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Authors

Robert Jotte, MD, PhD, is a medical oncologist/hematologist at Rocky Mountain Cancer Centers.

Robert Jotte, MD, PhD, discusses findings from the phase 3 KRYSTAL-12 study evaluating adagrasib in KRAS G12C-mutated NSCLC. 

Adagrasib Demonstrates Superiority in KRAS G12C NSCLC

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

Targeted Pulse

Adjuvant/Neoadjuvant Advances in Lung Cancer

The 22nd Annual Winter Lung Cancer Conference® will explore developments in early-stage, locally advanced, and metastatic lung cancer, highlighting key advances in neoadjuvant/adjuvant immunotherapy combined with chemotherapy for patients with early-stage non–small cell lung cancer (NSCLC). The conference, scheduled for January 31 to February 2, 2025, in Hollywood, Florida, is cochaired by Julie R. Brahmer, MD, MSc; Rogerio C. Lilenbaum, MD; and Mark A. Socinski, MD.

“This is a truly multidisciplinary conference that will bring together thoracic surgeons, radiation oncologists, and medical oncologists who treat patients across lung cancer settings,” Brahmer said in an interview with 

 “I think the most important advances we have seen recently are in early-stage NSCLC, with the advent of neoadjuvant immunotherapy plus chemotherapy.”

Brahmer is codirector, Upper Aerodigestive Department, Bloomberg~Kimmel Institute for Cancer Immunotherapy and director, Thoracic Oncology, at Johns Hopkins Medicine in Baltimore, Maryland.

The FDA Moves Obe-cel Forward For Relapsed/Refractory B-ALL

Obecabtagene autoleucel (obe-cel; Aucatzyl), a chimeric antigen receptor (CAR) T-cell therapy, has been approved by the FDA for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). This approval is based on data from the phase 1b/2 FELIX trial (NCT04404660), which were presented at the 

2023 American Society of Hematology (ASH) Annual Meeting and Exposition

In the study, the primary end point was overall remission rate as assessed by independent review and secondary end points were duration of remission, measurable residual disease -negative remission rate, safety, and CAR T expansion and persistence. Patients underwent lymphodepletion with fludarabine (4 doses of 30 mg/m²) and cyclophosphamide (2 doses of 500 mg/m²). Obe-cel was given as a split dose, targeting 410 x 10⁶ CAR T cells, on days 1 and 10, based on the bone marrow blast burden measured before lymphodepletion.

Transformative Therapies For Extensive-Stage SCLC


This year has brought exciting developments in the management of small cell lung cancer (SCLC), leading to transformative therapies and promising trial results. Ariel Lopez-Chavez, MD, discussed these advancements with Targeted Oncology

 (NCT05060016), the ADRIATIC (NCT03703297) study, and the IMforte (NCT05091567) study. He also addresses the next steps and emerging challenges that will drive these advancements forward.

“For years, the only things we had were topotecan and irinotecan, but as of May of 2020, we got the approval of lurbinectedin. Then more recently, we got the approval of tarlatamab in the second-line setting. Now, we have 4 agents. The use of these agents has been shifting to the newer agents, lurbinectedin and tarlatamab, because they have a better toxicity profile. It is very exciting to have more agents in this space now. The question [now] will be what to choose, in particular, between lurbinectedin and tarlatamab,” said Lopez-Chavez, medical oncologist, director of precision medicine and developmental therapeutics at Allegheny Health Network Cancer Institute, discussed recent developments in the SCLC space.

Evaluating How Apalutamide Improves Survival Vs Enzalutamide in mCSPC

According to real-world data, treatment with apalutamide (Erleada) improved survival compared with enzalutamide (Xtandi) at 24 months. Neal Shore, MD, FACS, offers an in-depth analysis of these real-world data, answering key questions and exploring next steps. Shore is United States chief medical officer of surgery and oncology at GenesisCare USA, and director of the Carolina Urologic Research Center in South Carolina.

“This was a retrospective, longitudinal cohort of patients, largely coming from the Flatiron registry, which is an electronic dataset and patient charts interrogated from January 1, 2013, through May 31, 2023,” Shore explained in the interview with Targeted Oncology

 “When we looked at important data metrics such as the date of death, their Social Security death index, and other confirmed sources, we took an analysis called an intention-to-treat approach. A Kaplan-Meier analysis used to describe the proportion of patients surviving 2 years, 24 months, postindex.”

LBL-034 Gains FDA Ground in Multiple Myeloma

The FDA has granted orphan drug designation to LBL-034, a humanized, bispecific T-cell-engaging antibody targeting GPRC5D and CD3 for the treatment of multiple myeloma. Investigators are evaluating the agent in a phase 1/2 trial (NCT06049290). Phase 1 will assess dose escalation and dose expansion, and phase 2 will evaluate efficacy. LBL-034 is the third GPRC5D-targeted CD3 T-cell engager in development, with increased potency, reduced risk of T-cell exhaustion, and lower cell death compared to others in its class.

“It is urgent to develop new and more effective treatment options. LBL-034 adopts a unique molecular design, and the preliminary clinical results indicate its promising antitumor efficacy and safety. We will expedite the clinical development of LBL-034 and strive to bring safe and effective treatment options to multiple myeloma patients around the world as early as possible,”said Charles Cai, MD, PhD, chief medical officer of Leads Biolabs, in a press release.

Thank you for joining us for this week’s 

In case you missed it, here is last week’s 

The 22nd Annual Winter Lung Cancer Conference® will explore advances in neoadjuvant/adjuvant therapies. The FDA has approved Obe-cel for R/R B-ALL, and new treatments in SCLC, lurbinectedin and tarlatamab, show promise. Apalutamide tops enzalutamide in real-world data for mCSPC, and LBL-034 gains orphan drug designation for multiple myeloma.

The Targeted Pulse: Discover Upcoming Meetings, FDA Action, and Key Insights in SCLC and mCSPC

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. 

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.

Robert Jotte, MD, PhD

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