [CheckMate 214 trial], so I [chose] ipilimumab/nivolumab.

 One of the other things that I take into consideration as a community oncologist is…how easy it is to give immunotherapy compared with adding a TKI [tyrosine kinase inhibitor] because the adverse events [AEs] are significant. Not always, but we need to do a lot of hand holding in terms of how we’re going to set the dose, and the timing of starting therapy because of pre-authorization process. I think that all the options are very valid, and I usually present all the options to the patients. But, in practicality, I like the idea of the ipilimumab/nivolumab and I’m more familiar with it, too.

 I think that’s a great point. First of all, when you look at [the 4 frontline trials,] there are different breakdowns for the different IMDC risk populations within the trial. Interestingly, the patients who have intermediate and poor risk tend to do better in these trials. I think that having a lower percentage of poor-risk patients is a disadvantage to that regimen because the favorable-risk patients do well almost regardless of what you give them. But I think the second point is accurate. All these regimens are 100% appropriate, but to choose one based on the ease of administration is completely reasonable.

I think we’ve been giving ipilimumab/nivolumab for the longest time of all these regimens because it was approved first. It has the longest follow-up, and when you look at the 5-year follow-up, approximately 50% of patients are still alive and approximately 30% are still progression-free.

 We’re comfortable giving it. It doesn’t require a TKI and [so] I give it as well.

 I voted for lenvatinib [Lenvima] and pembrolizumab [Keytruda]. The reason behind that is…patients like to see a little quicker response, so adding a TKI always give you a little quicker response than just IO [immunotherapy] plus IO. I have used all 4 regimens. I had a bad experience with axitinib [Inlyta] and pembrolizumab. The patient had a hypertensive crisis and was admitted to the hospital with seizures and delusions. We still do not know whether he had a posterior reversible encephalopathy versus just a hypertensive crisis. We had to discontinue axitinib and he is doing fine on pembrolizumab alone. Lately I've been using cabozantinib [Cabometyx] or lenvatinib/pembrolizumab, and I’m very comfortable with the combinations. I just have to do little dose adjustments. I’m in a community practice, so…I look at the risk factors but I’m not bound by the risk factors [for choosing which] combination I use. So far, I have not got pushback from the insurance companies. I have a few patients on lenvatinib/pembrolizumab and I’m very comfortable with that combination; they’re all doing very well.

 Great. It’s interesting to hear how much personal experience plays a role in decision making. If somebody has a bad experience with, let’s say, cabozantinib and nivolumab—in the context of having 3 other regimens approved, they’re not going back to it. So it’s interesting to hear that you have that experience with axitinib/pembrolizumab and you tried other regimens [and you were] comfortable with them.

 I’ve used axitinib/pembrolizumab and ipilimumab/nivolumab in this patient population, and both of these regimens have significant potential AEs. I have had patients on ipilimumab/nivolumab with significant AEs where I have to drop immunotherapy or at least 1 of the drugs, which made me a little bit reluctant to give it to patients whom I thought will do OK on axitinib and pembrolizumab. Having said that, I had patients with significant AEs with axitinib and had to either drop it or significantly dose reduce it. I use both of these regimens with caution, and the risk factors…but also clinical judgment is key. I use both of the regimens with excellent results and with patients who’ve had significant AEs.

 Is there a reason you would use axitinib/pembrolizumab over lenvatinib/pembrolizumab or cabozantinib/nivolumab or is it just you have the experience with axitinib/pembrolizumab?

 I definitely have much more experience with axitinib and pembrolizumab. For that very reason I don’t think I’ve ever use lenvatinib and pembrolizumab in metastatic RCC because I’m so much more familiar with the other regimens. I’ve used lenvatinib in other cancers and that can be a challenging drug, too.

 The lenvatinib/pembrolizumab looked like the best [drug] for progression-free survival, but…[the trial] had…very few patients with poor prognostic factors.

 I think comparing cross trial is not a good idea, in my opinion, because they do not have the same population enrolled. Personal experience is more important than this trial.

 I think the note that I would caution on is when you look at the subgroup analyses in these trials, the benefit is more significant in the patients who have intermediate and poor risk. So, one would expect that for a trial that has less than 10% of patients with poor risk, the outcomes would be a little bit worse than the other trials.

 I found lenvatinib the most difficult of these TKIs to manage out of all the TKIs that we have here. I have tended to use lenvatinib/pembrolizumab in patients who are very fit and very symptomatic since the objective response rate seems to be a bit higher.

 I have more experience with axitinib because at the Cleveland Clinic, we had the trial published by Brian Rini, MD, and we adopted it pretty fast.

 But, if somebody is at high cardiovascular risk, where TKIs would be very high risk, I have gone towards the IO/IO combination.

 Because we had a good chunk of patients on the trial and Dr Rini was here, we shifted to axitinib/pembrolizumab quickly when it got approved. And now there’s more of a smattering of different agents being used now that we have more approvals.

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

During a Targeted Oncology case-based roundtable event, Moshe Ornstein, MD, MA, discussed the factors influencing the choice of frontline therapy for a patient with stage IV clear cell renal cell carcinoma whose risk status was intermediate. 

Nina Svensen, PhD

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