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The FDA recently released 5 new draft guidance documents that promote broader patient eligibility for cancer clinical trials.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FDA Issues Draft Guidance to Broaden Clinical Trial Inclusion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

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

The patient is a 52-year-old postmenopausal woman with a history of T2N0M0 estrogen receptor–positive/progesterone receptor–positive, HER2 IHC 0 (0 expression by immunohistochemistry) breast cancer. She completed adjuvant docetaxel and cyclophosphamide followed by 5 years of letrozole. ​

Eight months after completion of letrozole, she presented with persistent low-back pain and fatigue that restricted exercise. Fludeoxyglucose (FDG) F18 PET/CT avid radiotracer uptake detected in L4-L5 vertebrae and right pubic bone​. Biopsy of L4 bone lesion showed malignant cytokeratin positive cells consistent with breast adenocarcinoma, leading to restaging of ​T2N0M1b (metastatic).

Molecular profile showed no mutations in 

 mutations​. First-line therapy with fulvestrant plus palbociclib (Ibrance) was initiated, which was well tolerated ​and elicited an initial partial response at 6 months​.

Twenty-two months after starting first-line therapy, she showed evidence of progressive disease with new areas of bone involvement in T-spine, left ribs, and L2​. circulating tumor DNA showed no actionable mutations, including 

. She received exemestane plus everolimus for 6 months​, and had radiographic evidence of progressive disease with numerous new bony metastases. Capecitabine (Xeloda) was initiated, which was well tolerated, with grade 1 hand-foot syndrome.

After 9 months of capecitabine​, a CT scan of the chest, abdomen, and pelvis and a bone scan showed significant findings:2 liver lesions measuring 1.8 cm and 2.4 cm respectively; persistent bony metastases consistent with disease progression; and lung lesions too small to characterize, but concerning in setting of other findings for metastatic disease​. Her ECOG performance status was 1 and laboratory profile was within normal limits.

Please discuss the rationale for your selection.​

If you chose chemotherapy or other, which agent(s) would you use?​

What next-line therapy would you recommend for this patient?

I had voted for ‘other’. I think it might be worthwhile, if possible, to repeat a biopsy at this point to see if there is any HER2-low expression, because she may be a candidate for trastuzumab deruxtecan [Enhertu; T-DXd]. I know that there are data that with repetitive biopsies, eventually, you're likely to find some HER2-low expression. I always prefer soft tissue over bone, but if it's not accessible, and if the patient was willing, I'd like to repeat a bone biopsy.

: …It's a great suggestion because there is tumor heterogeneity and there is heterogeneity by metastatic site. We now see that she has visceral disease for the first time. Our biopsies in the past have been in the bone and her primary [tumor] was HER2-zero, but I agree with you, it might be interesting to try for one of the liver or lung lesions to see if there's HER2-low [expression] there.

: I chose sacituzumab govitecan [Trodelvy] because the randomized data compared with single-agent chemotherapy seems to be better.

 It seems to be well tolerated and also had some success with central nervous system metastases, although that's not [present] in this patient, but still there may be some benefit there.

: You're referring to TROPiCS-02 [NCT03901339] in hormone receptor [HR]-positive breast cancer. Great point.

I've had insurance deny sacituzumab with HR-positive disease if they haven't progressed through 2 lines of chemotherapy. Someone had 1 dose of sacituzumab, and I got it approved after progression on capecitabine. She had HER2-zero expression on multiple biopsies. They refused to cover because she had not progressed through 2 lines of chemotherapy in the metastatic setting.

…When we get into the second-line setting, this is where HER2 status is important of stratifying our approach. For patients who have HER2-low breast cancer, the National Comprehensive Cancer Network is preferring T-DXd in that setting.

 If patients are not candidates for T-DXd, sacituzumab is the preferred option. Otherwise, [we have] other remaining systemic chemotherapies.

The indication for sacituzumab in HR-positive, HER2-negative disease, regardless of [whether] HER2 IHC 0, IHC 1+, or IHC 2+/ISH- is after endocrine therapy and 2 or more lines of therapy for metastatic disease. To Dr Fasano’s point, I think this is the precise letter of the law, although often, when patients have had prior [chemotherapy] exposure in the adjuvant setting [or neoadjuvant setting], or a short disease-free interval, we've been able to count that as a line and still be able to access sacituzumab.

Sacituzumab govitecan was initiated, and a best response of partial response observed, with further symptomatic improvement. The patient maintained an absolute neutrophil count of 3,900/μL and white blood cell count of 7,800/μL​. Follow-up [18F] FDG PET/CT demonstrates resolution of avidity in vertebral and pelvic bones.

When would you consider sacituzumab govitecan as second-line therapy for a patient with HR-positive, HER2 IHC 0 metastatic breast cancer, previously treated with adjuvant taxane chemotherapy plus an aromatase inhibitor plus a CDK4/6 inhibitor?

So, whether you're able to get it for your patients?

: The label says [it is indicated after] endocrine therapy plus 2 lines of systemic treatment.

Right, 2 lines of therapy. PARP inhibitor therapy would count if we're talking about our patients with germline 

 mutations. As I was saying, often if the disease-free interval was short from their adjuvant treatment, that can count as a line of therapy when we're getting approvals for insurance.

 Is there anything around toxicity or tolerability that might be a concern for anyone?

If they have compromised bone marrow from adjuvant chemotherapy or metastatic breast cancer in the bone marrow, then you have to be a little bit more careful.

Yes, we're a bit worried about cytopenias or neutropenia. Fortunately, we can support a lot of that with growth factor and dose modifications that are built in.

1. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. 

. 2022;40(29):3365-3376. doi:10.1200/JCO.22.01002

2. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2024. Accessed July 24, 2024. 

3. FDA approves sacituzumab govitecan-hziy for HR-positive breast cancer. FDA. February 3, 2023. Accessed July 24, 2024. 

During a Case-Based Roundtable® event, Tiffany A. Traina, MD, surveyed participants on treatment for a patient who had progressed following endocrine therapy for metastatic breast cancer in the first article of a 2-part series.


Peers Discuss Sacituzumab Govitecan in HR+ mBC Post Endocrine Therapy

A 64-year-old man presented with worsening fatigue, persistent dry cough, and mild progressive dyspnea over the past month, as well as some chest discomfort, especially during routine exercise. He had unintentional weight loss of 8 lbs over the past 4 months. He has a medical history of hypertension and hypercholesterolemia, which are both well controlled with medication. He is the father of 2 children and has never been a smoker.

A right lower lobe auscultation revealed decreased breath sounds. His ECOG performance status was1. A CT scan of the chest showed a 3.5-cm mass in the right lower lobe, a small right pleural effusion with nodularity, and mediastinal lymph node involvement. A PET/CT scan showed multiple bone metastases, including vertebrae and left scapula. A brain MRI was negative for metastasis. A mediastinal node endobronchial ultrasound confirmed the patient had stage IVB non–small cell lung cancer (NSCLC), TTF1-positive adenocarcinoma.

Would anybody do next-generation sequencing [NGS] alone—Tempus, Foundation Medicine, etc? Or are you doing NGS plus other things right now?

We’re doing NGS, fluorescence in situ hybridization [FISH], and immunohistochemistry [IHC].

We call it hot-spot for actionable [items].

I do NGS testing. In our institution, we are switching from Strata [Oncology] to Caris [Life Sciences]. Now I think they’re doing DNA- and RNA-based NGS together, so that’s great. We can maybe pick up some other rare fusions.

I think that’s where we’re heading. We don’t routinely do liquid biopsy unless there’s a difficulty in terms of getting a tissue or nondiagnostic result.

You’re at Kaiser Permanente Riverside [Medical Center], so is all of Kaiser moving away from Strata and going toward Caris?

Which mutation would you do polymerase chain reaction [PCR] for?

Classically, the PCR mutations are the ones that are single-point mutations, small insertions, or deletions. So all of 

, we only have V600E as actionable right now; 

— those are the ones we could PCR test for.

of just hot-spot mutations and a rapid assay. We’re not sequencing the whole thing. We’re just putting it on and sequencing with a couple of days turnaround so that we don’t have to wait for NGS because 

is so much more common than all the other ones.

In the United States patient population, there is a 15% frequency, but when we think about Asian women, never smokers, you’re up to a 50% to 60% frequency, which I know many of us on the West Coast will see these patients newly diagnosed and presenting [in the clinic]. So I like to have that 

test back very quickly, and then the rest of it we can wait for by NGS. To stress again, PD-L1 [testing is] only by IHC, only on the tissue, and can vary depending on where we biopsy.

The patient’s PD-L1 expression is negative, and the results of molecular testing by tissue DNA NGS are pending.

The patient is anxious to initiate therapy. What are you going to offer? The patient is symptomatic, needs therapy, [is a] never smoker, [and is] TTF1 positive. What are you going to do?

When I say chemotherapy, I usually mean I add bevacizumab [Avastin] as well.

Platinum doublet can include an antiangiogenic.

[What about] for a patient who has 2 mutations like 

My personal bias is to try to treat the more common one, and the less common one is statistically more likely to be a false-positive for whatever reason. But it is certainly possible to have acquired resistance of a second driver with an initial driver. Most of our cases where we have 

, they were false-positive FISH tests, and the 

was the driver alteration as evidenced by the 

I personally might hold off on the antiangiogenic and leave it until cycle 2 if we don’t find another molecular alteration. A decade ago, I would say 

During a Targeted Oncology™ Case-Based Roundtable™ event, Joel Neal, MD, PhD, discussed what options physicians would choose when treating a patient with non–small cell lung cancer who tested positive for an EGFR exon 20 insertion. 

Will Pass, DVM

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