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The FDA recently released 5 new draft guidance documents that promote broader patient eligibility for cancer clinical trials.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FDA Issues Draft Guidance to Broaden Clinical Trial Inclusion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

KEY TAKEAWAYS FROM ADITYA BARDIA, MD, MPH​, FASCO

Trastuzumab deruxtecan and sacituzumab govitecan can be given to patients with metastatic HER2-low breast cancer after endocrine therapy and chemotherapy.

Progression-free survival and overall survival favor trastuzumab deruxtecan over chemotherapy in HER2-low disease.

The DESTINY-Breast06 trial showed similar outcomes for HER2-low and HER2-ultralow disease.

A 52-year-old postmenopausal woman underwent breast-conserving surgery plus radiation therapy for pT2 N1 invasive ductal carcinoma of the right breast, grade 2, estrogen receptor (ER)–positive, progesterone receptor–positive, HER2 1+ by immunohistochemistry (IHC); 21-gene recurrence score: 27​.

She received dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and completed 10 years of tamoxifen.​

Five years later, she presented with disease recurrence in the liver, hormone receptor–positive, HER2-low, no actionable mutations on tissue next-generation sequencing​.

She received first-line letrozole plus ribociclib​ (Kisqali).

​She went on to receive ​fulvestrant for 6 months to disease progression in the bone and liver, then everolimus plus exemestane for 4 months to disease progression, followed by capecitabine for 6 months until disease progression.

Repeat circulating tumor DNA next-generation sequencing at each progression showed no actionable alteration.

Targeted Oncology: Do you consider this patient with metastatic breast cancer (mBC) to be eligible for sacituzumab govitecan (Trodelvy)?

If you look at the label of sacituzumab govitecan, it says 2 prior lines of systemic therapy; it does not say which kind, so you can make a case that the endocrine-based treatment was also systemic therapy.

 But the TROPiCS-02 trial [NCT03901339], which led to approval, required 2 prior lines of chemotherapy. Purely from a trial perspective, you should give 2 lines of chemotherapy, but in routine clinical practice, after capecitabine, that's when we consider trastuzumab deruxtecan [T-DXd] and sacituzumab govitecan.

Can you use T-DXd and sacituzumab one after another?

You can use them in sequence. There have been studies looking at the efficacy of one after the next,

 and there is some cross-resistance between these agents because they have similar payloads. In sacituzumab govitecan, SN38 is a topoisomerase-1 inhibitor. With T-DXd, deruxtecan is also a topoisomerase-1 inhibitor. But in some patients, it does work, and maybe in that setting, the disease progression is more because of the antigen, and so you're using a different antibody that works. But in some patients, you would see cross resistance.

If you look at our guidelines, you have both these drugs, T-DXd and sacituzumab govitecan. The guidelines would suggest T-DXd should be preferred for HER2-low disease.

 But if a patient is not a candidate for T-DXd, that's when you use sacituzumab. That could be either contraindication to T-DXd, or if a patient has HER2 IHC 0 mBC in that setting, you can use sacituzumab, and you can use them in sequence. If you start with one, you can use the other drug after that.

What data support the use of T-DXd in patients with HER2-low status?

This was based on DESTINY-Breast04 [NCT03734029], which looked at T-DXd vs standard chemotherapy for HER2-low, ER-positive breast cancer. It showed impressive improvement in both progression-free survival [PFS] and overall survival [OS]. We saw updated results last year, and essentially continue to see benefit with T-DXd vs a standard chemotherapy with median OS of about 24 months [vs 17.6 months for chemotherapy; HR, 0.69; 95% CI, 0.55-0.87].

 That's 2 years in the second line [and beyond] setting.

At least in DESTINY-Breast04, HER2 IHC 1+ vs 2+ didn't matter. We saw similar results, and in DESTINY-Breast04, any prior HER2-low specimen was allowed. That could be primary breast cancer. It could be the first metastatic [biopsy] specimen. Any prior specimen that was HER2-low was allowed, and they saw similar benefit. In terms of safety, the main adverse events [AEs] with T-DXd are neutropenia, alopecia, nausea, and then pneumonitis.

What is the significance of the DESTINYBreast06 trial (NCT04494425) in mBC?

DESTINY-Breast06 also included HER2-ultralow, which is IHC 0+, so just some cells with HER2 expression. The other big difference was it did not require prior chemotherapy for metastatic disease. The comparator was capecitabine, which was 60% in this trial, or taxanes.

It showed results somewhat similar to DESTINY-Breast04, maybe a bit less in terms of HR, but still meaningful [in the HER2-low subgroup]. The HR was 0.62 [95% CI, 0.51-0.74; 

 < .0002] and a 5-month improvement in PFS [median, 13.2 months vs 8.1 months with chemotherapy].

Then if we combine both HER2-low and -ultralow, in the intent-to-treat population, there were very similar results [PFS HR, 0.63; 95% CI, 0.53-0.75; 

 < .0001]. In terms of OS, there was a trend towards improvement in OS [HR, 0.83; 95% CI, 0.66-1.05] but the results are not mature at this time.

If we just look at HER2-ultralow, there were very similar results, improvement in PFS with a delta of about 5 months [median, 13.2 months vs 8.3 months for chemotherapy; HR, 0.78; 95% CI, 0.50-1.21], and a trend towards improvement in OS as well [HR, 0.75; 95% CI, 0.43-1.29].

Then if you look at response rate, it was close to 60% overall response rate with T-DXd, even with HER2-ultralow. That’s why we feel that this drug works regardless of the amount of HER2 expression.

In terms of AEs, nausea is the most common, with alopecia, and some diarrhea as well. This is a setting where you should remember to get EKGs, because you can have decrease in left ventricle ejection fraction.

1. Trodelvy. Prescribing information. Gilead Sciences, Inc; 2023. Accessed November 13, 2024. 

2. Huppert LA, Mahtanai RL, Fisch SC, et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): updated data and subgroup analyses by age, sites of disease, and use of intervening therapies. 

. 2024;42(suppl 16):1083. doi:10.1200/JCO.2024.42.16_suppl.1083

3. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 6.2024. Accessed November 13, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

4. Modi S, Jacot W, Iwata H, et al. 376O - Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Updated survival results of the randomized, phase III DESTINY-Breast04 study. 

. 2023;34(suppl 2):S334-S335. doi:10.1016/j.annonc.2023.09.553

5. Curigliano G, Hu X, Dent RA, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06). 

. 2024;42(suppl 17):LBA1000. doi:10.1200/JCO.2024.42.17_suppl.LBA1000

During a Case-Based Roundtable® event, Aditya Bardia, MD, MS, FASCO, discussed data from the DESTINY-Breast04 and DESTINY-Breast06 trials for HER2-low breast cancer in the second article of a 2-part series.

HER2-Low and -Ultralow Populations Benefit from T-DXd in HR+ mBC

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.

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. 

Will Pass, DVM

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