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Ishwaria M. Subbiah, MD, MS, FASCO, is the executive director of Cancer Care Equity & Professional Wellness with Sarah Cannon Research Institute, and medical director of Supportive Care Oncology, Health Equity & Professional Well-being with The US Oncology Network.

Cancer care disparities exist for underrepresented groups due to limited access to healthcare, clinical trials, and cultural barriers, but solutions like telemedicine and improved communication are emerging.

Insights and Innovative Approaches to Addressing Disparities in Cancer Care

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 73-year-old man presented with urinary retention, fatigue and decreased appetite​.

He had family history of prostate cancer​

He is active and is very involved in his grandchildren’s activities​

Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 8 (4+4) with disease in 10/12 cores.​

Prostate-specific antigen (PSA), 150 ng/mL; hemoglobin (Hb), 9.7 g/dL; absolute neutrophil count (ANC), 1.9​

Patient is diagnosed with localized high-grade prostate cancer​

He undergoes robotic radical prostatectomy with subsequent PSA decrease (0.2 ng/mL)​

CT and bone scans showed no residual disease​

Patient complains of right hip pain and abdominal pain​

Imaging with CT and bone scan showed multiple metastatic bone lesions in the pelvis and diffuse liver lesions​

Patient is diagnosed with metastatic prostate cancer​

He wishes to receive oral treatment/avoid chemotherapy and minimizing adverse events (AEs) is very important to him​

: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic castration-sensitive prostate cancer (mCSPC)?

 The NCCN guidelines for disease [with at least 1 metastasis] for mCSPC, are based on level 1 evidence that androgen deprivation therapy [ADT] should be used with 1 of these 4 agents. The apalutamide [Erleada] and enzalutamide [Xtandi] can be used for any patient, irrespective of disease volume.

 Docetaxel, at least in the CHAARTED study [NCT00309985], was indicated for high-volume disease, as it was in our patient here, and it was a selection [in the poll].

Abiraterone [Zytiga] was approved based on the LATITUDE study [NCT01715285], which only enrolled high-risk patients.

 So they were high-risk, [which is] very similar to high volume, except the threshold for bone disease is 3 or more bone metastases, with 1 outside of the axial skeleton. The patient had to have either visceral disease or a Gleason score of at least 8. Most of the patients who have high volume have high risk, and vice versa.

I want to emphasize that in patients who are presenting with metastatic disease with their primary tumor, 

 disease—if they have oligometastatic or low-volume disease—they should receive radiation to the primary tumor for an overall survival benefit. That was shown in the STAMPEDE [NCT00268476] and HORRAD trials,

 and in STAMPEDE there was an 8% absolute improvement in in 3-year survival with radiation to the primary tumor.

 The rationale for that is that the primary tumor represents a continued source of metastases, and we know from autopsy series when we sequence multiple metastases from a patient who’s succumbed to prostate cancer and we create a genetic tree; what we can see is that metastases are derived from the prostate, but can metastasize back to the prostate and then back out again. So, there is a rationale to remove the prostate, and there’s now empiric evidence to establish that it improves overall survival.

Low-volume disease is defined as not being high volume. High volume would be 4 or more bone metastases. If it were 3 or fewer, then we’d call that low volume.

How did the 4 approved therapies perform in clinical trials?

The hazard ratios for [abiraterone, enzalutamide, and apalutamide] are very similar.

 In the CHAARTED study, the hazard ratio was also in the 0.6 range for docetaxel, and that was for high volume disease.

 And, the enzalutamide and apalutamide both show, if anything, slightly more benefit for the patients with high-volume disease.

 So, if a patient has high-volume disease, there is no requirement to use [docetaxel] chemotherapy. You can use, with similar efficacy, 1 of the hormonal agents. AEs leading to discontinuation were slightly higher with chemotherapy.

 These are all fairly well-tolerated agents.

What practical considerations are there for physicians prescribing the 4 approved agents for mCSPC?

Abiraterone and methylprednisone is indicated for metastatic castration-resistant prostate cancer [mCRPC] and mCSPC.

 Apalutamide is indicated for mCSPC and nonmetastatic CRPC.

 and enzalutamide is mCRPC, mCSPC, as well as nonmetastatic CRPC.

I would emphasize with abiraterone, you do have mineralocorticoid excess.

 Adrenal insufficiency would be attributable to the prednisone and not abiraterone; the drug does not cause adrenal insufficiency. It inhibits CYP17 even in humans that have complete absence of CYP17 due to a congenital adrenal hyperplasia, they do not develop adrenal insufficiency, they only develop mineralocorticoid excess.

With enzalutamide and apalutamide, since these are older patients, I think you have to be careful with predisposing factors for seizures, because they both can cause seizures.

 Patients who had predisposing factors for seizures such as stroke, transient ischemic attack, and prior seizure were excluded from the studies.

 I always ask my patients about that, and let them know about of about a 0.5% risk of seizure.

 Risks of falls and fractures are also relevant in apalutamide and enzalutamide, because they’re more common in this population in general.

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2022. Accessed March 17, 2022. https://bit.ly/36tWz0j

2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. 

2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657

3. Docetaxel (Taxotere). Prescribing information. Sanofi; 2020. Accessed March 17, 2022. https://bit.ly/3CPEQwF

4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. 

 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

5. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. 

. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3

6. Boevé LMS, Hulshof MCCM, Vis AN, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: Data from the HORRAD trial. 

2019;75(3):410-418. doi:10.1016/j.eururo.2018.09.008

7. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer.

2019;381(1):13-24. doi:10.1056/NEJMoa1903307

8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. 

2019;381(2):121-131. doi:10.1056/NEJMoa1903835

9. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. 

 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

10. Armstrong AJ, Iguchi T, Azad A, et al. Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial. 

 2022;40(suppl 6):115. doi:10.1200/JCO.2022.40.6_suppl.115

11. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. 

2013;14(2):149-158. doi:10.1016/S1470-2045(12)70560-0

12. Abireterone acetate (Zytiga). Prescribing information. Janssen; 2020. Accessed March 17, 2022. https://bit.ly/3tnFOgg

13. Apalutamide (Erleada). Prescribing information. Janssen; 2018. Accessed March 17, 2022. https://bit.ly/3CQGFcN

During a live virtual event, Matthew B. Rettig, MD, discussed the guidelines and practical considerations for giving the 4 approved agents for metastatic castration-sensitive prostate cancer.

Ishwaria M. Subbiah, MD, MS, FASCO

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