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Thierry Conroy, MD, a medical oncologist and director at the Institut de Cancerologie de Lorraine in Nancy, France, shares some background on the PRODIGE 24/CCTG PA.6 trial where a modified FOLFIRINOX regimen was found superior to the adjuvant standard of care, gemcitabine, in patients with resected pancreatic cancer.

An Overview of a Practice-Changing Trial With mFOLFIRINOX in Pancreatic 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 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.

 If I use nivolumab/ipilimumab, which I think is a good choice and the first choice, I would use nivolumab/relatlimab in the second line. But I tend to lean towards it more because…compared with nivolumab/ipilimumab, the data are similar or better.

That’s a great point, weighing the relative benefit and toxicity and certain patient factors.

 I have usually used nivolumab/ipilimumab in the past, but now seeing the approval of nivolumab/relatlimab I [would] switch over. The tolerability is, in my experience, a lot better than the nivolumab/ipilimumab combination. I rarely have any patient have any significant adverse event like diarrhea or severe colitis that require [hospital] admission. So far, [my patients] all seem to get pretty good responses, including 1 who had a complete response. So far, it’s a very good experience for me.

 I will primarily use nivolumab/ipilimumab. There are some data also that you can restage the patient after 2 cycles.

 If there hasn’t been a response, you can drop the ipilimumab because the likelihood of response will be a lot less. But I will give a chance to nivolumab/ipilimumab based on the [slightly] superior response rate [vs nivolumab/relatlimab], and more maturity of the data.

 Good points. I think everyone’s made the points that we’re all thinking about, trying to weigh risk and benefit when we’re making decisions in clinic.

 mutation, what factors influence the first-line selection of immune monotherapy versus dual immunotherapy in a patient such as this?

 It seems like this is a group that is in favor of a dual checkpoint inhibitor therapy. What are the factors that go into your decision making for monotherapy vs dual immunotherapy? We’ve listed some things that we take into account, but how you make these decisions?

In my own practice, it certainly mirrors what many people here have talked about, favoring dual checkpoint inhibitor therapy…. The group that we now treat with monotherapy has become less and less common, based on some of the data. Although I think there are certain situations where monotherapy still may be warranted. Comorbidities…for example, underlying autoimmune disorders or other things where we might be worried about an increased risk of adverse events, depending on site of disease and extent of disease. Age of the patient can sometimes influence that. I’ve personally treated a few patients well into their 90s, and that’s an extreme example. Those are patients where I may be more likely to use monotherapy vs dual checkpoint inhibitor therapy.

: In the past, in patients who are frail, I would lean toward monotherapy, like pembrolizumab [Keytruda]. I think nivolumab/relatlimab is, from my experience, very tolerable so I’m leaning toward that direction now.

 [With] high LDH or higher tumor burden, I’m even more willing to do dual immunotherapy. Also, I think if they have the 

 mutation, they seem to do better if they have dual immunotherapy. There are some data saying that.

 Yes, there are [data] on different subgroups.

 So if they’re wild-type, have low LDH, have low tumor burden, or they’re older, you might consider monotherapy more in that type of patient. But in general, default is the doublet unless somebody needs monotherapy for those other reasons that you state [such as] comorbidities.

 That’s a great point. We could talk for hours on why there’s not a biomarker for selecting immunotherapy, [but] I don’t use PD-L1 or LAG-3 expression in melanoma. PD-L1 expression is predictive, but it’s not adequate to select 1 type of therapy over another. It sounds like most [physicians] are not using that, which is good to hear.

1. Lebbe C, Meyer N, Mortier L, et al. Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: Three-year results of CheckMate 511. 

. 2021;39(suppl 15):9516. doi:10.1200/JCO.2021.39.15_suppl.9516

2. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

 2022;386(1):24-34. doi:10.1056/NEJMoa2109970

3. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. 

. 2022;40(2):127-137. doi:10.1200/JCO.21.02229

4. Postow MA, Goldman DA, Shoushtari AN, et al. Adaptive dosing of nivolumab + ipilimumab immunotherapy based upon early, interim radiographic assessment in advanced melanoma (The ADAPT-IT Study). 

 2022;40(10):1059-1067. doi:10.1200/JCO.21.01570

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. 

Immunotherapy Options for an Older Patient With Metastatic Melanoma

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. 

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


2. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC).

2021;32(suppl_5):S678-S724. doi: 10.1016/annonc/annonc675

3. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

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

4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

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. 

Thierry Conroy, MD

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