Nitin Ohri, MD, MS, is a professor of radiation oncology at Montefiore Einstein Comprehensive Cancer Center 

Non–small cell lung cancer (NSCLC) causes approximately 2 million deaths each year worldwide.

 Approximately one-third of patients initially present with locally advanced disease, meaning that the cancer is bulky and/or involves regional lymph nodes but has not spread to distant locations.

A standard treatment for patients with locally advanced NSCLC consists of a 6-week course of daily thoracic radiotherapy along with concurrent radiosensitizing chemotherapy, often followed by adjuvant immunotherapy.

 With respect to radiotherapy dosing, systemic agents used, and treatment sequencing, patients are currently treated with a one-size-fits-all approach. Some patients may experience severe adverse effects (AEs) during or after chemoradiotherapy, including esophagitis, lung inflammation, and immuno- suppression.

Many patients never reach the adjuvant immunotherapy phase because they experience severe AEs from chemoradiotherapy. In addition, immunosuppression resulting from chemoradiotherapy may render immunotherapy ineffective. Five-year survival rates remain below 50% for this patient population.

New lung cancer treatment options have emerged in recent years, and several groups are exploring personalized treatment strategies that omit chemotherapy for some patients with locally advanced NSCLC. Chemotherapy-free lung cancer treatment would be especially helpful for patients who are frail or older, or who have biopsy findings that suggest that immunotherapy would be effective.

Advancing Personalized Lung Cancer Treatment 

Chemotherapy can cause significant toxicity and is not always effective in preventing disease spread. Establishing chemotherapy-free treatment approaches for locally advanced NSCLC using biomarker testing to identify patients who could be treated effectively without chemotherapy would represent a major advance.

The phase 2 SPRINT trial (NCT03523702) was recently completed at Montefiore Einstein Comprehensive Cancer Center (MECCC), an National Cancer Institute–designated Comprehensive Cancer Center, Bronx, New York. Investigators evaluated patients with locally advanced NSCLC with high expression of PD-L1, which is a predictor of immunotherapy efficacy.

. Kaplan-Meier Curve for Overall Survival in Phase 2 SPRINT Trial

Unlike many other studies testing chemotherapy-free treatment for locally advanced NSCLC, the SPRINT trial enrolled patients who were fit enough to receive standard chemotherapy and radiotherapy.

 Additionally, SPRINT participants received induction immunotherapy before radiotherapy to shrink their tumors and ensure they received immunotherapy, as most patients following the existing protocol do not make it to that phase of treatment. SPRINT participants then received 3 cycles of induction pembrolizumab (Keytruda); a 4-week course of personalized radiotherapy, often with lower doses; and additional pembrolizumab. SPRINT’s personalized radiotherapy strategy, which was piloted at MECCC to minimize the risk of treatment toxicity and risk of acute and delayed AEs (including immunosuppression) without compromising disease control, was another novel aspect of SPRINT that took treatment personalization to a new level.

Few serious AEs related to study therapy occurred, and approximately 50% of treated patients (n = 25) had significant disease shrinkage after induction immunotherapy. Progression-free survival and overall survival rates exceeded expectations for this patient population, and disease improvement after induction immunotherapy was identified as a powerful predictor of long-term treatment efficacy (Figure).

 This finding indicates that measuring responses to induction therapy could help researchers quickly determine which novel immunotherapy agents should be tested in large trials for the management of locally advanced NSCLC to improve patient outcomes.

Future Immunotherapy and Chemotherapy-Free Studies

Clinical trials offer patients with locally advanced NSCLC access to novel treatments, along with the support of their respective health care team.

Building on the SPRINT findings, MECCC investigators are leading the multi-institutional phase 2 TRIPL (NCT06865339) and SPRINT2 trials in 2025, testing combinations of promising novel immunotherapy drugs targeting LAG3, NKG2A, and CD73, and more established drugs targeting PD-1/PD-L1. Both trials will incorporate induction dual-agent immunotherapy, which will be followed by personalized radiotherapy and then additional immunotherapy. Favorable results from these trials would support subsequent pivotal phase 3 trials looking to establish new treatment options for patients with locally advanced NSCLC.

In addition to these clinical trials, other treatment approaches being taken by MECCC investigators include the use of proton beam radiotherapy as well as primary tumor stereotactic body radiotherapy, the latter of which is being tested in the phase 3 NRG-LU008 trial (NCT05624996), with the overarching goal of improving cure rates and reducing treatment toxicity.

Nitin Ohri, MD, MS, is a professor of radiation oncology at Montefiore Einstein Comprehensive Cancer Center in Bronx, New York. 

Li C, Lei S, Ding L, et al. Global burden and trends of lung cancer incidence and mortality. 

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Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

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Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308

Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG oncology RTOG 0617: standard-versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. 

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Ohri N, Bodner WR, Kabarriti R, et al. Positron emission tomography-adjusted intensity modulated radiation therapy for locally advanced non-small cell lung cancer. 

. 2018;102(4):709-715. doi:10.1016/j.ijrobp.2017.10.032

Giaddui T, Chen W, Yu J, et al. Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC. 

. 2015;11:66. doi:10.1186/s13014-016-0640-8

Articles

Non-small cell lung cancer (NSCLC) remains a significant global health challenge, with high mortality rates and limited five-year survival for locally advanced cases. Traditional treatment involves chemoradiotherapy, often leading to severe adverse effects and immunosuppression. Recent advancements focus on personalized, chemotherapy-free strategies, particularly for patients with high PD-L1 expression. The SPRINT trial demonstrated promising results with induction immunotherapy and personalized radiotherapy, reducing toxicity and improving survival outcomes. Future trials, such as TRIPL and SPRINT2, aim to further explore novel immunotherapy combinations, potentially transforming NSCLC management.

New lung cancer treatment options have emerged, and several groups are exploring treatment strategies that omit chemotherapy for locally advanced NSCLC. 

Personalizing Lung Cancer Treatment Reduces Toxicity and Improves Cure Rates

The idea to provide wearable devices to my patients first came to me 6 years ago at a charity spinning event. A head and neck cancer nurse who was training for a marathon showed me her new Fitbit. It occurred to me that the data she was using to guide her training would be valuable for clinicians caring for individuals with cancer. Additionally, the use of wearable devices could also open the door to initiate effective dialogue and enhanced partnerships with our patients. Within a few months, my colleagues and I at Montefiore Einstein Cancer Center in the Bronx, New York, opened our first clinical trial using wearables to monitor patients receiving radiotherapy with concurrent chemotherapy. 

More than one-quarter of the Bronx population lives in poverty,

 approximately 14% of residents have their bachelor’s degree, and anecdotally, few of our patients routinely engage with modern wearable devices. Therefore, Montefiore is well suited to both study the capacity for wearable devices to enhance cancer care and to identify barriers to wearable device use in an underprivileged patient population. The latter has also given us a gut check on the Digital Divide. We are proud to have developed a novel program utilizing wearables to monitor patients during radiotherapy in the Bronx.

The Digital Divide is the notion that as digital health becomes a routine component of patient care, we will see an exacerbation of outcome disparities across various subgroups in our society. Early work from our team suggests that low socioeconomic status (SES), rather than belonging to a racial or ethnic minority group, is the key predictor of patients’ inability to benefit from the digital health revolution. 

We previously identified low SES as a risk factor for treatment interruptions and hospitalizations during radiotherapy.

 As a result of that research, we have navigator programs to assist patients through all steps of care, including enhanced support services such as social work and helping patients overcome obstacles to care such as transportation and housing. Though most of our patients are amenable to using a wearable device provided by our study team, we have observed that SES may affect our ability to collect digital health data.

For our wearable device trials, we selected a waterproof, user-friendly device that did not require charging. We also offered to download individuals’ step data during their routine clinic visits. This workflow allowed us to achieve a 94% data collection rate in our initial pilot study with approximately 40 subjects.3 In that first study (NCT02649569), we found a powerful association between daily step counts and hospitalization risk, with a 38% reduction in acute hospitalization risk for every 1000 steps per day. That finding has been reproduced in our follow-up trials, which now include more than 200 additional participants.

Importantly, we found that wearable devices provide new insights about patients’ functional status. Performance status, which is the most common measure clinicians use to try to quantify general well-being for patients with cancer, is highly subjective and only loosely correlates with clinical outcomes. We have discovered that activity data are superior to performance status as a predictor of hospitalizations, disease recurrence, and death.

As an example, among patients who utilized wearables device while receiving chemoradiotherapy for advanced non–small cell lung cancer, study participants with low baseline activity levels—defined as having a step count average below the 25th percentile of age-matched healthy controls—were more likely than active patients to be hospitalized during the radiation therapy course (50% vs 9%, respectively; P = .004) and less likely to complete radiotherapy without a 1 week or more delay (67% vs 97%; P = .006).

 Further, patients with low baseline activity were 5 times more likely to experience disease recurrence or death. The median progression-free survival was 5.3 months vs 18.3 months (HR for inactivity, 5.10; P < .001).

We recently completed a study utilizing wearable devices to monitor patients receiving systemic therapy for metastatic malignancies, and we are seeing identical effects. It is just a matter of time before wearable device data are routinely incorporated in oncology clinics.

Incomplete wearable device data collection has been more common in our study subjects with low SES. Therefore, we are designing studies to better understand and address this phenomenon, focusing on issues such as internet availability at home and digital health literacy. These insights will be invaluable as we are leading numerous trials, including multi-institutional studies, where patients use wearable devices during cancer therapy. Study objectives include leveraging wearable device data to improve supportive care and prevent hospital admissions, as well as using wearables to understand the toxicity profiles of novel radiotherapy and immunotherapy combinations.

We are also evaluating our ability to collect data using more advanced devices in our patient population. One study will include patients treated at the New York Proton Center, which is the only proton therapy facility in New York and is operated by a consortium of city-based institutions that includes Montefiore, Memorial Sloan Kettering Cancer Center, and Mount Sinai Health System. This novel study will provide insight into how proton radiotherapy preserves patients’ functional status and quality of life compared with standard radiotherapy.

Future studies will expand the scope of how digital health technology can improve cancer patient care. This includes evaluating strategies that may bring more advanced devices to our patient population so we can understand the clinical significance of metrics beyond daily step count, such as heart rate variability.

We have seen that our patients appreciate the close monitoring and personalized care that wearable devices can facilitate. By better understanding barriers to the use of wearables, we can integrate digital health data into our electronic medical records and our routine clinic workflows (FIGURE

). We look forward to reporting the outcomes of more of these trials and sharing lessons learned so that more individuals affected by cancer can benefit from the digital health revolution, regardless of SES.

QuickFacts Bronx County, New York; United States. United States Census Bureau. Accessed November 22, 2021. https:// www.census.gov/quickfacts/fact/table/bronxcountynewyork,US/IPE120220 

Ohri N, Rapkin BD, Guha C, Kalnicki S, Garg M. Radiation therapy noncompliance and clinical outcomes in an urban academic cancer center. Int J Radiat Oncol Biol Phys. 106;95(2):563-570. doi:10.1016/j.ijrobp.2016.01.043 

Ohri N, Kabarriti R, Bodner WR, et al. Continuous activity monitoring during concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2017;97(5):1061-1065. doi:10.1016/j. ijrobp.2016.12.030 

Ohri N, Halmos B, Bodner WR, et al. Daily step counts: a new prognostic factor in locally advanced non–small cell lung cancer? Int J Radiat Oncol Biol Phys. 2019;105(4):745-751. doi:10.1016/j.ijrobp.2019.07.055 

Izmailova E, Huang C, Cantor M, Ellis R, Ohri N. Daily step counts to predict hospitalizations during concurrent chemoradiotherapy for solid tumors. J Clin Oncol. 2019;37(suppl 27):293. doi:10.1200/JCO.2019.37.27_suppl.293

The idea to provide wearable devices to my patients first came to me 6 years ago at a charity spinning event. 

A Gut Check on the Digital Divide: How Wearable Devices Are Changing Cancer Care

Nitin Ohri, MD, associate professor, Department of Radiation Oncology, Albert Einstein College of Medicine, radiation oncologist, Montefiore Medical Center, discusses the role of chemoradiation therapy in locally advanced non–small cell lung cancer (NSCLC).

Historical data, including those from the Intergroup 0139 (RTOG 93-09) trial, have shown that patients with locally advanced NSCLC benefit more from definitive chemoradiotherapy versus combination approaches that include surgical resection, says Ohri.

Now, significant improvements with radiation therapy, diagnostic and staging techniques, supportive care, and adjuvant systemic therapy approaches, such as immunotherapy after chemoradiation, have improved outcomes for patients with locally advanced disease, Ohri explains. Additionally, these advances favor the use of chemoradiation therapy without surgical resection for the majority of patients with locally advanced NSCLC, concludes Ohri.

Videos

Nitin Ohri, MD, discusses the role of chemoradiation therapy in locally advanced non–small cell lung cancer.  



Nitin Ohri, MD, MS

Articles

Personalizing Lung Cancer Treatment Reduces Toxicity and Improves Cure Rates

A Gut Check on the Digital Divide: How Wearable Devices Are Changing Cancer Care

Dr. Ohri on the Role of Chemoradiation in Locally Advanced NSCLC