A better understanding of endocrine therapy (ET) resistance mechanisms has guided the development of targeted combination therapies for HR-positive/HER2-negative (HR+/HER2–) breast cancer, but resistance evolution complicates long-term disease management.

The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have
become foundational in the first-line treatment of HR+/HER2– breast
cancer, significantly improving survival outcomes.

Emerging next-generation targeted therapies, such as capivasertib
and elacestrant, target resistance mechanisms like ESR1 mutations
and alterations in the PI3K/AKT/mTOR pathway. These biomarker driven
approaches are critical but require testing standardization
across institutions.

Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan, represent a paradigm shift in treating ET-refractory metastatic breast cancer, showing efficacy even in heavily pretreated populations.

Despite improved outcomes with targeted therapies and their combinations, challenges remain regarding their optimal sequencing and rechallenge strategies post progression in the HR+/HER2– breast cancer treatment algorithm.

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Targeted Therapies in HR+/HER2– Breast Cancer

Following in the footsteps of the cytokine interleukin (IL)-2, IL-15 affords investigators similar qualities as a target without the associated toxicities of its immunotherapeutic predecessor.

Because IL-15 represents a potential potent immune modulator, leveraging its ability to activate effector T and natural killer (NK) cells may rely on the development of immune cytokines with additional antibodies to enhance antibody-dependent cellular cytotoxicity.

IL-15 and IL-2 activate downstream JAK/ STAT signaling pathways through shared β and γ receptor subunits; however, distinctions between IL-2 and IL-15 become more evident in adaptive immune response and their role in the immunomodulation of T and NK cells in the tumor microenvironment (FIGURE).

 IL-15 has demonstrated similar receptor binding, biologic activity, and signaling as IL-2, but without the adverse effect (AE) profile, including the induction of severe capillary leak syndrome.

FIGURE. Interaction of IL-2 and IL-15 With Receptors and Down Signaling Pathways

One of the shortcomings with IL-15, however, is the short half-life because of its small molecular size. Investigators sought to optimize IL-15 with the development of fusion proteins with IL-15Rα bound by flexible linkers that enhance the affinity for IL-15βγ.1,2 This circumvents the need for dendritic cells expressing the subunit receptors for IL-15 to be in proximity for maximum efficacy.

Investigational superagonists have demonstrated preclinical effects in murine models including increased half-life from 7 to 20 hours, increased IL-15 potency, and serum stability, with detectability in patient serum up to 7 days after subcutaneous injection. Further, restricted tumor growth and improved median overall survival were also observed in breast and colon cancer tumors, with improved efficacy observed when combined with anti-CTLA or anti–PD-L1 therapies. In terms of hematologic models, when IL-15 was combined with anti-CD20 antibodies, NK cell responses were improved in murine B cell lymphomas.

Investigators have observed preclinical efficacy of IL-15–directed therapies in combination with other targeted therapies has paved the way for investigators to evaluate IL-15 superagonists in phase 1 and phase 2 trials.

N-803 (Anktiva) is a first-in-class IL-15 superagonist consisting of 3 key structural components: the cytokine (IL-15N72D), the cytokine fusion (IL-15Rα), and the antibody (IgG1 Fc). Specifically, the cytokine and antibody work in tandem to proliferate endogenous NK cells/CD8-positive T cells without inducing T-regulatory stimulation in the tumor microenvironment. Additionally, the IgG1 Fc has demonstrated the ability increase the agent’s half-life and increase honing to the CD16 receptors expressed on NK cells and macrophages.

Preliminary data from the phase 2 QUILT 3.055 trial (NCT03228667) demonstrated the tolerability of the IL-15 superagonist across multiple cohorts of patients who received N-803 in combination immune checkpoint inhibitors (ICIs) after prior treatment with ICIs.3 Specifically, among the 140 patients who received therapy, serious treatment-related AEs (TRAEs) were observed in 8% of patients, including respiratory failure in 1 patient that was grade 5 and attributed to N-803 and the ICI.

Investigators also reported that compared with standard chemotherapy-containing regimens, the investigative approach had lower rates of AEs. In terms of efficacy, 49% of individuals on the trial had stable disease (SD), with 36% having SD more than 2 months and 16% having SD more than 6 months. Overall, 13 patients had a partial response to therapy.

N-803 received a breakthrough therapy designation from the FDA in December 2019 for the treatment of patients with BCG-unresponsive non–muscle invasive bladder cancer following promising results from a phase 1/2 study (NCT02138734) of the agent in combination with BCG.

Data from the ongoing phase 2/3 QUILT-3.032 trial (NCT03022825) of the combination have met the primary end point. In updated data from cohort A of the trial presented at the 2021 American Urological Association Annual Meeting, the complete response (CR) rate was 72% (95% CI, 61%-81%) among the 81 patients enrolled.

 Additionally, investigators reported that patients who had a response had a 58.6% (95% CI, 43.1%-71.2%) probability of maintaining a CR for at least 12 months. At a median follow-up of 20.4 months, the median duration of CR was 19.9 months (95% CI, 7.8–not reached). As of data cutoff of May 19, 2021, 30% of patients had a durable response at 18 months.

Investigators aimed to curb the incidence of patients progressing to radical cystectomy. In the trial, 85% of patients were able to avoid cystectomy following administration of 50 mg of BCG plus 400 mg of intravesical N-803 weekly for 6 weeks. Of note, the patient population was heavily pretreated, with patients having received a median of 12 prior BCG instillations and a median of 5 prior transurethral resections of bladder tumors, as well as 42% of patients having received prior treatment with chemotherapy in addition to BCG.

In terms of safety, the combination was well tolerated, with no grade 4/5 AEs. Two patients experienced grade 3 TRAEs (urinary tract infection and arthralgia). The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

Combinations Fuel Progress in Pancreatic Cancer

Pancreatic cancer is notoriously difficul to treat. Investigators in the phase 2 QUILT-88 trial (NCT04390399) are hoping to elicit the activation of a patient’s entire immune system with a unique combination of low-dose chemoradiation, cytokine-induced NK-cell and T-cell activation, and PD-L1–targeted high-affinity NK cell (t-haNK) infusion. The QUILT-88 trial leverages N-803 in combination with standard-of-care chemotherapy, aldoxorubicin hydrochloride (a type II DNA topoisomerase inhibitor), stereotactic body radiation therapy, and an off-the-shelf PD-L1 t-haNK.

The study protocol was designed to evaluate the treatment across 3 cohorts stratified by line of the therapy (first, second, and third or later), with a primary end point of progression-free survival. Data from the cohort of 61 patients who received therapy in the third or later line were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The median overall survival (OS) in the overall cohort was 5.8 months (95% CI, 3.9-6.9). For those who received treatment with the investigational combination in the third line, the median OS was 6.8 months (95% CI, 5.0-9.8), which investigators noted more than doubled the median OS vs historical standards after second-line therapies. TRAEs were uncommon and occurred in 8% of patients, with no treatment-related deaths reported. Additionally, investigators noted that all treatments were administered in an outpatient setting.

Forward-Looking Prospects Include Lung and Breast Cancers

In patients with stage IIIB or IV non–small cell lung cancer (NSCLC), investigators hope to build on early synergistic effects of N-803 plus PD-1 inhibitors.

 Investigators of the phase 3 QUILT 2.023 trial (NCT03520686) will assess N-803 in combination with anti–PD-1 standard-of-care regimens pembrolizumab (Keytruda) with or without chemotherapy vs standard of care alone.

Additionally, in October 2021, the combination of N-803 and pembrolizumab was selected for investigation as part of the Lung Cancer Master Protocol, or Lung-MAP.9 The precision medicine trial is a collaboration between the National Cancer Institute, Southwestern Oncology Group Cancer Research, Friends of Cancer Research, the Foundation for the National Institutes of Health, and private companies. Investigators of the phase 2/3 trial (NCT05096663) will evaluate the safety and efficacy of the investigative combination vs investigator’s choice of docetaxel, gemcitabine, or pemetrexed in combination with ramucirumab (Cyramza). The trial is expected to enroll approximately 478 patients with advanced NSCLC.

Investigators also seek to capitalize on retreatment efficacy of N-803 by including it as a component of a chemoimmunotherapy backbone in the ongoing QUILT 3.058 trial (NCT04927884) in combination with sacituzumab govitecan-hziy (Trodelvy) for patients with triple-negative breast cancer who have had at least 2 prior therapies. N-803 will administered subcutaneously at 15 μg/kg with cyclophosphamide (25 mg) and PD-L1 t-haNK (approximately 2 × 109).

Knudsin KM, Hodge JW, Schlom J, Gameiro SR. Rationale for IL-15 superagonists in cancer immunotherapy. Expert Opin Biol Ther. 2020;20(7):705-709. doi:10.1080/14712598.2020. 1738379

Yang Y, Lundqvist A. Immunomodulatory effects of IL-1 and IL-15; implications for cancer immunotherapy. Cancers (Basel). 2020;12(12):3586. doi:10.3390/cancers12123586 

Wrangle JM, Awad MM, Badin FB, et al. Preliminary data from QUILT 3.055: a phase 2 multicohort study of N803 (IL-15 superagonist) in combination with checkpoint inhibitors (CPI). J Clin Oncol. 2021;39(suppl 15):2596. doi:10.1200/JCO.2021.39.15_ suppl.2596

ImmunityBio granted FDA breakthrough therapy designation for N-803 IL-15 superagonist in non-muscle invasive bladder cancer. News release. ImmunityBio. December 4, 2019. Accessed April 21, 2022. bit.ly/38XruU4

Chamie K, Chang S, Gonzalgo M, et al. Phase 2/3 clinical results of IL-15RAFC superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients. J Urol. 2021;206(suppl 3):e120-e121. doi:10.1097/JU.0000000000001977.05

Seery TE, Nangia CS, McKean HA, et al. Promising survival and disease control in third-line or greater metastatic or locally advanced pancreatic cancer patients following chemo-radiation and novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy. J Clin Oncol. 2022;40(suppl 4):582. doi:10.1200/JCO.2022.40.4_suppl.582

Wrangle JM, Velcheti V, Patel MR, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018;19(5):694-704. doi:10.1016/ S1470-2045(18)30148-7

QUILT 2.023: a study of N-803 in combination with current standard of care vs standard of care as first-line treatment for patients with stage 3 or 4 NSCLC. ClinicalTrials.gov. Updated April 4, 2022. Accessed April 21, 2022. https://clinicaltrials.gov/ct2/ show/NCT03520686

National Cancer Institute selects ImmunityBio’s N-803 IL-15 receptor agonist to combine with Keytruda in 700-site Lung-MAP clinical trial of a chemo-free therapy. News release. ImmunityBio. October 4, 2021. Accessed April 21, 2022. bit.ly/36z5Swq

Testing the use of combination immunotherapy treatment (N-803 [ALT-803] plus pembrolizumab) against the usual treatment for advanced non-small cell lung cancer (a Lung-MAP treatment trial). ClinicalTrials.gov. Updated October 27, 2021. Accessed April 21, 2022. https://clinicaltrials.gov/ct2/show/ NCT05096663

FDA authorizes ImmunityBio study of Anktiva and PD-L1 t-haNK to increase effectiveness of Trodelvy in triple-negative breast cancer. News release. ImmunityBio. June 15, 2021. Accessed April 21, 2022. bwnews.pr/3v5IekS

Following in the footsteps of the cytokine interleukin-2, IL-15 affords investigators similar qualities as a target without the associated toxicities of its immunotherapeutic predecessor.

Superagonists Pull IL-15 Into Focus  in Oncology Care

Data from the phase 2 ROCKstar trial demonstrated that belumosudil induced clinically meaningful, durable responses in patients with chronic graft-vs-host disease, irrespective of previous treatment received, severity of disease, and number of organs involved. Moreover, these findings supported the FDA approval of the agent for use in adult and pediatric patients 12 years and older with chronic GVHD following failure of at least 2 prior lines of systemic therapy.

The approval of the ROCK2 inhibitor affords investigators another option to fill the treatment void that exists for patients with disease progression following treatment with other available therapies including ibrutinib (Imbruvica) and ruxolitinib (Jakafi).

“Ibrutinib [was] the first approved therapy [for] this disease and was a great step forward for us; [however] it’s not effective in all patients,” said study investigator Corey S. Cutler, MD, MPH, FRCPC, in an interview with OncologyLive®. Cutler is an associate professor of medicine at Harvard Medical School and medical director of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

“Many patients who initially respond to ibrutinib eventually progress and require later [lines of] therapy. Having more than one option for these patients is really something that our patients need,” he said.

ROCK2 inhibition rebalances immune response to treat at the level of the germinal center by downregulating Th17 cells and upregulating regulatory T cells.2 Data from the ROCKstar study showed that patients who received belumosudil achieved a clinically meaningful response across all key subgroups. Investigators for ROCKstar examined the agent in 2 cohorts of patients—200 mg of belumosudil once daily and 200 mg of belumosudil twice daily.

In previously reported data, the response rates between the 2 arms were similar, and the FDA approved the 200-mg once-daily dose. Specifically, 65 patients received belumosudil 200 mg once daily, and overall response rate (ORR) was assessed through day 1 of cycle 7 per ROCKstar protocol. 

The ORR was 75% (95% CI, 63%-85%), with 6% being complete responses and 69% being partial responses.1 The median time to first response was 1.8 months (95% CI, 1.0-1.9), with a median duration of response of 1.9 months (95% CI, 1.2-2.9), which was determined as time of first response to progression, death, or new systemic therapies for chronic GVHD. In patients who achieved response (n = 49), 62% did not initiate a new systemic therapy or die for at least 12 months since response.

ORRs stratified by organ involvement, a subgroup analysis of interest, were recently published in Blood.2 The analysis included combined data from the 2 arms of the study (N = 132). In total 75% had involvement in joint/fascia, 10% lower gastrointestinal (GI), 17% upper GI, 55% mouth, 24% esophagus, 74% eyes, 83% skin, 10% liver, and 38% lungs. The ORR was greatest for those with joint/fascia involvement at 71%, with 51% complete responses and 20% partial responses. For patients with lower and upper GI involvement, the ORRs were 69% and 51%, respectively. Further, the ORRs were reported for mouth (55%), esophagus (45%), eyes (42%), skin (37%), liver (39%), and lungs (26%).

Across all study participants, failure-free survival rates at 6 and 12 months were 75% and 56%, respectively.

“[Similar to] any drug in GVHD that we have tested in the past, we tend to use these agents in patients who have very few options left for their therapy,” Cutler said. “The natural thing to think about for the compound—and really any other compound following development—is to look at its activity in earlier stages of chronic GVHD. [This includes] either frontline steroid failures or front line [in combination with] steroids, potentially even frontline [use] instead of steroids. There is always the idea of whether this is an appropriate agent to use for prophylaxis of chronic GVHD or not.”

Cutler noted that investigators are interested in examining the efficacy of the agent in subtypes of GVHD, including patients with fibrosis as one of their prominent features, because ROCK regulates multiple profibrotic processes including myofibroblast activation.2 “There stands to be at least a reasonable chance that this drug can reverse established fibrosis,” he said. “We would also like to see it tested in larger groups of patients with chronic GVHD–induced fibrosis to determine how effective it can be in reversing established fibrosis.”

The updated analysis demonstrated that the efficacy of belumosudil was maintained, regardless of previous treatment with ibrutinib (n = 46) or ruxolitinib (n = 38). The ORRs in the ruxolitinib and ibrutinib subsets were 68% (95% CI, 51%-83%) and 74% (95% CI, 59%-86%), respectively. Although belumosudil represents a treatment option for patients who experience failure of these agents, future head-to-head studies may provide insights to where this agent best fits into the treatment paradigm. 

“We would like to see this agent tested earlier in the treatment of patients with chronic GVHD, perhaps in direct comparison to other commonly used agents,” Cutler said. “There still will be a need for other agents in this space. Some patients will not respond to this drug, and others may require a combination of therapies to maximize the likelihood of successful chronic GVHD outcomes.”

FDA approves belumosudil for chronic graft-versus-host disease. FDA. Updated July 16, 2021. Accessed August 16, 2021. bit.ly/3mc5Sbg 2. 3. Cutler CS, Lee S, Arai S, et al. 

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study (KD025-213). Presented at: European Hematology Association 2021 Virtual Congress; June 7-9, 2021; Accessed August 16, 2021. bit.ly/3y6vzfr 

Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study. Blood. Published online July 15, 2021. doi:10.1182/blood.2021012021

Data from the phase 2 ROCKstar trial demonstrated that belumosudil induced  clinically meaningful, durable responses in patients with chronic graft-vs-host disease, irrespective of previous treatment received, severity of disease, and  number of organs involved. 

Belumosudil Expands Treatment Options for Chronic GVHD

The past year presented opportunities for innovative and collaborative change across the spectrum of oncology care, as investigators and institutions worked to adapt practice during the COVID-19 pandemic. Patients with lung cancer were identified as an at-risk group for developing severe complications as a result of SARS-CoV-2 infection, and thoracic oncologists were fast to respond with the establishment of the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). The global registry collected characteristics and outcomes of patients with thoracic cancers affected by COVID-19, providing oncologists with a database of knowledge for the treatment of similar cases in their clinics.

Data from the registry showed a 34.6% death rate (n = 66/191), with 52 (79%) deaths attributed to complications from COVID-19 only and 7 (11%) as cancer progression only. Further, 3 (5%) deaths were due to complications from COVID-19 and cancer progression.

Marina Chiara Garassino, MD, chief investigator of research for TERAVOLT, spoke with 

 about stepping up to meet this unprecedented challenge in thoracic oncology. 

Garassino, formerly with the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and now a professor in the Department of Medicine, Section of Hematology/Oncology, at the University of Chicago Medicine in Illinois, also discussed the revolution in lung cancer treatment, the COVID-19 pandemic, and what 2021 holds for the field.

In the past decade, patients with lung cancer have benefitted from several new treatment avenues, including immunotherapy and targeted treatments. Where does the field stand now?

Throughout my career, I’ve been a part of many studies that have advanced the field, including the identification of patients who are good candidates for targeted-agent therapies for genetic alterations. I was an investigator on 2 trials–CheckMate 017 [NCT01642004] and CheckMate057 [NCT01673867]–the results of which showed for the first time the effectiveness of immunotherapy [in non–small cell lung cancer]. Additionally, results of the KEYNOTE-189 trial [NCT02578680] showed that immunotherapy and chemotherapy together were superior to chemotherapy alone.

Now oncologists have multiple avenues to treat patients with lung cancer, including targeted therapies for many patients who have never smoked and chemotherapy combined with immunotherapy for patients without targetable alterations. Survival rates have increased, and many patients live several years. 

That said, the next big unmet need is figuring out how to overcome resistance to these therapies. To treat patients with lung cancer, it is important to have multidisciplinary teams like we have at UChicago Medicine, where specialists in different fields share the best treatment strategies for every single patient.

COVID-19 has been particularly tough on patients with lung cancer, and you made headlines in 2020 with the TERAVOLT registry. Can you expand on how the registry came to be?

When the pandemic began, I was in Milan. The city was totally unprepared, and we were hit really hard. I sent an email to all my friends in the field around the globe saying that they needed to be prepared, because the virus would spread everywhere. I said we needed to collect data to help cancer patients. In 1 week, we were able to write the protocol, get IRB [institutional review board] approval, and share the protocol with 220 centers around the world. We were able to present our f irst data within a month, which showed that patients with thoracic cancer with COVID-19 had a 32% mortality rate, higher than other patients with cancer. The community of oncologists came together and ultimately collected data on more than 1500 patients. This information helped us continue to treat our patients during the pandemic. We were also able to demonstrate that immunotherapy and targeted treatments did not worsen infections.

What does the TERAVOLT research mean for patients with thoracic cancer in 2021? 

We issued a call to action to the World Health Organization and other agencies to advocate for early vaccinations for patients with thoracic malignancies. [The information will also allow us to] better treat these patients if they do get COVID-19. It was a wonderful academic effort and incredible opportunity, and now we are working on the final paper of our results.

What does 2021 hold for the future of lung cancer research? 

This is a transition year. Of course, we want the survival rate to be 100% and we don’t want patients to become resistant to therapies. Several things are at the forefront now. 

The research will focus on putting the treatments in the correct sequence. Another big [area of] development this year will be in neoadjuvant therapy. We are going to continue to find more targeted agents to overcome this resistance. Cancer metabolism will play a big role. 

For immunotherapies, we will not just target T cells, but also macrophages and other components of the immune system. Also, vaccines and cellular therapies are now emerging. Patients must be aware of the multiple possibilities to treat lung cancer, and they must be active in selecting the right treatments based on their desires and needs.

You recently moved to University of Chicago Medicine. How will that affect your research?

I’m excited to be a part of the University of Chicago Medicine Comprehensive Cancer Center. I love the diversity and the tradition of research and innovation. I’m looking forward to working with colleagues in different fields. I’m interested in the idea of immune metabolism to shape and create the best condition for immunotherapy. I’m also looking forward to doing more research in artificial intelligence to improve early diagnosis and personalized medicine.

When I first started in this field, my friends told me I was treating a dreadful disease because many of my patients died. But throughout my career, I have seen a revolution in treatments. I see patients living longer. It’s been incredible to dedicate my life to this.

Garassino MC, Whisenant JG, Huang LC, et al; TERAVOLT Investigators. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. 

. 2020;21(7):914-922. doi:10.1016/S1470-2045(20)30314-4

Patients with lung cancer were identified as an at-risk group for developing severe complications as a result of SARS-CoV-2 infection, and thoracic oncologists were fast to respond with the establishment of the Thoracic Cancers International COVID-19 Collaboration. 

Oncology Live® Staff

Articles

Targeted Therapies in HR+/HER2– Breast Cancer

Superagonists Pull IL-15 Into Focus in Oncology Care

Belumosudil Expands Treatment Options for Chronic GVHD

Garassino Highlights What’s In Store for Lung Cancer