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The FDA recently released 5 new draft guidance documents that promote broader patient eligibility for cancer clinical trials. The policies encourage inclusion of certain individuals who were previously disqualified due to medical conditions or biological factors, including brain metastases, organ dysfunction, prior or concurrent malignancies, chronic infections, and age.

FDA Issues Draft Guidance to Broaden Clinical Trial Inclusion

Due to an active research landscape, the National Comprehensive Cancer Network Guidelines for non&ndash;small cell lung cancer have had 3 recent updates that include numerous clinically relevant recommendations.

Treatment Advancements in NSCLC Change Therapy Recommendations in 2019 NCCN Guidelines

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 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

The patient is a 61-year-old man who is married with 2 grown children and 5 grandchildren who live nearby. He has an active lifestyle including daily walks and golfing regularly. He has a history of metastatic renal cell carcinoma (mRCC) and had a left nephrectomy and adrenalectomy due to clear cell RCC (ccRCC) with metastases in the adrenal​ gland.

Four years later, he has a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, this had been present on scans for at least 2 years prior​. He was observed based on low volume and indolency of the disease and patient preference​.

Eighteen months later, there is continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis that is 2.0 x 1.5 cm. He has an ECOG performance status of 0.​

Would your choice of therapy change in based on the number of metastases? Why or why not?

 I initially chose lenvatinib [Lenvima] plus pembrolizumab [Keytruda] because [the CLEAR study; NCT02811861] had the highest progression-free survival compared with other trials.1 But in my practice, I’ve seen cabozantinib [Cabometyx] plus nivolumab [Opdivo] has been tolerated better than lenvatinib/pembrolizumab, so I usually start patients on cabozantinib/nivolumab. I think that if you look at long-term data on doublet immunotherapy, 30% to 35% of patients still had a good response after many years.2 So, if patient has more organ involvement or more metastatic sites, I decided to change to ipilimumab [Yervoy] plus nivolumab.

 I chose the lenvatinib/pembrolizumab [in both cases] because of the recent data, and also because I had a patient on axitinib [Inlyta] plus pembrolizumab who progressed and had lymph node metastases in his neck. I changed to lenvatinib/pembrolizumab, and the lymph node metastases completely went away. The problem I have is he developed all these mouth sores, and so we had to stop it for a while, and I don’t know what’s going to happen. He has had it for 7 years now, so he’s had a lot of these other things that are [difficult]….But, that’s why I chose that [combination], because it worked on this patient that failed the other one, even though the pembrolizumab was the same. But then, on the other hand, I had problems with adverse events with both of those.

 What proportion of patients do you typically see with 2 or more sites of metastases?

 I think maybe 30% to 40% might have widespread [disease]; I’ve seen patients with 2 areas, maybe [in 1 or 2 sites] in the lung and 1 in the adrenal. But, to have extensive liver and lung metastases, would probably be more symptomatic.

 Yes, that’s usually [indicative of] more advanced stages.

What factors affect your choice of therapy?

 The data look quite robust [for all 4 regimens]. What is your favorite regimen do you use in your practice, for a patient with favorable risk?

During a live virtual event, Ulka N. Vaishampayan, MBBS, discussed the choice of first-line therapy for clear cell renal cell carcinoma and whether the approach to treatment would change with other disease histologies. 

Will Pass, DVM

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