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Radiation therapy is a critical component of cancer care that is currently being used in approximately 50% of all patients with cancer.

 For all treatment sites, there is a delicate balance between treating the cancer cells with a dose of radiation high enough to kill the entire tumor and minimizing the impact to surrounding normal tissue to reduce adverse effects (AEs).

Technology has progressed significantly, allowing for better targeting of conventional radiation treatment using x-rays or photons. Radiation therapy comes in many forms, including photons, radioactive sources or drugs, or particle therapy, such as proton beam radiation. Numerous studies have demonstrated benefits in terms of reducing toxicities associated with chemoradiotherapy treatments by treating patients with proton as opposed to photon radiation therapy, without compromising tumor control.

Proton beam radiation therapy is unique compared with conventional or photon radiation therapy because there is no exit dose of radiation. With proton beam radiation therapy, the highest dose is delivered at the end of the beam (Bragg peak) and has a sharp falloff, which allows us to “paint” the target, minimizing radiation exposure to healthy tissues surrounding the tumor. Proton therapy can also be delivered on the millimeter scale using pencil beam scanning (PBS), which ensures precise treatment in the desired areas. Because of the sharp dose falloff, extra care must be taken during treatment to account for changes in the tumor, such as tissue swelling, tumor shrinkage, and/or a shift in its location due to weight loss during treatment, in the path of beam to ensure the Bragg peak remains in the target region. Thus, patients undergoing proton therapy may require additional scans and potential changes to their treatment plan over the course of their therapy to account for any anatomical changes.

Despite advances in technology, equitable access to proton therapy is a challenge. A retrospective study by Nogueira et al of all patients in the National Cancer Database treated with proton beam therapy from 2004 to 2018 revealed that Black patients were less likely to be treated with proton beam therapy compared with White patients (OR, 0.67; 95% CI, 0.64-0.71).

In August 2019, the New York Proton Center (NYPC) opened its doors in East Harlem as a consortium effort between 3 premier academic institutions in New York, New York: Montefiore Health System, Memorial Sloan Kettering Cancer Center, and Mount Sinai Health System. As the only proton beam treatment facility in the state of New York and one of the busiest proton centers in the country, the NYPC has treated nearly 5000 patients. Prior to the opening of the NYPC, individuals had to travel to New Jersey or Massachusetts, to receive this type of treatment, which was cost and time prohibitive.

Now through the NYPC, we are providing more patients with access to top-quality cancer care, particularly historically underrepresented populations, such as our Bronx community. Collaborative partnerships like the NYPC not only benefit people in the communities we serve, but they also make sense from an economic perspective. The expenditures for cancer treatment for a recurrent cancer are close to 6 times what we spend the first time around, and cure rates are more than 8 times lower.

Proton therapy was first approved by the FDA for human treatment in 1988. Only 1 center in the United States was providing this cutting-edge treatment before 2001. Since then, 44 other centers have opened across the country, with more in development.

Due to the relative nascency of this technology and lack of robust clinical trials, the American Society for Radiation Oncology published preliminary guidelines for conditions that may necessitate proton beam therapy. Specific conditions listed in these recommendations include reirradiation, pediatric patients, ocular tumors, skull base tumors, malignant or benign primary central nervous system tumors, retroperitoneal sarcomas, advanced stage cancers of the head and neck, pelvic tumors with significant nodal disease, and patients requiring craniospinal irradiation. Additionally, primary cancers of the nasopharynx, nasal cavity, paranasal sinuses, esophagus, mediastinum, mesothelioma, hepatocellular, and intrahepatic biliary cancers are included.

Ultimately, any patient for whom a plan with conventional photon therapy cannot be generated with acceptable radiation doses to surrounding tissues, which is relatively common for those with head and neck cancers, is recommended to receive proton beam therapy. The Department of Radiation Oncology at Montefiore Einstein Comprehensive Cancer Center (MECCC) routinely refers these cases to the NYPC under the care and supervision of their MECCC radiation oncologist. For example, we recently treated a young patient with classic Hodgkin lymphoma that abutted the left atrium of the heart. The tumor partially responded to initial chemotherapy but also required radiation therapy. Because of his young age and the proximity of the tumor to his heart, he was referred to NYPC where we generated a comparison plan using conventional radiation techniques, which clearly demonstrated that protons would reduce the radiation dose to the heart by approximately 50% and to the spinal cord by one-third. Although both photon and proton treatments would have treated this patient’s tumor with equal clinical efficacy, the advantage of proton treatment was that it could potentially reduce late toxicities, such as heart disease, spinal cord injury, and/or pulmonary toxicity.

Most patients we refer to the NYPC do not have metastatic disease, but there are some indications for proton therapy in the metastatic disease setting. For example, a patient with a history of locally advanced rectal cancer who had previously been treated with chemotherapy, radiation, and surgery developed a single, large metastasis in the liver 4 years later. After discussion with our colleagues and the patient, we referred him to the NYPC to deliver radiation therapy that could better spare his normal, uninvolved liver. He is now more than 1 year post treatment, and his tumor is shrinking without evidence of further disease. Another patient who had been diagnosed and treated for her primary cancer developed a solitary metastasis in her right nasal cavity 3 years later, which progressed through systemic therapy. She underwent surgical debulking, as the entire tumor was not able to be removed due to proximity to her brain and eyes, and she was recommended for postoperative radiation. 

Building on the activities taking place at the NYPC, MECCC participates in more than 20 open proton clinical trials, including investigator-initiated trials and national research group trials. We are also leveraging computational modeling to evaluate the benefits of treatment and potential AEs.

In 2019, we used an advanced computational model to evaluate treatment for people who have oropharyngeal cancer and determined that proton therapy improves quality-adjusted life years in these patients, mostly due to reductions in long-term complications such as difficulty or pain with swallowing and dry mouth. The benefit of proton therapy in this model was especially apparent in younger patients with minimal smoking history (no more than 10 years) whose oropharyngeal tumors were driven by human papillomavirus (HPV).

A separate computer model was devised to determine the individual quality-of-life benefit and cost-effectiveness of proton therapy for patients with oropharyngeal cancer. Findings obtained with the model showed that patients whose tumors were HPV mediated and required radiation to both sides of the neck had the most cost-effective benefit with proton therapy when compared with those whose tumors were not HPV mediated or who only required radiation to 1 side of the neck.

The NYPC is also studying a specific use of proton beam therapy, called FLASH proton therapy, which can further decrease the risks to surrounding normal tissue by manipulating the rate of dose delivery to ultrahigh rates more than 100 times that of conventional treatments, potentially decreasing normal tissue injury and/or increasing tumor control. Many studies utilizing FLASH proton therapy use transmission beams that minimize risk of potential uncertainty by placing the Bragg peak outside the body and utilize the entry pathway only for treatment. PBS Bragg peak FLASH utilizes the same technique described above that we use for our patient treatments, but with FLASH dose rates. This technique takes advantage of the lack of exit dose in proton beam therapy but requires a much more rigorous planning process. The NYPC team used novel planning techniques to compare radiation plans for patients undergoing reirradiation to the head and neck where doses delivered to normal tissues must be controlled to avoid serious AEs. The model revealed that PBS Bragg peak FLASH was better able to spare normal tissues from radiation than transmission FLASH or conventional proton beam radiation.

To broaden the applications of this potentially revolutionary treatment, Montefiore-NYPC proton PBS Bragg peak FLASH landmark preclinical studies are being conducted to deliver curative doses of radiation to abdominal tumors while reducing serious toxicities in the gastrointestinal tract under the leadership of Chandan Guha , MBBS, PhD, associate director of innovation/tech transfer at MECCC, director of Einstein Institute of Oncophysics, and vice chair of the Department of Radiation Oncology at Albert Einstein College of Medicine. With the goal of eliminating unnecessary treatment AEs, we are focused on studying how to use proton beam therapy for not only precise cancer care today but to also redefine successful outcomes for anyone affected by cancer.

1. Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. 

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2. Baumann BC, Mitra N, Harton JG, et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. 

. 2020;6(2):237-246. doi:10.1001/jamaoncol.2019.4889

3. Nogueira LM, Sineshaw HM, Jemal A, Pollack CE, Efstathiou JA, Yabroff KR. Association of race with receipt of proton beam therapy for patients with newly diagnosed cancer in the US, 2004-2018. 

. 2022;5(4):e228970. doi:10.1001/jamanetworkopen.2022.8970

4. Hartsell WF, Simone CB II, Godes D, et al. Temporal evolution and diagnostic diversification of patients receiving proton therapy in the United States: a ten-year trend analysis (2012 to 2021) from the National Association for Proton Therapy. 

. Published online December 30, 2023. doi:10.1016/j.ijrobp.2023.12.041

5. American Society for Radiation Oncology. Proton beam therapy (PBT). In: 

. American Medical Association;2022:1-21.

6. Brodin NP, Kabarriti R, Pankuch M, et al. A quantitative clinical decision-support strategy identifying which patients with oropharyngeal head and neck cancer may benefit the most from proton radiation therapy. 

. 2019;104(3):540-552. doi:10.1016/j.ijrobp.2018.11.039

7. Brodin NP, Kabarriti R, Schechter CB, et al. Individualized quality of life benefit and cost-effectiveness estimates of proton therapy for patients with oropharyngeal cancer. 

. 2021;16(1):19. doi:10.1186/s13014-021-01745-1

8. Pennock M, Wei S, Cheng C, et al. Proton Bragg peak FLASH enables organ sparing and ultra-high dose-rate delivery: proof of principle in recurrent head and neck cancer. 

. 2023;15(15):3828. doi:10.3390/cancers15153828

Articles

Radiation therapy, a cornerstone of cancer treatment, has evolved with technological advancements, particularly in proton beam therapy, which offers precise targeting and reduced toxicity. Despite its benefits, access disparities exist, notably among Black patients. The New York Proton Center (NYPC) addresses this by providing equitable access. Proton therapy is recommended for specific conditions, with ongoing clinical trials exploring its efficacy and cost-effectiveness. Innovations like FLASH proton therapy show promise in minimizing normal tissue damage. Collaborative efforts aim to redefine cancer care outcomes and reduce treatment-related adverse effects.

Partner Perspective

Precision Cancer Care: Preserving Normal Tissue With Proton Therapy

As the frontline setting of chronic lymphocytic leukemia (CLL) further examines the use of combination strategies, the selection of optimal Bruton tyrosine kinase (BTK) inhibitors in the relapsed or refractory setting remains, with sequencing questions arising as well.

Chronic Lymphocytic Leukemia: Applying the Latest Data to Clinical Practice

, Mazyar Shadman, MD, MPH, moderated a program with 11 expert clinicians in the field of hematologic oncology focused on treatment approaches in the frontline and relapsed/refractory settings in CLL; updated data regarding the use of zanubrutinib (Brukinsa), acalabrutinib (Calquence), and other agents were key focuses.

Shadman is the Innovators Network Endowed Chair and an associate professor in the Clinical Research Division at Fred Hutch Cancer Center, and an associate professor in the Medical Oncology Division at the University of Washington School of Medicine, both in Seattle, Washington.

Efficacy in the Frontline: Examining BTK Inhibitors

Zanubrutinib Shows Efficacy as Monotherapy

The phase 3 SEQUOIA trial (NCT03336333) examined zanubrutinib vs bendamustine plus rituximab (Rituxan) in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL). At a median follow-up of 43.7 months (range, 0.0-60.0), the median overall survival (OS) for patients in cohort 1, which enrolled those without a del(17p) mutation, was not evaluable (NE; 95% CI, NE-NE) in the zanubrutinib arm (n = 241) compared with NE (95% CI, NE-NE) in the bendamustine plus rituximab arm (n = 238; HR, 0.87; 95% CI, 0.50-1.48; 

 = .5995); the 42-month OS rates were 89.4% vs 88.3%, respectively. Additionally, the median progression-free survival (PFS) was NE (95% CI, NE-NE) with zanubrutinib vs 42.2 months (95% CI, 38.4-49.8) with bendamustine plus rituximab (HR, 0.30; 95% CI, 0.21-0.43; 

Additional data revealed that, at a median follow-up of 47.9 months (range, 5.0-56.9), patients with del(17p) mutations, which comprised the cohort 2 population, who received zanubrutinib (n = 110) achieved a 42-month OS rate of 89.5% (95% CI, 81.9%-94.1%) and a 42-month PFS rate of 79.4% (95% CI, 70.4%-85.9%).

“The take-home point is that patients with 

-mutated [disease] are also seeing benefit with zanubrutinib and there’s not much of a difference in terms of PFS in del17p or normal 

 [patients],” Shadman explained. “[There were also] no new safety signals—the hypertension rate and atrial fibrillation rates [in the zanubrutinib arm] were not different from the bendamustine plus rituximab [group] in the unplanned analysis that was done.”

 mutations in cohort 1 treated with zanubrutinib (n = 109) achieved a median PFS of NE (95% CI, NE-NE) vs 49.4 months (95% CI, 44.4-NE) in the bendamustine plus rituximab arm (n = 110; HR, 0.35; 95% CI, 0.19-0.64; 

-unmutated group, patients treated with zanubrutinib vs bendamustine plus rituximab achieved a median PFS of NE (95% CI, NE-NE) vs 33.7 months (95% CI, 29.5-39.1), respectively (HR, 0.23; 95% CI, 0.14-0.37; 

When asked about the use of acalabrutinib plus obinutuzumab (Gazyva) in treatment-naive CLL based on findings from the phase 3 ELEVATE-TN trial (NCT02475681) during the workshop, Alan Skarbnik, MD, explained that “more [clinicians] are picking it up based on these data, but most patients that we’re putting on continuous BTK [inhibition] of this day and age are patients who have del17p or 

 mutations where the addition of obinutuzumab makes no difference. I am of the thought that if we’re going to do obinutuzumab, let’s do obinutuzumab [plus] venetoclax [Venclexta] because a lot of the time you’re giving acalabrutinib because of the ease. [Certain] patients have 

aid, ‘I don’t want to have all-day infusion.’ It’s still okay, but we [usually] prefer a fixed-duration therapy, except for in high-risk patients. [Additionally], in patients with high-risk disease obinutuzumab made no difference, so I don’t see a reason to add that.”

Skarbnik is the director of the lymphoma and chronic lymphocytic leukemia program and director of experimental therapeutics, malignant hematology, at Novant Health in Charlotte, North Carolina.

Furthermore, updates from ELEVATE-TN presented at the 65th American Society of Hematology Annual Meeting & Exposition (ASH 2023), which took place in December 2023, revealed that acalabrutinib plus obinutuzumab (n = 179) improved investigator-assessed PFS vs acalabrutinib monotherapy (n = 179) in patients with untreated CLL who were 65 years or older or aged 18 to 64 years with comorbidities (HR, 0.58; 95% CI, 0.39-0.86; 

 = .0229). Acalabrutinib plus obinutuzumab also improved PFS vs chlorambucil plus obinutuzumab (n = 177; HR, 0.14; 95% CI, 0.10-0.20; 

“The phase 3 CLL14 study [NCT02242942] is another study that we are getting updates from very routinely. The 6-year follow-up [revealed that] 5 years after stopping the 1-year therapy [with obinutuzumab and venetoclax], the 6-year PFS rate was 53.1%, which is amazing in all comers. We now know that both the 

 mutation predict a shorter PFS [too in this patient population],” Shadman said.

The clinicians went on to discuss additional relevant data in CLL, including findings from a phase 2 trial (NCT03824483) which demonstrated that patients with untreated CLL/SLL given zanubrutinib plus obinutuzumab with ramp-up venetoclax (n = 52) achieved frequent undetectable minimal residual disease (MRD; < 10

) in the peripheral blood (96%) and in both the peripheral blood and bone marrow (92%); the median MRD-free survival was 29.8 months (range, 3.6-35.1+).

“If you’re going to do an MRD-[guided] treatment, you need venetoclax [as part of the regimen],” Skarbnik said. Clinicians also discussed the option of enrolling patients in the phase 3 MAJIC trial (NCT05057494), as treatment with acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab is MRD-guided.

Safety Considerations With BTK Inhibitors in Relapsed/Refractory CLL

All eyes are on various combination strategies with the BTK inhibitors acalabrutinib, ibrutinib (Imbruvica), and zanubrutinib, with updated safety findings from the phase 3 ELEVATE-RR (NCT02477696) and ALPINE (NCT03734016) trials presented during ASH 2023 (

Safety data from ELEVATE-RR revealed that the rate of discontinuation due to adverse effects (AEs) was lower for patients who received acalabrutinib (n = 266) compared with those treated with ibrutinib (n = 263; HR, 0.62; 95% CI, 0.41-0.93). Incidences of cardiac events overall were similar between the 2 arms. The common any-grade AEs of diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib than acalabrutinib with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. However, headache and cough occurred more frequently with acalabrutinib vs ibrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rates, respectively.

Further, rates of cardiac AEs were lower for patients who received zanubrutinib (n = 324) vs ibrutinib (n = 324), according to updated data from ALPINE. Any-grade (23.5% vs 33.0%), grade 3 or higher (7.1% vs 11.1%), and serious (3.1% vs 9.6%) cardiac AEs were observed in both arms, respectively. Additionally, no patients died from cardiac AEs in the zanubrutinib arm compared with 6 patients in the ibrutinib arm. The discontinuation rates due to cardiac toxicities were 0.6% vs 4.6%, respectively.

“Ibrutinib and zanubrutinib have similar rates of hypertension, [and] acalabrutinib has [lower rates] than ibrutinib,” Skarbnik said. “There’s more headache with acalabrutinib for some patients—I’ve had patients who had to stop [treatment] because of bad headaches. You have to nitpick here. To some extent in terms of efficacy, they’re somewhat interchangeable [drugs] here. To the point that if I prescribe acalabrutinib and insurance tells me you have to use zanubrutinib, I’m not going to argue and the other way around [too]. [However], I will argue if they tell me I have to use ibrutinib.”

Clinicians in the workshop also added that when determining between acalabrutinib and zanubrutinib, they will consider AEs and adherence to the dosing schedules of both agents.

Up Next: Noncovalent Inhibition With Pirtobrutinib

The accelerated approval of pirtobrutinib (Jaypirca) by the FDA, which occurred in December 2023 and was supported by findings from the phase 1/2 BRUIN trial (NCT03740529), represents a notable advancement in the relapsed/refractory CLL treatment paradigm, and clinicians highlighted that additional sequencing data are needed as a next step.

Subgroup analysis results from BRUIN presented during ASH 2023 showed that patients who did not receive a prior BCL2 inhibitor and were treated with pirtobrutinib (n = 154) achieved a median PFS of 23.0 months (95% CI, 19.6-28.4); 6-, 12-, 18-, and 24-month PFS rates were 87.1%, 72.8%, 62.5%, and 48.3%, respectively. Patients treated with pirtobrutinib who previously received a BCL2 inhibitor (n = 128) experienced a median PFS of 15.9 months (95% CI, 13.6-17.5); 6-, 12-, 18-, and 24-month PFS rates were 82.2%, 60.7%, 39.6%, and 24.3%, respectively.

Regarding safety, AEs of special interest occurring at any grade vs grade 3 or higher with pirtobrutinib included infections (71.0% vs 28.1%), bleeding (42.6% vs 2.2%), neutropenia (32.5% vs 26.8%), bruising (30.3% vs 0.0%), hemorrhage (21.1% vs 2.2%), hypertension (14.2% vs 3.5%), and atrial fibrillation/flutter (3.8% vs 1.3%).

 Shadman added that he “believes clinicians will use a lot of pirtobrutinib plus a covalent BTK inhibitor,” and that checking mutation status is key.

Shadman M, Munir T, Robak T, et al. Zanubrutinib vs bendamustine + rituximab in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland. Abstract 154.

Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. 

. 2023;142(suppl 1):636. doi:10.1182/blood-2023-174750

Soumerai JD, Dogan A, Seshan V, et al. Long-term follow-up of multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated patients with CLL/SLL. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland.

Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. 

. 2023;142(8):687-699. doi:10.1182/blood.2022018818

Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). 

. 2023;142(suppl 1):202. doi:10.1182/blood-2023-174289

FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed April 18, 2024. bit.ly/3xIdNVy

Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study. 

. 2023;142(suppl 1):325. doi:10.1182/blood-2023-185852

Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. 

. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696

The management of chronic lymphocytic leukemia (CLL) is evolving with the exploration of combination strategies and the selection of optimal Bruton tyrosine kinase (BTK) inhibitors. Zanubrutinib and acalabrutinib have shown efficacy in treatment-naive and relapsed/refractory settings, with zanubrutinib demonstrating significant progression-free survival benefits. Safety profiles of BTK inhibitors, including acalabrutinib, ibrutinib, and zanubrutinib, are being closely monitored, with acalabrutinib showing fewer adverse effects. The recent FDA approval of pirtobrutinib marks a significant advancement, though further sequencing data is needed to optimize treatment strategies.

Clinical Perspectives 

Mazyar Shadman, MD, MPH, details the efficacy of BTK inhibitors in the frontline treatment of CLL as well as safety considerations in the relapsed/refractory setting. 

BTK Inhibitor Combinations  Move to Forefront of CLL Investigations, Conversations 

As the cost of cancer treatment continues to rise for both patients and providers, independent clinicians are being forced to consolidate with larger health care systems to stay financially afloat. However, some clinicians believe this trend has negatively affected their ability to provide patients with timely, personalized care. To combat the rising costs and avoid the monopolization of cancer care by large health care systems, clinicians are partnering with managed service organizations to help handle the business aspects of practice without losing their autonomy.

According to a survey of patients with cancer and cancer survivors (n = 1218) conducted by the American Cancer Society Cancer Action Network, 73% of patients and survivors were concerned about their ability to pay current or future costs of their care and 70% are worried about accruing medical debt as a result of their cancer care and treatment. Additionally, 51% of patients and survivors reported that they were in medical debt following their treatment, with 53% and 46% facing collections and observing a negative impact on their credit score, respectively. Moreover, clinician payments from Medicare declined by 29% from 2001 to 2024 adjusting for inflation in practice costs, according to the American Medical Association.

“The fundamental fact is that the old standard physician models are being challenged by declining reimbursement and new regulatory programs, such as the Medicare Access and CHIP Reauthorization Act of 2015 and the Merit-based Incentive Payments System,” David Eagle, MD, the chair of legislative affairs and patient advocacy at New York Cancer & Blood Specialists and the chair of the Advocacy Committee for OneOncology, said in an interview with 

. “A lot of practices feel like they have to go somewhere. Historically, the main place they’ve been able to go is the hospital. But that has higher costs and facility fees, [can have] less productivity, and [provides] less convenient care for patients. We’re really excited about [managed care organizations] that offer a different pathway for practices to manage those challenges and stay independent.”

Research has indicated that in addition to a greater level of personalized care and responsiveness to the needs of individual patients that naturally come with treating fewer patients in a more intimate setting, independent clinicians can offer a significant cost-saving advantage to their patients. According to findings from a matched-claims analysis of claims from the IMS LifeLink database spanning 2010 to 2015, patients with breast, lung, and colorectal cancer (n = 6675) experienced significantly increased costs of care when treated at hospital-based clinics compared with those who received care at community- based clinics.

Findings from the study, which were published in 

, demonstrated that the mean cost per patient per month was $12,548 (SD, $10,507) among patients treated in the community setting compared with $20,060 (SD, $16,555) for those treated in the hospital setting (

 < .001). The mean chemotherapy costs per patient per month were also lower in the community setting vs the hospital setting, at $4,933 (SD, $4,983) vs $8,443 (SD, $10,391), respectively (

 < .001). Notably, the lower cost in the community setting was irrespective of chemotherapy regimen or tumor type and the baseline characteristics were well balanced between the 2 groups.

“We have seen this pivot from a volumebased [care] to a value-based [care] world; over 20%, almost 25%, of all of our patients are in a value-based arrangement,” Fred Divers, MD, a hematologist and oncologist at the Genesis Cancer and Blood Institute in Arkansas, as well as the chief medical officer and advisory board chairman of the American Oncology Network, said in an interview with 

. “[Large] health systems have no interest in participating in that and don’t have the bandwidth or wherewithal to really perform in those models.”

Despite the treatment-related cost savings they can offer to patients, independent providers are becoming rarer due to the increasing consolidation of providers into larger institutions. From 2015 to 2022, the number of medical oncologists increased by 14.5% from 11,727 to 13,433; however, the number of practices decreased by 18.0%, from 2,774 to 2,276, according to a study using Medicare data published in 

. The mean number of medical oncologists per practice also increased by 40%, from 4.26 to 5.95 (

Using the Herfindahl-Hirschman Index (HHI), a measure of market concentration that compares the size of firms within an industry and is calculated by summing the square of each firm’s market share, the degree of consolidation among practices with medical oncologists increased significantly from 2015 to 2022. The median HHI was 0.3204 (interquartile range [IQR], 0.2130-0.5273) vs 0.3480 (IQR, 0.2295-0.5200) in 2015 and 2022, respectively, corresponding to a 9% increase.

The percentage of medical oncologists working in solo practices decreased from 8.8% to 5.7% from 2015 to 2022. Additionally, the percentage of medical oncologists working in small (2-10 medical oncologists) practices decreased from 37.2% to 28.1% over the study period and the percentage working in medium (11-24 medical oncologists) and large practices (≥ 25 medical oncologists) increased from 21.2% to 22.5% and 33.6% to 43.7%, respectively, over this time frame (

“Consolidation is going to continue, [but] managed service organizations allow physicians to stay independent,” Jeff Patton, MD, the CEO of OneOncology, said in an interview with 

. “Patients should have the option to go to an independent private practice doctor, an academic medical center, or a hospital-based system. Consolidation within the private world will be managed service organization driven and we’ll see continued hospital consolidation.”

“The managed service organization model is horizontal consolidation, whereas vertical consolidation, such as hospitals buying practices, has very different effects, markets, pricing, and the look and feel of medicine. [Managed service organizations] provide networking of good private practices across the country, creating the best processes and practice support. That has a very different impact on local markets than vertical consolidation inside a hospital,” Eagle added.

Managed Service Organizations Offer a Potential Solution

Managed service organizations are institutions that serve the purpose of separating the clinical aspect of medical practice from the business and administrative side. Managed service organizations can assist independent clinicians with services such as patient scheduling, equipment and space leasing, bill paying and bookkeeping, and compliance issues, as well as patient billing, coding, and collection.

“It allows doctors to be doctors; all of the clinical decisions are made by physicians,” Patton explained. “Many of us have central democratic boards, where we get together and try to develop consensus best practice. But even after we do that, the individual doctors get to adopt that consensus decision or not. [Managed service organizations] take away the burden of running a business.”

Patton also noted that managed service organizations can provide smaller oncology practices with access to capital outside the large health care ecosystem to recruit new talent, grow in their market, and offer the latest advances in care. Most physicians are limited liability corporations that zero out their books every year without retaining any capital to invest in themselves; managed service organizations can offer an avenue to capital to compete in a market that includes large health care systems that have the resources to put smaller practices out of business in a competitive marketplace, Patton said.

By allowing clinicians to focus on patient care, the managed service organization model allows room for greater innovations in care and allows individual providers to showcase their unique talents, said Divers. “We have providers who are keenly interested in developing research, we have providers who are interested in developing data analytics, and providers who are interested in pursuing patient advocacy and policy changes. Those individuals are not in the same building; they’re not in the same town. But because they’re part of a larger managed service organization network, you can learn just by best practices from each of those strengths. The talent pool of a managed service organization is a huge value add because they’re bringing in talent from all different areas of that network.”

Another benefit of the managed service organization model is that it better equips clinicians working in practices in rural areas to provide the best care possible for patients who often do not have the option of seeking treatment at a large health care center. Beyond the larger geographic reach of preserving smaller clinics in more remote areas, managed service organizations can also provide these practices with the resources to stay afloat and provide better care in these underserved areas. The expanded staffing of the model allows smaller rural practices to provide drugs to uninsured patients through the employment of financial counselors and prior authorization teams and also provides data informatics services that would often be too expensive for these types of practices. Additionally, partnership with a managed service organization allows for better access to clinical trials for rural patients and at the same time enables the trial to get a better representation of the entire population that may eventually receive a new agent.

“The barriers to entry [for independent clinicians] without some structured support are so high; also the need and appetite are going to continue to grow to be a better steward of the health care dollar while maintaining high-quality care for the patient,” Divers said in conclusion. “In my view, when I talk about value-based care, quality care, I don’t mean capitated expenses. I mean finding the right therapy for the right patient at the right time. That’s where the precision medicine, data analytics, [as well as] the backdrop and support of a [managed service organization] network allow you to be a much better steward of the health care dollar.”

Survivor views: cancer & medical debt. American Cancer Society Cancer Action Network. March 17, 2022. Accessed April 23, 2024. https://www.fightcancer.org/policy-resources/survivor-views-cancer-medical-debt

Medicare updates compared to inflation in practice costs (2001–2024). American Medical Association. March 2024. Accessed April 23, 2024. https://www.ama-assn.org/system/files/2024-medicare-updates-inflation-chart.pdf

Gordan L, Blazer M, Saundankar V, Kazzaz D, Weidner S, Eaddy M. Cost differences associated with oncology care delivered in a community setting versus a hospital setting: a matched-claims analysis of patients with breast, colorectal, and lung cancers. 

Milligan M, Erfani P, Orav EJ, Schleicher S, Brooks GA, Lam MB. Practice consolidation among US medical oncologists, 2015-2022. 

. Published online February 26, 2024. doi:10.1200/OP.23.00748

MSOs for oncology practitioners. Cohen Healthcare Law Group. Accessed April 23, 2024. https://cohenhealthcarelaw.com/2023/01/msos-for-oncology-practitioners/

Rising cancer treatment costs are driving independent clinicians to consolidate with larger healthcare systems, impacting personalized care. Managed service organizations (MSOs) offer a solution by handling business aspects, allowing clinicians to maintain autonomy. Patients express concerns over treatment affordability, with many facing medical debt. Independent practices provide cost-effective care compared to hospital settings. Despite benefits, consolidation is increasing, reducing independent providers. MSOs support independent practices by offering resources, capital, and networking, enabling them to compete with larger systems and improve care, especially in rural areas, while fostering innovation and value-based care.

Oncology Business Management 

To combat the rising costs of cancer care, clinicians are partnering with managed service organizations to handle the business aspects of practice.

Leveraging Managed Service Organizations to Provide More Affordable, Personalized Cancer Care

As investigators parse out the unique mechanism of action of nadofaragene firadenovec-vncg (Adstiladrin), which has set the stage as the first gene therapy approved for bladder cancer, additional gene therapies with unique mechanisms of action are under development in high-risk, BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC).

The proposed mechanism of action of nadofaragene firadenovec is likely due to the pleiotropic nature of interferon-α2b (IFN-α2b) and its direct and indirect antitumor activities, according to investigators. Vikram M. Narayan, MD, explained that the agent “includes a nonreplicating adenovirus that delivers the payload of IFNα-2b. IFN is an immune-stimulatory agent, and [clinicians] have previously given IFN in the bladder with BCG or by itself but have found limited efficacy. Nadofaragene firadenovec uses the adenoviral vector to deliver IFN directly into urothelial cells to hijack the machinery of urothelial cells to produce the IFNα-2b protein. Then that goes on to have immunomodulatory effects that result in tumor and cell death—you can trigger apoptosis [and] antiangiogenesis; there are various pathways.”

He added, “We see cell death with TRAIL-mediated apoptosis, antiangiogenesis, and increased antitumor activity of natural killer cells, which preferentially target bladder cancer cells. All those things taken together result in cell death.”

Narayan practices at Emory University Hospital and serves as director of urological oncology at Grady Memorial Hospital, and is an assistant professor in the Department of Urology at Emory University School of Medicine and a member of the Winship Cancer Institute in Atlanta, Georgia. He highlighted that the polyamide surfactant and synthetic excipient Syn3 is a key component of the gene therapy (

“Syn3 is a detergent that helps break down the glycosaminoglycan layer of the bladder, [which] was historically thought to be why giving IFN alone would not work. One of the reasons why we can do every-3-month dosing with nadofaragene firadenovec is because we’re creating a bit of a bioreactor in the bladder of the patient to produce this IFNα-2b protein,” he explained.

As approximately 60% to 70% of patients with high-risk NMIBC are likely to experience recurrence and 10% to 45% may have disease progression to muscle-invasive or metastatic bladder cancer within 5 years, gene therapies provide a potential way to improve outcomes for patients. When looking at the standard of care with BCG, approximately one-third of this patient population will not respond to BCG, and among those who do experience an initial response, approximately 50% will experience recurrence or progression.

“[Nadofaragene firadenovec] is a gene therapy drug, but it’s a nonreplicating adenoviral vector. It has local effects,” Narayan said. “In studies, there was not systemic absorption or systemic effects noted. Understanding the immune-modulating effects of the drug [is important].”

Examining the Data With Nadofaragene Firadenovec

In the phase 3, single-arm trial supporting nadofaragene firadenovec’s approval, Study CS-003 (NCT02773849), the complete response (CR) rate at 3 months for adult patients with BCG-unresponsive NMIBC enrolled in the carcinoma in situ (CIS) cohort (n = 103) was 53.4% (95% CI, 43.3%- 63.3%). In the high-grade Ta or T1 disease cohort (n = 48), 72.9% (95% CI, 58.2%-84.7%) of patients were free of highgrade recurrence at 3 months.

Referencing the CIS cohort, Narayan said, “There’s still more work to be done. We would like to see those numbers [improve], but one of the hopes we have is to stimulate interest and discussion in ways that nadofaragene firadenovec can be augmented, combined with other therapies potentially, or maybe even redosed to improve that long-term CR rate.”

The duration of CR or high-grade recurrence-free survival for patients treated with nadofaragene firadenovec was 9.69 months (95% CI, 9.17-not estimable [NE]) in the CIS cohort vs 12.35 months (95% CI, 6.67-NE) in the high-grade Ta or T1 cohort. At 12 months, 24.3% (95% CI, 16.4%-33.7%) of patients with CIS were free from high-grade recurrence compared with 43.8% (95% CI, 29.5%-58.8%) of those with high-grade Ta or T1 disease. Notably, 45.5% of patients who reached a CR at 3 months in the CIS cohort maintained this through 12 months.

In the trial, patients received 75 mL of the gene therapy via intravesical instillation—3 × 10

 viral particles/ mL—once every 3 months for up to 12 months or until unacceptable toxicity or recurrent high-grade NMIBC.

 In the absence of high-grade recurrence, patients were allowed to continue nadofaragene firadenovec every 3 months. Notably, the median number of prior BCG instillations was 12 (range, 8-18), and the median number of nadofaragene firadenovec instillations was 2 (range, 1-5).

“Clinicians will likely be very familiar with the handling and other operational pieces [of nadofaragene firadenovec],” Narayan noted. “The one thing that clinicians need to know is it’s shipped frozen on dry ice [and] does need to be thawed and then used within 24 hours, or it needs to be stored frozen until it’s used. In terms of handling, it’s very similar to BCG.”

Narayan also noted that nadofaragene firadenovec was well tolerated and that the safety profile of the agent observed in CS-003 was similar to that of BCG. In the safety population (n = 157), grade 1 or 2 adverse effects (AEs) included instillation site discharge (33%), fatigue (24%), bladder spasm (20%), micturition urgency (19%), hematuria (17%), dysuria (16%), chills (16%), and pyrexia (15%). No grade 4 or 5 AEs were observed and only 1.9% of patients discontinued treatment while on study (

Data that supported the approval came from 98 patients in the BCG-unresponsive CIS cohort of CS-003; patients achieved a CR rate of 51% (95% CI, 41%-61%) with a median duration of response (DOR) of 9.7 months (range, 3 to 52+), and 46% of responding patients remained in CR for at least 1 year.

“The American Urological Association [AUA] guidelines recently included nadofaragene firadenovec as an option for patients with BCG-unresponsive NMIBC. Patients are now coming to us in the clinic asking about this treatment, to know more about it and have access to it,” Narayan added.

The AUA guidelines include nadofaragene firadenovec under the “Intravesical Therapy; BCG/Maintenance; Chemotherapy/BCG Combinations” section. The section notes that a physician may recommend nadofaragene firadenovec as an alternative intravesical therapy for patients with persistent or recurrent high-grade NMIBC who are not candidates for or do not want cystectomy within 12 months of completion of adequate BCG therapy; BCG therapy includes 2 induction courses or 1 induction course plus 1 maintenance cycle. Alternatives to the gene therapy include clinical trials or intravesical chemotherapies such as gemcitabine or docetaxel.

Furthermore, Narayan noted that “the question of whether redosing nadofaragene firadenovec [is ideal remains]. In the original trial, if therapy failed or patients had recurrence of high-grade disease, they would not get additional treatments; they would be switched to an alternative therapy because when we were designing [the CS-003] trial, the interest was to make sure that patients were safe and not given treatments that wouldn’t work. Now that we have data on efficacy, it’s reasonable to see whether a second treatment does offer benefit if a patient recurs initially. There’s justification for that [because] patients will often get repeat induction BCG, and some of the other drugs that are being developed in this space also have redosing regimens if they have failures.”

Further Novel Therapies Are Under Evaluation in BCG-Unresponsive Disease

The investigational engineered oncolytic immunotherapy cretostimogene grenadenorepvec (CG0070) received both fast track and breakthrough therapy designations from the FDA in December 2023 for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS with or without Ta or T1 tumors.

 Cretostimogene grenadenorepvec was designed to preferentially replicate in retinoblastoma gene pathway–defective cells that are present in most urothelial carcinomas and trigger an antitumor immune response. Modifications made for tumor selectivity and potency to the agent include the insertion of an E2F1 promoter and the insertion of the gene for the cytokine granulocyte-macrophage colony stimulation factor

Findings from the phase 3 BOND-003 trial (NCT04452591) revealed that 75.7% of patients with high-risk BCG-unresponsive NMIBC treated with cretostimogene grenadenorepvec (n = 66) achieved a CR; the 3- and 6-month CR rates were 68.2% and 63.6%, respectively.

 Additionally, interim results from the phase 2 BOND-002 trial (NCT02365818) demonstrated this patient population (n = 45) experienced a 47% (95% CI, 32%-62%) CR rate at 6 months. Cretostimogene grenadenorepvec was well tolerated with no grade 4 or 5 AEs observed; grade 3 treatment-related effects included dysuria (3.0%) and hypotension (1.5%).

The agent is currently under evaluation for NMIBC in the phase 3 PIVOT-006 trial (NCT06111235), which is currently recruiting patients in the US and Canada. It is also being examined in combination with pembrolizumab (Keytruda) in the active phase 2 CORE-001 trial (NCT04387461).

“Gene therapy is emerging as a [potential] significant option for patients who have BCG-unresponsive disease and bladder cancer in general,” Narayan said. “We’re likely going to see more of [these therapies], and we may even look at different payloads [of nadofaragene firadenovec in particular], but the bladder is a natural cavity for safe gene therapy treatment options because it’s easily accessible via catheter, you can provide contact-based delivery of the drugs that you’re using, and we know from preclinical data that for many agents, the absorption systemically is very low, assuming there isn’t a raw surface or something along those lines or active hematuria. For that reason, [in] bladder cancer at least in the antitumor space, there’s a lot of interest in gene therapy. With the approval of nadofaragene firadenovec, we’ll likely see other agents emerge as well in this space.”

Detalimogene voraplasmid (EG-70) has also emerged in the gene therapy space, receiving fast track designation from the FDA in 2020 for BCG-unresponsive NMIBC.

 The nonviral gene therapy is a nanoparticle formulation of plasmids; the plasmid encodes IL-12 and activators of the innate immune receptor RIG-I. The agent elicited a 3-month CR rate of 71% in patients with CIS (n = 17), according to data presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium from the phase 1/2 LEGEND trial (NCT04752722).

“The biggest unmet need is having a durable treatment for BCG-unresponsive NMIBC. The concern that patients have [occurs] when we tell them they [did not respond to] BCG and all the other treatments we have are not as efficacious or they involve life-altering surgery in the form of removal of the bladder. When we compare this with pembrolizumab, which was also FDA approved, the big advantage that nadofaragene firadenovec offers is that it’s given in the bladder intravesically and dosed once every 3 months,” Narayan explained. “[This] is a much more favorable dosing regimen for patients than once a week for 6 weeks [with other treatment options].”

Pembrolizumab’s January 2020 approval for patients with BCG-unresponsive, highrisk NMIBC with CIS with or without papillary tumors was based on data from the phase 2 KEYNOTE-057 trial (NCT02625961). Patients in this population (n = 96) experienced a CR rate of 41% (95% CI, 31%-51%) with a median DOR of 16.2 months (range, 0.0+ to 30.4+).

Although options for patients with high-risk, BCG-unresponsive NMIBC have expanded for patients who are ineligible for or decline cystectomy to include intravesical chemotherapy, pembrolizumab, and nadofaragene firadenovec, combination therapies may be on the horizon. Narayan noted that it is worthwhile to consider combination strategies with nadofaragene firadenovec to augment responses.

Narayan VM, Meeks JJ, Jakobsen JS, Shore ND, Sant GR, Konety BR. Mechanism of action of nadofaragene firadenovec-vncg. 

. 2024;14:1359725. doi:10.3389/fonc.2024.1359725

Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. 

. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. FDA. Updated December 19, 2022. Accessed April 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin

Adstiladrin. Prescribing information. Ferring Pharmaceuticals; 2023. Accessed April 11, 2024. https://www.ferringusa.com/wp-content/uploads/sites/12/2023/10/ADSTILADRIN-USPI-CLEAN-AR-changes-09-2023.pdf

Holzbeierlein JM, Bixler BR, Buckley DI, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline: 2024 amendment. 

. 2024;211(4):533-538. doi:10.1097/JU.0000000000003846

CG Oncology receives both FDA fast track and breakthrough therapy designation for cretostimogene grenadenorepvec in high-risk BCG-unresponsive non-muscle invasive bladder cancer. News release. CG Oncology Inc. December 5, 2023. Accessed April 11, 2024. https://cgoncology.com/cg-oncology-receives-both-fda-fast-track-and-breakthrough-therapy-designation-for-cretostimogene-grenadenorepvec-in-high-risk-bcg-unresponsive-non-muscle-invasive-bladder-cancer/

Unique mechanism of action. CG Oncology. Accessed April 11, 2024. https://cgoncology.com/science/#moa

Lidagoster S, Ben-David R, De Leon B, Sfakianos JP. BCG and alternative therapies to BCG therapy for non-muscle-invasive bladder cancer. 

. 2024;31(2):1063-1078. doi:10.3390/curroncol31020079

Cretostimogene grenadenorepvec monotherapy first results show 75.7% complete response rate at any time in patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer. News release. CG Oncology. November 30, 2023. Accessed April 5, 2024. https://www.businesswire.com/news/home/20231130351326/en

Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. 

. 2018;36(10):440-447. doi:10.1016/j.urolonc.2017.07.005

Ongoing clinical studies in bladder cancer. CG Oncology. Accessed April 11, 2024. https://cgoncology.com/science/ongoing-clinical-studies/

enGene announces positive preliminary phase 1/2 data with EG-70 in BCG-unresponsive non-muscle invasive bladder cancer. News release. enGene. February 8, 2022. Accessed April 11, 2024. https://engene.com/engene-announces-positive-preliminary-phase-1-2-data-with-eg-70-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer/

Steinberg GD, Kalota SJ, Lotan Y, Warner L, Dauphinee S, Mazanet R. Clinical results of a phase 1 study of intravesical EG-70 in patients with BCG-unresponsive NMIBC. 

. 2023;41(suppl 6):512. doi:10.1200/JCO.2023.41.6_suppl.512

FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. FDA. January 8, 2020. Accessed April 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer

Nadofaragene firadenovec-vncg (Adstiladrin) is the first gene therapy approved for bladder cancer, specifically targeting high-risk, BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). It utilizes a nonreplicating adenovirus to deliver interferon-α2b directly into urothelial cells, inducing antitumor effects. Clinical trials demonstrated promising complete response rates, though further improvements are needed. Other gene therapies, such as cretostimogene grenadenorepvec and detalimogene voraplasmid, are under investigation. The American Urological Association now includes nadofaragene firadenovec as a treatment option, highlighting its potential in NMIBC management.

Pathways

As investigators parse out the mechanism of action of nadofaragene firadenovec, additional gene therapies are under development in BCG-unresponsive NMIBC.

Nadofaragene Firadenovec Sets the Stage for Gene Therapies in NMIBC

As researchers begin to shift from a uniform approach in small cell lung cancer (SCLC) to a more targeted approach, the idea of transcriptomic or molecular subtypes has surfaced, with 4 main subtypes of SCLC identified and others gaining traction thus far.

 Three subtypes of SCLC that have been identified include SCLC-A, which is defined by activation of the 

gene. Further, SCLC-I has been identified as a fourth major subtype, which is characterized by certain inflammatory characteristics

“We’re starting to understand more about the biology of SCLC. [Our] work over the years shows that there is heterogeneity, there are different ways to classify SCLC, and, more recently, this idea of transcriptomic or molecular subtypes [has emerged],” Anne Chiang, MD, PhD, associate professor of medicine and associate cancer center director, clinical initiatives, at Yale School of Medicine in New Haven, Connecticut, said in an interview with 

An analysis of the phase 3 IMpower133 trial (NCT02763579) revealed that a higher proportion of long-term survivors (LTS) vs non-LTS with extensive-stage SCLC (ES-SCLC) in both the atezolizumab (Tecentriq) plus carboplatin and etoposide arm and placebo plus carboplatin and etoposide arm had the SCLC-I subtype. Among patients with SCLC-I, a higher proportion of patients were LTS compared with non-LTS (28% vs 11%, respectively) in the atezolizumab arm, as well as the placebo arm (32% vs 18%). LTS were defined as patients who survived at least 18 months post random assignment. Notably, patients with the SCLC-P subtype experienced poor long-term survival.

Investigators are also beginning to examine the YAP1 transcription regulator and its role in defining a SCLC subset with the proposed SCLC-Y subgroup.

“The idea of being able to subtype SCLC, and that different subtypes have therapeutic vulnerabilities, is interesting. Another example of a predictive biomarker for targeting the DNA damage response that looks promising is the SLFN11 protein,” Chiang said. “The phase 2 S1929 [study (NCT04334941)] in the maintenance setting took patients who had SLFN11-positive disease by immunohistochemistry and found that those patients, when treated with maintenance with a PARP inhibitor hitting the DNA repair pathway, seemed to do significantly better than patients who were SLFN11 negative.”

In S1929, maintenance atezolizumab plus talazoparib (Talzenna) improved progression-free survival (PFS) vs maintenance atezolizumab monotherapy in patients with SLFN11-positive ES-SCLC, meeting the study’s primary end point. Investigators noted that the study’s outcomes represent the feasibility of conducting biomarker selected trials in SCLC.

Data from the trial demonstrated that the median PFS for patients treated with atezolizumab plus talazoparib (n = 54) was 4.2 months (80% CI, 2.8-4.7) vs 2.8 months (80% CI, 2.0-2.9) with atezolizumab alone (n = 52; HR, 0.70; 80% CI, 0.52-0.94; 1-sided log rank stratified 

Preliminary overall survival (OS) data revealed patients experienced a median OS of 9.4 months (80% CI, 8.1-14.2) in the doublet arm compared with 8.5 months (80% CI, 7.4-12.7) in the monotherapy arm (HR, 1.17; 80% CI, 0.80-1.71; 1-sided log rank stratified 

 = .30). Further, response rates in evaluable patients were 12% (80% CI, 5%-22%) in the doublet arm (n = 34) vs 16% (80% CI, 8%-27%) in the monotherapy arm (n = 32), respectively. Hematologic adverse effects were increased with the addition of talazoparib, occurring at rates of 50% vs 4%, respectively (

“There’s no clear biomarker for SCLC, like PD-L1 status in NSCLC patients. In the past, we thought that high tumor mutational burden might predict response to immunotherapy, but it didn’t pan out. But we’re gaining more information to see that this myth that all SCLC should be treated the same may not be true,” Chiang said.

Tissue Samples Are Needed in SCLC to Further Elucidate
the Use of Biomarkers

We need to understand the heterogeneity of SCLC and which patients may respond to a targeted therapy approach, and a key part of that is getting tissue,” Chiang explained. “Another myth is that there’s [not enough] tissue for SCLC because there’s crush artifact or because we often use fine-needle aspiration. But patients with SCLC often present with very bulky disease that is very accessible. For patients with non–small cell lung cancer [NSCLC], we require tissue for a biomarker, PD-L1 status, to guide treatment. If we had arequirement for a biomarker for SCLC, I believe we’d have no problem getting adequate tissue samples from patients with SCLC.”

Chiang was the principal investigator of a phase 2 study (NCT03670056) conducted at Yale Cancer Center, which found that dual checkpoint blockade using nivolumab (Opdivo) plus ipilimumab (Yervoy) has a prominent immunomodulatory role in ES-SCLC. Investigators obtained biopsies of patients enrolled (n = 22) at baseline, week 4, and progression, and a genomic analysis revealed that patients with progressive disease had more deleterious HLA-A gene mutations at baseline compared with those who experienced clinical activity with the combination.

“Having those paired biopsies allowed us to look at which patients responded after 2 cycles of treatment and correlate what was happening in the tumor microenvironment,” Chiang noted.

Further, 40% of evaluable patients (n = 15) experienced clinical activity in the form of partial responses or stable disease; all these patients had the SCLC-A subtype. Increased local adaptive immune responses, such as T-cell activation and PD-1 signaling, were associated with treatment sensitivity or resistance to dual checkpoint blockade.

“To push the field forward, we need to be able to get tissue [from] patients so we can understand what’s going on and [determine] which patients might be able to respond to targeted therapies,” Chiang added. 

Understanding the biology of these tumors is important—especially for SCLC—to get tissue, be able to understand what subtypes there are, and see whether we can target our therapies to those subtypes.”

Chiang is leading development of a key new biomarker-driven trial through the Southwest Oncology Group, the phase 2 multicohort PRISM study (S2409). The study is examining durvalumab (Imfinzi) vs biomarker-directed novel agents in combination with durvalumab in patients with different subtypes of ES-SCLC.

Advancements in small cell lung cancer (SCLC) research have identified four main molecular subtypes, each with distinct therapeutic vulnerabilities. The SCLC-I subtype shows a higher proportion of long-term survivors, while SCLC-P is associated with poor survival. The SLFN11 protein emerges as a promising biomarker for targeted therapy. The phase 2 S1929 study demonstrated improved progression-free survival with atezolizumab plus talazoparib in SLFN11-positive patients. Ongoing trials, such as PRISM and TRITON, continue to explore genetic mutations and novel therapies, including bispecific antibodies like tarlatamab, to enhance treatment outcomes.

Anne Chiang, MD, PhD, discusses understanding the heterogeneity of SCLC to determine which patients will respond to targeted therapy. 

Vol. 25 No. 7 | Oncology Live®

Precision Cancer Care: Preserving Normal Tissue With Proton Therapy

BTK Inhibitor Combinations Move to Forefront of CLL Investigations, Conversations

Leveraging Managed Service Organizations to Provide More Affordable, Personalized Cancer Care

Nadofaragene Firadenovec Sets the Stage for Gene Therapies in NMIBC

Applying the Heterogeneous Approach From NSCLC to SCLC

The Benefits Outweigh the Risks: Unpacking the Recent ODAC Decisions in Myeloma

Advances in MRD Testing Help Guide Optimal Colorectal Cancer Therapy

Improved Survival in Randomized Trials: A Meaningful Outcome but Increasingly Difficult to Demonstrate