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Ali Duffens, MD, is an internal medicine physician at Kaiser Permanente.

Ali Duffens, MD, discusses the relative effectiveness of different detection modalities in identifying breast cancer recurrences. 


Assessing Detection Modalities for Breast Cancer Recurrence

Ali Duffens, MD, discusses a study in which investigators assessed the mode of detection for breast cancer recurrence within an integrated health system by assessing the utility and outcomes of current surveillance guidelines recommended by the National Comprehensive Cancer Network. 


Study Evaluates Methods for Breast Cancer Recurrence Surveillance

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

Revolutionizing CLL Care With Targeted and Cellular Therapies

Cyrus M. Khan, MD, hematologist in the Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network, highlights some of the most recent and significant advancements in chronic lymphocytic leukemia (CLL) treatment.


In recent years, there have been significant advancements in non-chemotherapy treatments for CLL, including the approval of targeted therapies and immunotherapies. One major breakthrough, according to Khan, is the approval of chimeric antigen receptor (CAR) T-cell therapy for patients with CLL, especially those who have not responded to other treatments.

Bruton’s tyrosine kinase (BTK) inhibitors like ibrutinib (Imbruvica), zanubrutinib (Brukinsa), and acalabrutinib (Calquence) have been effective, but until recently, there were no options for patients who progressed on these drugs. Now, Khan explains that a new BTK inhibitor, pirtobrutinib (Jaypirca), offers an alternative for these patients, representing yet another significant progress in CLL treatment options.

We have had a lot over the last few years, a lot of advancements, [especially] as non-chemotherapeutic interventions are concerned. For example, we have had a lot of targeted agents that have been approved, a lot of immunotherapy. I think the newest advancement has been the approval of CAR T-cell therapy now for patients with CLL, which is the most sort of advancement.

We have also had BTK inhibitors like ibrutinib, zanubrutinib, and acalabrutinib for quite some time, and they’ve been very effective treatments. However, until recently, we didn’t have a solution for patients who progressed on those BTK inhibitors. Now, we have a new drug called pirtobrutinib, which works for patients who have progressed on any of the three BTK inhibitors. This allows patients to continue with an oral treatment option.

Then we never had a great cellular therapy option for patients who had progressed on the standard oral treatments and immunotherapies. Now, fortunately, CAR T-cell therapy is available for those patients as well, and it has been effective. This is a major breakthrough for patients with CLL.

Cyrus M. Khan, MD, highlights some of the most recent and significant advancements in chronic lymphocytic leukemia treatment.


Peers & Perspectives in Oncology: What options do the National Comprehensive Cancer Network (NCCN) guidelines prefer for this patient? 

We always try a clinical trial whenever you have a clinical trial available, but obviously that’s not always the case. Cabozantinib [Cabometyx], based on [findings from] the PAPMET study [NCT02761057], was compared with sunitinib [Sutent] and showed superiority, so it became the standard of care 4 or 5 years ago. Cabozantinib plus nivolumab [Opdivo] and lenvatinib [Lenvima] plus pembrolizumab [Keytruda] are the [more recent] preferred regimens.

Then we have very specific types, like hereditary leiomyomatosis with RCC [HLRCC]. Those specifically do well with erlotinib [Tarceva] and bevacizumab [Avastin]. This regimen came out of [findings from a phase 2 trial (NCT01130519)] about 5 years ago, and those patients specifically do well with this. Those patients are typically the ones who have a history of uterine fibroma or fibromas on their skin, so that could be a hint [because] in our case, they had [a family] history of fibroids. It raises the suspicion for HLRCC histology. There are other regimens [recommended], like everolimus/lenvatinib…but those are not the preferred regimens. There are other options if you have contraindication for immunotherapy, for example.

Could you describe the phase 2 KEYNOTE-B61 trial (NCT04704219)?

This clinical trial was presented at the [2023] American Society of Clinical Oncology Annual Meeting, combining pembrolizumab and lenvatinib in patients who had nccRCC, who were treatment naive and had locally advanced or metastatic disease with no prior therapies. They had measurable disease and good performance status. There were 158 patients, a sizable number of patients for nccRCC, yet it was a single-arm study. Those patients were given pembrolizumab at 400 mg every 6 weeks up to 2 years, along with lenvatinib at 20 mg [daily], which is the same dose that is [given in] clear cell RCC. The primary end point was overall response rate [ORR] per RECIST by blinded central review and multiple secondary end points included disease control rate, duration of response [DOR], and progression-free survival [PFS]. 

In the intention-to-treat population of 158 patients, the ORR was 50%; I found it quite surprising to see high responses in nccRCC [Figure

]. I was not expecting that when I first saw these data, and 8% of them had complete responses [CRs]. It’s a mixed bag of subtypes, including papillary [n = 93], chromophobe [n = 28], 20 unclassified, 6 with translocations, and [10 with] other subtype not specified. Papillary [histology] was in the majority of patients here, which makes sense.

I find it good to consider the more than 50% ORR. If you look at the depths of the response in the waterfall plot, the majority of patients had some shrinkage of their disease. [The depth of response was presented for] the papillary, the unclassified, and the chromophobe [histologies]. Despite the fact it’s a singlearm study with a smaller number of patients, I especially like to see this type of waterfall plot where the majority of patients are having some shrinkage of their disease, and some of these responses are durable.

 They are going beyond 12 months [median DOR, 19.5 months; 50.6% with 18-month or greater DOR].

 We do not have granularity on which ones are more aggressive. Are the aggressive ones responding more than the favorable [disease cases]? We did not have those data per se.

Looking at the PFS, the median in the total population was approximately 17.9 months.

 Interestingly, in the chromophobe [subgroup], it was about 26 months of median PFS. Median overall survival was not reached in [the total population or in] the papillary and the chromophobe [subgroups]. 

That was sufficient for the FDA to grant it as a label for firstline nccRCC, and it made it to the NCCN as a preferred regimen. Looking at the adverse event [AE] profile, we are experienced from clear cell RCC at utilizing this IO/TKI [immunotherapy plus tyrosine kinase inhibitor] regimen. [There is] nothing surprising: hypertension, diarrhea, hypothyroidism, hand-foot syndrome are the common AEs that you see with any TKI.

 [Although] they did document grade 4 AEs in 5 patients…no alarming AE profile was documented in this trial.

What data supported the other IO/TKI combination for nccRCC? 

The other clinical trial [was for] the combination of cabozantinib plus nivolumab. This is a slightly different design [but] still [a phase 2] single-arm trial [NCT03635892] in nccRCC. They allowed [patients who were] treatment naive or had 1 prior line of therapy; that’s the difference between the 2 trials. Here, the primary end point was ORR with multiple secondary end points…. This trial had 2 cohorts. Cohort 1 was papillary, unclassified, or translocation. That was 40 patients. Cohort 2 [for chromophobe histology] was closed early at 7 patients because of no signal [0% ORR].

In looking at the type of responses we are seeing, this is the unfortunate part of this clinical trial. Because it’s a rare disease, there is slow accrual, and then you have a mixed bag. You put everything in the same bucket: papillary, chromophobe…. They are all different [disease types], but given the rarity of these tumors, we still look at the data as an aggregate. To add on top of this, this trial allowed patients [treated in the] first line and second line. What I would take from this is that it’s reassuring to see the responses across the groups [ORR: 54%], despite the fact some of these numbers are small, like 2 patients [with translocation], 6 patients [unclassified], 32 patients [with papillary histology]. It’s reassuring to see a significant number of patients are benefiting from this combination. 

From the waterfall plot, the majority of them are having some shrinkage of their tumor, and with longer follow-up, many patients are beyond even 2 years. So [findings from] a smaller trial give us a hint that this is a regimen that is acceptable to use given the lack of large clinical trials.

If you look at the median PFS in the intention-to-treat population, it was 13 months, and in the first line, 11 months, and in the second line, 13 months.… It does not make sense that in the second line, they seem to do better, but you are looking at a smaller number of patients. Nevertheless, I think the signal is there, so it’s an acceptable regimen to use in your practice, especially extrapolating from another IO/TKI regimen showing interesting results. It’s reassuring to see that these data are not contradicting each other.

We are experienced in how to handle these AEs, nothing alarming here. It’s the same thing [as with lenvatinib/pembrolizumab]: fatigue, hand-foot syndrome, diarrhea, dry mouth, hypertension. We have seen it all in clinic. 

I don’t like to do cross-trial [comparisons]. My takehome [message] here is that it’s reassuring to see that these 2 regimens are not total opposites of each other. You’re seeing a 50% ORR with both regimens and quite good numbers of CR rates. This is almost mimicking the [data in] clear cell RCC, although I was not expecting to see the higher responses in nccRCC based on the biology of these different tumors.

How do you approach the dosing of the TKIs?

[Cabozantinib was given at] 40 mg; 60 mg in combination was not studied. Both [cabozantinib and lenvatinib] can be toxic at higher doses. In CheckMate 9ER [NCT03141177], cabozantinib was studied at 40 mg in combination with nivolumab. When it was studied in CABOSUN [NCT01835158] and METEOR [NCT01865747] on its own, it was studied at 60 mg. Almost universally, nobody tolerates 60 mg. With the combination, they went down to 40 mg, and in my practice, a lot of patients go down to 20 mg. They do not do well even on 40 mg. It’s the same thing with lenvatinib. We start at 20 mg with pembrolizumab, but we de-escalate to 14 mg or even 10 mg, and I have a few patients on 8 mg, because it can be rough. Usually, having a low threshold to hold the dose and lower the dose is key in order to keep the patient for a longer period on these treatments. 

We have reported real-world data with axitinib [Inlyta] and pembrolizumab 2 years ago, and what we have shown is the patients who have dose interruption and lower doses tend to do better in the long run.

 In your practice, don’t be afraid to lower the dose or give them a good period of interruption, especially in those patients who are responding well to the treatment, especially with cabozantinib, [which has] a longer half-life.

In what circumstances would lenvatinib plus everolimus be used?

[There was] another study that was testing lenvatinib/ everolimus. This was run prior to the IO/TKI combinations, and this was lenvatinib/everolimus as a first-line treatment for nccRCC. The number of patients for each disease group: 20 [papillary], 9 [chromophobe], and 2 for unclassified, so it was a smaller study here. The results were not as impressive as the IO/TKI combination, especially with papillary [histology], but 70% of them had stable disease.6 In the presence of the other IO/TKI regimen, this would be more of an alternative regimen, especially for those patients who are not fit for or have a contraindication to immunotherapy, like with autoimmune disease. This could be a fine alternative as a first-line treatment, but if they are fit to have an IO/TKI, I would go with that first.

Yousef Zakharia, MD, discussed some of the available combination therapies for non–clear cell renal cell carcinoma treatment.

Publications

Zakharia Evaluates Available Combination Options for Non–Clear Cell RCC

SH-105 is a ready-to-dilute formulation of a treatment for breast or ovary adenocarcinoma.

The new formulation offers clinicians and patients easier access and administration of the agent.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of June 29, 2024.

The FDA has accepted a new drug application (NDA) of SH-105, a ready-to-dilute formula of an existing treatment for adenocarcinoma of the breast or ovary. The PDUFA target action date is June 24, 2024.

“This innovative drug will offer hospital pharmacists and patients access to a differentiated, ready to administer, injectable product with unique characteristics that’s expected to facilitate rapid adoption once approved,” said Orlaith Ryan, chief technical officer and co-founder of Shorla Oncology, in a press release.

The original agent SH-105 improved upon was approved in the 1950s and has not been updated since, according to Ryan.

The ready-to-dilute formulation simplifies the drug reconstitution process, which can improve efficiency and reduce preparation risks for clinicians, therefore increasing satisfaction and safety for patients.

Shorla Oncology has several other agents in its development pipeline. SH-110 is an oral treatment for glioma, and the company has had a pre-investigational new drug application meeting with the FDA. SH-201 is an oral treatment for chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, and gastrointestinal tumors. The company plans to submit an NDA to the FDA for SH-201 in Q1 of this year. The company also manufactuers Jylamvo, the only approved, oral methotrexate solution for adults, and nelarabine, an injection for the treatment of T-cell ALL and T-cell lymphoblastic lymphoma.

REFERENCES:
1. Shorla Oncology announces FDA filing acceptance of new drug application for novel formulation to treat breast and ovarian cancer. News release. Shorla Oncology. January 9, 2024. Accessed January 9, 2024. 

2. Ireland’s Shorla nabs $8.3m to bring improved cancer meds to the U.S. News release. Fierce Biotect. June 3, 2020. Accessed January 9, 2024. 

3. Shorla Oncology. Accessed January 9, 2024. 

The FDA has approved the new drug application of a ready-to-dilute formulation of a treatment for breast and ovary adenocarcinoma. 

FDA OKs NDA for SH-105 in Breast and Ovarian Cancer

An accelerated approval was granted by the FDA to sacituzumab govitecan (Trodelvy) for the treatment of patients with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.

Data from the phase 2 TROPHY-U-01 trial (IMMU-132-06; NCT03547973) clinical trial served as the basis for the approval after sacituzumab govitecan achieved a confirmed objective response rate (ORR) of 27.7% (95% CI, 19.6%-36.9%). Responses observed with patients in the study included complete responses in 5.4% and partial responses in 22.3%. Responses were also durable with the median duration of response (DOR) being 7.2 months (95% CI, 4.7-8.6; range, 1.4+ to 13.7) with sacituzumab govitecan.

In the study, the use of sacituzumab govitecan was evaluated in 112 patients with locally advanced or mUC who received prior treatment with a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. The study followed a Simon 2-stage design and was 90% powered to reject the null hypothesis of an ORR of 12% or less. The agent was administered to patients at 10 mg/kg intravenously, on days 1 and 8 of a 21-day cycle.

Prior results from IMMU-132-01 showed an ORR of 31%, a median progression-free survival (PFS) of 7.3 months, and median overall survival (OS) of 16.3 months. The agent also appeared to have an acceptable safety profile.

Of the patients enrolled in the study, the median age was 66 years, with 23% of patients being 75 years of age or older. Notably, 78% of the population was male and 74% of patients were White. An ECOG performance status of 0 was observed in 28% of the population, and 72% had an ECOG performance status of 1. In terms of metastatic site, 62% of patients had visceral metastases, 40% had lung metastases, 28% had liver metastases, and the remaining 12% had other sites of metastatic disease.

Final analysis data showed that 14% of patients continued to receive treatment with sacituzumab govitecan after data cutoff. Most of the treatment discontinuations (66%) were related to disease progression. Discontinuation due to toxicity was also observed in 7% of patients. In addition, 3 percent of patients withdrew consent, and 3% died. The median time on treatment was 3.7 months.

In terms of safety, the most common adverse events (≥25%) reported with the agent include neutropenia, nausea, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain.

Sacituzumab govitecan is a Trop-2–directed antibody-drug conjugate. Approval of the agent was based upon the impressive tumor responses and DOR. For continued approval of this indication, the efficacy and safety of sacituzumab govitecan must be verified in the confirmatory phase 3 TROPiCS-04 trial (NCT04527991).

An accelerated approval was granted by the FDA to sacituzumab govitecan for the treatment of patients with locally advanced or metastatic urothelial cancer who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.










Ali Duffens, MD

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