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Joseph A. Sparano, MD, who recently gave a talk during the 19th Annual School of Breast Oncology, discusses prolonging responses to therapy in patients with advanced breast cancer. 


Prolonging Responses in Locally Advanced Breast Cancer

Joseph A. Sparano, MD, discusses how identifying the risk of recurrence in patients with breast cancer can help inform treatment decisions.

Determining Risk of Recurrence in Patients With Breast Cancer Could Inform Treatment Decisions

The Evolution of Endocrine Therapy in Breast Cancer

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

Harnessing the power of the immune system has emerged as a key approach in addressing T-cell malignancies, with efforts to leverage the immune system leading to significant improvements beyond the traditional scope of surgery, radiation therapy, and chemotherapy.

In a presentation at the Twelfth Annual Meeting of the Society of Hematologic Oncology, 

, provided an overview of immunotherapies in T-cell lymphomas: those targeting surface antigens and those targeting immune checkpoints. In the immune checkpoint category, there are T-cell checkpoints and macrophage checkpoints.

“Most of our experience with T-cell lymphoma has been with therapies that target PD-1 and PD-L1 inhibitors, and several clinical trials have been performed evaluating single agents,” Barta, leader, T-Cell Lymphoma Program, Abramson Cancer Center, University of Pennsylvania in Philadelphia, said. “We have seen modest responses that may depend on the [T-cell lymphoma] subtypes,” Barta added.

Phagocytosis is another way the immune system controls cancer, primarily through macrophage activity and controlled by the promacrophage signal, “EAT ME,” and the antiphagocytic signal, “DON’T EAT ME.”

Treatments that target surface antigens in T-cell lymphomas include monoclonal antibodies, antibody-drug conjugates (ADCs), and recombinant fusion proteins. Among monoclonal antibodies, agents that have been evaluated include 

mogamulizumab-kpkc (Poteligeo®; Kyowa Kirin)

alemtuzumab (Campath®; Millennium and ILEX),

daratumumab (Darazlex®; Johnson & Johnson Innovative Medicine)

brentuximab vedotin (Adcetris®; Seagen) 

denileukin diftitox-cxdl (Lymphir™; Citius Oncology)

Turning to chimeric antigen receptor (CAR) T-cell therapy, “though promising, especially in B-cell lymphomas,” Barta said, “the approach does have its challenges in T-cell lymphomas, primarily because the antigens that are being targeted are also shared by normal T cells.”

Cancer cells that share the same antigen can cause CAR T cells to attack each other and normal T cells, resulting in CAR T-cell fratricide and T-cell aplasia.

Another challenge with the manufacture of CAR T cells is reduced expansion and exhausting the T cells, resulting in a less effective product. “There is also the theoretical concern about contamination, and this can result in CAR T cells developing chemoresistance or becoming immunotherapy resistant,” Barta said.

There are several strategies to address these challenges. “One option is to reduce the expression of the antigen that you're targeting on the CAR T cells, and that can be done, for example, by protein expression blockers that inhibit the trafficking of the antigen to the cell surface,” Barta said.

Another option is to knock out the gene that is responsible for expression of the antigen. Switches can be introduced to turn on or turn off the gene expression. “For example, you can switch off the antigen expression during manufacturing and then, so that fratricide does not occur, switch it back on,” Barta continued.

Another option is to select T cells that do not express the antigen that is being targeted. “CD7 is not expressed in about 90% of normal T cells, and those can be selected to then introduce the CAR among those that are negative on the antigen,” Barta said.

Several studies have explored these strategies. CD30 is a transmembrane glycoprotein belonging to the tumor necrosis factor receptor superfamily. Ramos et al,

 conducted a phase I dose-escalation study in which 9 patients with relapsed/refractory Hodgkin lymphoma or anaplastic large cell lymphoma were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR. Further, Lu et al,

demonstrated that naturally selected 7CAR (NS7CAR) T cells from bulk T cells were able to overcome major fratricide by minimizing accessible CD7 epitopes.

Another notable target is CD70. For example, Barta highlighted an allogeneic product that disrupts expression to prevent any graft-vs-host effect that has promising results shown in the COBALT-LYM trial (NCT04502446), an open-label, multicenter, global study evaluating the safety and efficacy of CTX130.

Another trial that evaluated the TRBC1-directed CAR T-cell therapy was the phase 1/2 LibrA T1 study (NCT03590574), which has demonstrated the ability to produce responses among patients with relapsed/refractory peripheral T-cell lymphoma.

“We are excited to see these come to fruition,” Barta said.

T-cell malignancies have been associated with poor prognosis, “but leveraging the immune system has led to significant improvements in outcomes. The administration of cellular therapy has ushered in a new era for approaches in T-cell lymphoma,” Barta concluded.

1. Barta SK. The Promise of Immunotherapies in T-Cell Lymphoma. Presented at: 12th Annual Meeting of the Society of Hematologic Oncology (SOHO 2024). September 4-7, 2024. Houston, TX.

2. Kelley SM, Ravichandran KS. Putting the brakes on phagocytosis: "don't-eat-me" signaling in physiology and disease. 

. 2021;22(6):e52564. doi:10.15252/embr.202152564

3. Ren A, Tong X, Xu N, Zhang T, Zhou F, Zhu H. CAR T-cell immunotherapy treating T-ALL: challenges and opportunities. 

. 2023;11(1):165. doi:10.3390/vaccines11010165

4. Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. 

. 2017;127(9):3462-3471. doi:10.1172/JCI94306

5. Lu P, Liu Y, Yang J, et al. Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase 1 clinical trial. 

. 2022;140(4):321–334. doi:10.1182/blood.2021014498

6. Iyer SP, Sica RA, Ho PJ, et al. The COBALT-LYM study of CTX130: a phase 1 dose escalation study of CD70-targeted allogeneic CRISPR-Cas9–engineered CAR T cells in patients with relapsed/refractory (R/R) T-cell malignancies. 

. 2022;6:163-164. doi: 10.1097/01.HS9.0000843940.96598.e2

7. Autolus Therapeutics presents positive results from AUTO4 in relapsed/refractory TRBC1-positive peripheral T-cell lymphoma. News release. Autolus Therapeutics plc. June 16, 2023. Accessed September 4, 2024. 

Conference News

Immunotherapy Opens a “New Era” in Treating T-Cell Malignancies

The FDA has given accelerated approved to tarlatamab-dlle (Imdelltra), a bispecific T-cell engager (BiTE) for the treatment of small cell lung cancer (SCLC) that has progressed on or after platinum-based chemotherapy.

The approval is based on findings from the phase 2 DeLLphi-301 study (NCT05060016).

This marks the first BiTE therapy to be approved for the treatment of a major solid tumor.

The FDA granted accelerated approval to tarlatamab for the treatment of patients with SCLC that has progressed on or after platinum-based chemotherapy, making it the first BiTE approved for a major solid tumor and the first therapeutic option for the treatment of extensive-stage SCLC.

The approval is supported by data from the phase 2 DeLLphi-301 trial that were published in the 

2023 European Society of Medical Oncology Congress

. The objective response rate for patients treated with 10 mg of tarlatamab was 40% (97.5% CI, 29%-52%) vs 32% (97.5% CI, 21%-44%) with the 100-mg dose. Fifty-eight percent of patients in the 10-mg group responded to tarlatamab for at least 6 months compared with 61% in the 100 mg group.

Among patients treated with either dose level, the median progression-free survival was 4.9 months (95% CI, 2.9-6.7) and 3.9 months (95% CI, 2.6-4.4), respectively, and the median overall survival (OS) was 14.3 months (95% CI, 10.8-not estimable [NE]) and NE (95% CI, 12.4-NE). While OS data were not mature, at the last follow-up, 57% of patients in the 10 mg group and 51% of those in the 100 mg group were still alive.

“Tarlatamab has shown manageable safety profile and activity,” Luis Paz-Ares, MD, PhD, chair of the medical oncology department at the Hospital Doce de Octubre, associate professor at the Universidad Complutense, and head of the lung cancer unit at the CNIO in Madrid, Spain, said during the presentation of the data. “We have chosen 10 mg to go to further development.”

The most common treatment-emergent adverse event (TEAE) was cytokine release syndrome (CRS), which occurred in 49% of patients in the 10-mg group and 61% in the 100-mg group. CRS primarily occurred during the first cycle and was mostly grade 1 or 2. Grade 3 CRS was seen in 5.7% of patients treated with the 100 mg dose.

TEAEs that led to either dose interruption or reduction were reported in 14% of patients treated with the 10 mg dose and 29% in those treated with the 100 mg dose.

 to the biologics license application of tarlatamab. In October 2023, tarlatamab was granted breakthrough therapy designation.

“Tarlatamab represents a new immunotherapeutic approach for small cell lung cancer, a tumor type that is characterized by an immunosuppressive microenvironment,” the researchers wrote in the simultaneous publication of the findings in the 

1. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News release. US FDA. May 16, 2024. Accessed May 16, 2024. 

2. Paz-Ares L, Ahn M, Felip E, et al. Tarlatamab for patients (pts) with previously treated small cell lung cancer (SCLC): Primary analysis of the phase II DeLLphi-301 study. Presented at: European Society for Medical Oncology Congress 2023; October 20-24, 2023; Madrid, Spain. Abstract LBA92.

3. FDA grants priority review to Amgen’s tarlatamab application for advanced small cell lung cancer. News release. Amgen. December 13, 2023. Accessed April 19, 2024. 

4. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. 

. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980

The FDA accelerated approval of tarlatamab makes it the first bispecific T-cell engager therapy for a major solid tumor.

Joseph A. Sparano, MD

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