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Immune checkpoint inhibitors are approved for dMMR/MSI-H gastrointestinal cancer treatment; however, approximately half of patients with dMMR/MSI-H gastrointestinal cancer exhibit primary resistance to them.

Overcoming Resistance in Gastrointestinal Cancers

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 52-year-old, postmenopausal woman had a history of grade 2, node-negative invasive ductal carcinoma (IDC).

Estrogen receptor positive (ER+) and progesterone receptor positive (PR+); HER2 immunohistochemistry (IHC) 0; Ki-67 20%​ of the right breast; 21-gene recurrence score, 27

Initial therapy included chemotherapy, radiation therapy, and 5 years of adjuvant anastrozole.

Three years after completing anastrozole​, metastatic progression was discovered, including symptomatic bone involvement (multiple vertebrae and bilateral iliac crests).

Bone marrow aspiration confirmed ER+/PR+, HER2 IHC 0, stage IV IDC.

The patient started letrozole and ribociclib (Kisqali) with denosumab (Xgeva), with good clinical response and marked improvement in her pain​.

Required 1 dose reduction to 400 mg ribociclib due to neutropenia.

Twenty months after starting therapy, routine staging scans showed new FDG-avid sclerotic and lytic bone lesions​.

She noted mild increase in lower back pain​.

Circulating tumor DNA (ctDNA) analysis confirmed an 

Fulvestrant + a different CDK 4/6 inhibitor 

 Using fulvestrant plus a different CDK4/6 inhibitor would not be an unreasonable choice if the patient didn't have an 

 mutation. Fulvestrant alone isn’t a [definite] option for a patient like this. I probably wouldn't use exemestane plus everolimus [Afinitor] here because I don't think this patient has definitively endocrine-resistant disease. Likewise, I probably wouldn't give single-agent chemotherapy. So I would agree with the participants and give elacestrant [Orserdu].

 I absolutely agree. I think elacestrant would be a preferred option.

 But there are some other circumstances where somebody doesn't have access to elacestrant. The 

 mutation would drive me towards a selective estrogen receptor degrader over an aromatase inhibitor combination. So thinking about fulvestrant is also a reasonable option, but I think elacestrant [is a recommended] option.

 The patient received ribociclib in the first-line setting—if she got palbociclib [Ibrance], would you consider, if she didn't have any sort of mutation, fulvestrant plus ribociclib based on the MAINTAIN trial [NCT02632045]?

 I think [we take into account] the MAINTAIN data.

 They are certainly compelling. I have done that very thing in patients who lack other targetable mutations, had a good run on first-line palbociclib, and just have a small amount of progression. We did see data that ribociclib plus fulvestrant was better than fulvestrant alone in that population. I would consider that, remembering that phase 2 hypothesis-generating study.

 mutation, what comes first? How do you deal with that?

 It's a very good question. It's a data-free zone, but I think given the toxicity profile, I probably would lean towards elacestrant.

 I think this depends on the patient in front of you and the volume of their disease. Are they symptomatic, and are we feeling comfortable with single-agent endocrine therapy knowing that we still have the ability to target the PIK3CA pathway at the subsequent progression? I think in the absence of data, it's an art-of-medicine decision. I think there's a place for single-agent endocrine therapy, given the constellation of risk-benefit balance.

 When you look at SOLAR-1 [NCT02437318], the benefit with alpelisib [Piqray] was pretty significant.

 We just don't know the answer right now. And I think you're absolutely right, it depends on the patient.

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 2.2024. Accessed June 6, 2024. 

2. Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized phase II trial of endocrine therapy with or without ribociclib after progression on cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: MAINTAIN trial. 

. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392

3. André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. 

. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011

During a Case-Based Roundtable® event, Ruth M. O'Regan, MD, looks at options for a patients with hormone receptor–positive, HER2-negative breast cancer and an ESR1 mutation in the second article of a 2-part series.

Second-Line Targeted Options Considered in ESR1-Mutated Breast Cancer

Holistically Defining Cancer Survivorship

Cancer survivorship is a complex concept that can be defined in various ways, depending on the context and perspective. Some common approaches include time-based definitions, state-based definitions like "living with cancer" or "cancer-free," or quality-of-life-focused definitions. 

More holistic definitions can identify cancer survivorship as a journey, with a perspective that recognizes that survivorship is a continuous process involving physical, emotional, and psychological challenges. Survivorship can also be thought of as a community, emphasizing the importance of support networks and shared experiences among cancer patients. 

These definitions are not mutually exclusive and can be used in combination to provide a more comprehensive understanding of cancer survivorship. The specific definition that is most appropriate will depend on the research question, clinical context, and individual perspective.

Here, Amy Selly, CNP, AOCNP, Allina Health medical oncology advanced practice provider lead, discusses the different definitions of survivorship. 

People have so many different view lenses on what defines survivorship. I think the the most general, or most agreed upon, is that survivorship really starts at the time of diagnosis, and it continues through end of life. So as we're talking to patients, I hear a lot that they feel like they're not a survivor until they have been told by their cancer team that they are in remission. And so really that survivorship should start, you know, that that clock starts ticking at the time of diagnosis. 

And really, when you're looking at survivorship as as a whole, we're really looking at everything that is impacting that patient, from the the physical to the mental to the emotional, you know, the social, the financial effects, and everything that goes into what goes with that cancer diagnosis. So we don't want to pigeonhole it into one particular time, right? I know that for a lot of us, when we define survivorship programs, a lot of it does start at completion of treatment, and where we really start to provide patients with that long-term follow-up plan and what they need to be watching for and identifying some of those longer-term resources.

Amy Selly, CNP, AOCNP, discusses the different definitions of cancer survivorship. 

The Role of Support in Cancer Survivorship

Support plays a crucial role in the cancer survivorship experience, providing emotional, social, and practical assistance to patients throughout their journey. Emotional support can help reduce stress and anxiety, provide a sense of belonging, and offer hope and encouragement. Social support helps maintain relationships, offers practical assistance, and reduces feeling of isolation. Practical support provides information and resources, advocates for survivors, and helps navigate the health care system. 

Support is essential for cancer survivors. By connecting with others who understand their experiences, cancer survivors can find strength, hope, and a sense of community.

Here, Amy Selly, CNP, AOCNP, Allina Health medical oncology advanced practice provider lead, discusses the discusses the importance and impact of support on the cancer survivor journey. 

t's a major impact on how the patients move through their cancer journey. Strong, strong social support. Through us working anecdotally with patients and through research has showed that it can really help a patient have a more positive experience with their cancer diagnosis, that it will build better resiliency with them as they move forward. It provides comfort and it improves their coping as they're moving through the cancer. And I think it's equally important to talk about the low when patients have low level of support. 

With those patients, we see higher levels of depression. We see lower functional statuses with them. We see more symptoms and side effects from the treatment. We also see more challenges with getting them initially through treatment, so, you know, making it to the appointments, as well as having long-term follow up and moving through that surveillance period to help make sure that we're giving them all of the tools that they need to be successful moving forward.

Amy Selly, CNP, AOCNP, discusses the role support plays in the cancer survivor experience. 

Working With Underserved Populations of Cancer Survivors

Cancer survivors from underserved populations often face unique challenges that can significantly impact their quality of life. These challenges may be exacerbated by factors like socioeconomic disparities, cultural barriers, systemic inequalities, and health disparities. Addressing these challenges requires a multifaceted approach. 

Here, Amy Selly, CNP, AOCNP, Allina Health medical oncology advanced practice provider lead, discusses the challenges facing these patients. 

 When you're looking at the different cultures and ethnic backgrounds when we're working with patients, if you have language barriers, that is going to be the first. And really making sure that you have high-quality interpreters and that any printed materials that you're given are provided in the correct language to help. I have found that sometimes we need to bring in leaders within those cultural communities to help us overcome some of the what could be potential barriers. So, you know, really providing that education so that patients feel comfortable with the recommendations that are made to move forward, so that that could really happen culturally. 

And then we just in general, have that underserved, or you know, underinsured population, and those as well, we have that sort of higher risk of them not continuing to follow for surveillance afterwards. Getting access to the resources that can really benefit them in improving their emotional impact, their functional status, really getting them physically back to their optimum self following the end of treatment. It really can be challenging. 

Amy Selly, CNP, AOCNP, discusses the challenges facing cancer survivors from underserved populations. 

Challenges Facing Cancer Survivors

Cancer survivors often face a unique set of challenges that can impact their physical, emotional, and social well-being. Some of the most common challenges include physical like fatigue or pain, emotional, social, and financial.

These challenges can vary significantly from patient to patient, and not all survivors will experience all of them. Additionally, the support and resources available to cancer survivors can vary widely depending on location and individual circumstances.

Here, Amy Selly, CNP, AOCNP, Allina Health medical oncology advanced practice provider lead, discusses the varying challenges facing cancer patients and survivors. 

Everything is really dependent, not only on their cancer diagnosis, their stage of diagnosis, what their treatment has been throughout, whether it be surgery, radiation, chemotherapy, immunotherapy, you know, potentially stem cell transplants, whatever that may be. It may be a combination of any of those. So, depending upon where those treatments lie in kind of increases what those risks are for certain long-term physical side effects, things that can happen within the long term. So some of these treatments will have the risk of having long-term heart issues or long-term neuropathy or long-term cognitive changes. So those are some of the physical, more common physical things that we see. Sort of that long-term neuropathy, fatigue that goes with many of these diagnoses, although the majority of patients over time, many of these long-term side effects do decrease, and they return back to sort of more of a precancer diagnosis normal. 

But then there's not only those physical impacts, but the emotional impact that goes with it, and sometimes that can be a longer-term challenge for patients as well. So just having been through that cancer diagnosis and those fears of recurrence and fears that go in with every provider visit that happened with it. So those, and then financially. For many patients, the financial impact is felt long term, I think, particularly when we're looking at cancer as a chronic illness. Many of these medicines that help our patients live longer come with, you know, pretty significant financial toxicity, and if you add that, maybe loss of work, and being a primary provider for a family, those are going to significantly impact patients long term.

Amy Selly, CNP, AOCNP, discusses the varying challenges facing cancer patients and survivors. 

Nina Svenson, PhD

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