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Winer says patients who do well on carboplatin and show both a good pathologic complete response and good disease free survival may be patients who have refractory disease and are responding well to the treatment, while others may be patients who were bound to do well regardless.

Dr. Eric P. Winer on Pathologic Complete Response and Disease Free Survival in Breast Cancer

Eric P. Winer, MD, discusses the survival rates of women with early stage breast cancer who received bevacizumab and/or carboplatin. 

Dr. Eric Winer on Carboplatin and/or Bevacizumab in Triple-Negative Breast Cancer

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 71-year-old woman presented to her primary care physician with rib pain after a fall and reported increasing shortness of breath and fatigue. She had no history of smoking. Imaging showed a right hilar mass, rib metastases, and adrenal metastases, but a brain MRI was negative for brain metastases. She had an ECOG performance score of 1 and was diagnosed with stage IV lung adenocarcinoma.

Molecular testing of lymph node tissue showed a 

 exon 14 skipping alteration. We have a lot of options but unfortunately not a lot of guidance in terms of sequencing. So what would you do next? Capmatinib [Tabrecta], or tepotinib [Tepmetko], or crizotinib [Xalkori] are the 3 available type 1 

 inhibitors; chemotherapy would be chemoimmunotherapy; an immune checkpoint inhibitor alone; or other, which we can assume is a clinical trial.

 The first in market, capmatinib, captured the largest share of the poll. That’s very interesting. Tepotinib has 2 votes and crizotinib has 2 votes, and none would use chemotherapy. Who would use the immune checkpoint inhibitor? It’s not wrong, but I’d just be just curious what the thought process was. Is it the label, is it that it’s not exclusive, like we had seen with the EGFR and other inhibitors?

 I voted for that because I didn’t know the other agents that well.

 That’s why we’re here, so that’s a good thing. Aside from a [billable] standpoint, MET, unlike EGFR and ALK [inhibitors]—there’s nothing that speaks against immune checkpoint inhibitors in the first-line setting, with or without chemotherapy. Looking at the guidelines, I think we had a pretty good distribution between the targeted inhibitors and the checkpoint inhibitor. Who voted for the crizotinib? Did you care to comment? Is it a sequencing approach, where you do crizotinib first and use one of the newer MET inhibitors second?

 Well, I voted for crizotinib, and the reason is that I’m familiar with the drug, and I’ve used it in other patients with other mutations. These patients that we’re discussing here are so uncommon that I’m not as familiar with the other agents as maybe I should be.

 Familiarity with the drug is certainly a big factor for treatment. Crizotinib has multiple approvals in the settings of 

 Exactly, so that probably drove my decision to use crizotinib.

 That sounds very reasonable. Any thoughts on capmatinib vs tepotinib?

 I chose capmatinib, like most of the people in the group, because based on the phase 2 trial, the first line and second line, the response rate of the first line was pretty high compared with a chemoimmunotherapy, if you take any trial of a chemoimmunotherapy. Based on that, and also [considering that] the PFS was higher, too, I chose capmatinib. Tepotinib could be a choice; I didn’t choose it because while there’s no [direct] comparison, I think tepotinib has a lower response rate numerically, whether the patient received prior chemotherapy or not, compared with capmatinib—a higher response rate in treatment-naive patients, around 70%. So that’s why I chose capmatinib.

 We’re fortunate to have, in a relatively small space, 3 approved agents for the mutation, 2 being highly selective with good response rates, and a very similar safety profile. There are some differences in terms of dosing and convenience, but from a performance standpoint, I think we have 2 very good choices.

 exon 14 skipping mutation discovered before first-line therapy, the 2 preferred agents [by the National Comprehensive Cancer Network] are capmatinib or tepotinib; crizotinib is an additional option.

 Then, basically in acknowledgment of the guidelines and the FDA labels, also the standard non-driver mutation regimens can be utilized in the first-line setting, with a recommendation upon progression to move back into one of the MET inhibitors. If you discovered the 

 exon 14 mutation after initial treatment initiation, it becomes very difficult to decide how to switch, because there’s no real good data how to do that, whether you do it at progression, arbitrarily, or immediately upon the discovery of the mutation.

I think that the capmatinib and tepotinib data are a little bit cleaner than crizotinib, and mostly the paradigm of targeted therapy before chemoimmunotherapy, especially in this subtype. [

 mutation that is not as responsive to immunotherapy. I think I see a reasonable recommendation summary of the data. Has anybody used tepotinib yet in the first line, in the setting of 

 It seems to be similar to capmatinib. I don’t see a major difference. We’re very biased because we don’t know which one is better. They were approved in different studies. Traditionally, we use capmatinib first, because it’s approved first, and now we have tepotinib later, also.

 on-target effects there, and the edema is probably the main handling issue. A little bit of hypoalbuminemia, sometimes a little bit of increase in kidney function, or liver function test abnormalities, but it’s pretty balanced. I think that’s the non-selective nature of 

The FDA approval [of tepotinib] came earlier this year on February 3.

 Metastatic non–small cell lung cancer, any histology, with a MET exon 14 skipping alteration.

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2021. Accessed November 8, 2021. https://bit.ly/3025IKZ

2. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA. Published February 3, 2021. Accessed November 8, 2021. https://bit.ly/2YuQA86

At a live virtual event, Martin Dietrich, MD, PhD, discusses treatment options for a patient with non–small cell lung cancer when molecular testing shows a MET exon 14 skipping mutation. 

Part 2: Choosing a Treatment for NSCLC with MET Exon 14 Skipping Mutation

Gregory says the MonumenTAL-1 study enrolled patients with high-risk features seen in the real world.

Talquetamab showed high efficacy across the cohorts of the study.

Unique toxicities of talquetamab include skin, oral, and nails.

An analysis showed reduced dose intensity improved some toxicities and maintained efficacy on the trial.

Targeted Oncology: What was the significance of the MonumenTAL-1 trial (NCT03399799/NCT04634552) of talquetamab (Talvey) in the relapsed/refractory multiple myeloma population?

Talquetamab was [investigated in] the MonumenTAL-1 study, and there was a phase 1 and phase 2 component. What I think is fantastic about the study is that first they're trying to figure out their dosing schema. Do you have a smaller dose every week, or do you go every other week?… They also had these patients profiled [based on whether] they had seen anti B-cell maturation antigen therapy before.

All of these patients were triple class [exposed]; there were high [rates of] penta-refractory disease, and a lot of high-risk cytogenetics.

 I expect [patients with high-risk cytogenetics] to be approximately 30% in my trials. If I don't have at least 30% or more, I don't have an adequate myeloma study for a product. [For] extramedullary plasmacytomas, they [often exclude] these patients from studies. A lot of times, studies only want 10% of patients who have extramedullary disease. These [cohorts] have a 20% to 30% extramedullary disease rate—those are typically going to be your patients with more aggressive [disease]. They're further along down the line. Their plasma cell [is not behaving the way it] should behave anymore. Plasmas cells shouldn't know how to make lumps and tumors. By the time they learn how to make lumps and tumors, biologically, they've changed, and they're more aggressive. In this study, belantamab mafodotin [Blenrep], for the most part, was the prior anti [BCMA therapy], because that's where we were in terms of the drug use.

Ultimately, you can see an overall response rate [ORR] of 74% [in the once-weekly cohort], 69% [in the every-2-weeks cohort], and 66% [in the prior T-cell therapy cohort].

 These patients are not supposed to be with us in 5 months. When you go to the higher dose every other month, we see a duration of response of approximately a year and a half. This is helping us get to the next [line of therapy].

What safety outcomes stood out in the MonumenTAL-1 trial of talquetamab?

[In terms of] safety data, what I'll highlight is cytokine release syndrome [CRS]. CRS is not as high as with chimeric antigen receptor [CAR] T-cell therapy. With a CAR T-cell therapy, we expect [the rate of any-grade] CRS to be in the 90th percent. [With talquetamab], we're in the [range of] 70%, so it's definitely [present].

 But my question is always going to be: are we talking about a grade 1 adverse event [AE], which is a fever? I can tell the patient to take acetaminophen for a fever. That's manageable. What's harder to manage is the grade 2 and grade 3 CRS, and if you go into the subsets, the majority of these patients are going to [only] have fever.

What's impressive here are the off-target AEs.

 There are not a lot of cytopenias. With a GPRC5D [bispecific]…you can expect them to lose 10% of their body weight, and they don't eat [sufficiently] for approximately a year.… So if you have somebody who's starting with low body weight, this gets pretty [concerning]. After approximately 1 year you start to see that go away. In the clinical trial with the GPRC5D CAR T-cell therapies, that lasts for approximately 1 month and it's gone, so it's interesting. Their nails can become completely brittle…the skin rash is [serious]. It looks like a grade 2 or grade 3 graft-vs-host disease skin rash.

Why is it important to reduce dose intensity of talquetamab?

This is where we are now: do we have to keep pushing so hard on these T cells? Remember, we're causing a lot of T cell exhaustion. Is there a point at which we can drive these patients’ [dose intensity] down? I always tell my patients about the myeloma iceberg. That’s our analogy,when your myeloma gets diagnosed, your disease is up here, and by the time I have you in a partial remission, you're just a bit under the surface, and I'm trying to melt that iceberg as far down as I can get it. Now we have minimal residual disease negativity. So if I have the iceberg melted pretty far down, maybe I don't need to keep [exhausting] these T cells.

[On the MonumenTAL-1 trial], there was a group where they waited to do the dose reduction until they hit their best response, and then they dose reduced. Then in the other group, it was prospective, so the plan was to dose reduce [or reduce dose frequency] based on time of exposure.

[Reported data] are focusing only on the patients who were dose reduced after they had best response.

 We’re not comparing with what we saw in the other group. The patients who hit best response were able to be dose reduced. [Other] patients were never dose reduced, because they didn't hit optimal response. What you can tell is that patients who get a fabulous response [can] ride that out beautifully [with dose reduction], so that's what you want.

This is what's making me think in my practice that if my patients are not [responding], am I going to add something else in? Because there are other clinical trials that you're going to see coming out with the combinations, like talquetamab plus carfilzomib [Kyprolis], talquetamab plus daratumumab [Darzalex], talquetamab plus pomalidomide [Pomalyst] and daratumumab—those kinds of [regimens]. Is that what we're going to start doing next based on response? Some of us are starting to do that; we've agreed as a community, if you don't see that great response by 3 to 6 months, you need to think about adding something in if you can get it.

How did the patients who had dose reductions prospectively perform?

Ultimately…the ORR here was still [nearly] 80% of patients.

 The median progression-free survival was 13 months. They're doing very well. They still had an excellent response even with a prospective dose reduction. For the most part, this is what we're doing in our practice now; we prospectively dose reduce.

Is there a correlation between dose reductions and the toxicities that a patient experiences?

Yes, there is. [In the prospective cohort, dose reductions were] because of toxicity. As you dose reduce, your [skin and oral] toxicities go down, and patients stay on the drug and they're more tolerant of it. What does not get better is the weight loss and the nail toxicity.

1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma. 

. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591

2. Rasche L, Schinke C, Tozeau C, et al. Long-term efficacy and safety results from the phase 1/2 monumental-1 study of talquetamab, a GPRC5D × CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. 

. 2024;8(suppl_1):P915. doi:10.1002/hem3.104

3. Chari A, Oriol A, Krishnan A, et al. Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. 

. 2023;142(suppl_1):1010. doi:10.1182/blood-2023-181228

During a Case-Based Roundtable® event, Tara K. Gregory, MD, discussed the MonumenTAL-1 trial of talquetamab in patients with relapsed/refractory multiple myeloma in the first article of a 2-part series.


Eric Winer, MD

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