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As telehealth is now routinely offered in health care, determining how at-home care fits into oncologic care is top of mind, with the subcutaneous formulation of agents serving as a more feasible administration pathway as opposed to that of intravenous (IV) therapy. As such, investigators have initiated a first-of-its-kind clinical trial where patients with non–small cell lung cancer (NSCLC) will receive subcutaneous immunotherapy in the comfort of their own homes.

“The loosening of regulations around payments for telemedicine have done wonders for the field. Before, patients had to do the telemedicine visits at their rural critical access hospitals—they weren’t able to be at home. Being able to use consumer platform technologies does simplify the process. There’s no need for special equipment or unusual technological requirements as we had before the COVID-19 pandemic,” Jorge J. Nieva, MD, a medical oncologist at Keck Medicine of University of Southern California (USC) and an associate professor of clinical medicine at Keck School of Medicine in Los Angeles, explained in an interview with 

Currently indicated for IV use in the US, atezolizumab (Tecentriq) is being evaluated in a subcutaneous delivery route to allow for safe and effective administration by a nurse to patients at home in a phase 2 study (NCT05340309) conducted by USC/Norris Comprehensive Cancer Center.

 Telemedicine appointments and remote monitoring through wearable trackers are additional components of the study. Nieva, who is the lead investigator of the clinical trial, added that telemedicine has come a long way from its inception.

“I have been around telemedicine for a long time,” Nieva noted. “I spent approximately 7 years practicing medicine in Montana, and we did a lot of telemedicine long before the COVID-19 [pandemic]. It was an essential aspect of care for patients who lived in rural environments near critical access hospitals.”

He added, “What makes this clinical trial unique is it’s the first home administration of immunotherapy for solid tumors and it’s [a trial] where we’re leveraging consumer-grade technologies for fitness monitoring and using them for performance status assessments. We’ve also built a network for getting laboratory studies into our electronic medical record through our partnerships with third-party laboratory vendors such as Labcorp and Quest Diagnostics. We try to ensure that CT monitoring is done in ways where we can view the images and deliver the results to the patients through telemedicine.”

The Subcutaneous Route Allows for Flexibility and Cost Savings Over the IV Route

As oral medicines become more common, particularly for patients with actionable driver mutations, Nieva noted that agents given via the subcutaneous route are growing in scope as well due to the ease they provide with administration.

“In this clinical trial, we ensure safety by [administering] the first 3 infusions in the office to be sure that there aren’t going to be problems with allergic reactions. This medicine, [atezolizumab], is a monoclonal antibody, and there is a long experience with biological agents and monoclonal antibodies being delivered at home through subcutaneous infusions. Gamma globulin is one example; recombinant factors for people with hemophilia is another. There isn’t a priori reason that monoclonal antibodies could not be delivered at home through subcutaneous routes,” Nieva said.

In most recent subcutaneous news, the FDA accepted a biologics license application in May 2024 for the subcutaneous formulation of nivolumab (Opdivo) coformulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20) for the treatment of adult patients who are eligible for prior solid tumor nivolumab indications; this includes monotherapy, monotherapy maintenance following completion of nivolumab plusipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Findings from a study also revealed that cost savings with subcutaneous formulations of agents could be large; a model developed to estimate cost differences for transitioning 20% of a patient cohort from IV to subcutaneous rituximab (Rituxan) found that in a plan of 1 million individuals this could save $153,000 in total from a payer perspective. From a practice perspective, $124,000 could be saved, and provider capacity could be increased by 270 hours of staff time. The model found that in addition to potentially generating significant US health system value via payer savings, increased practice capacity and patient time would generate value.

The 20% transition in the model from IV to subcutaneous formulation was projected to save approximately 470 hours of patient time as well. When examined by tumor type, patients with diffuse large B-cell lymphoma and follicular lymphoma were found to have an estimated IV infusion duration of 234 minutes and for chronic lymphocytic leukemia, the duration is estimated at 273 minutes; overall, subcutaneous administration is estimated at 60 minutes across all service levels.

In addition to cost savings as a reason to consider subcutaneous administration, including in cases where this care can be given at home, countries outside the US have administered subcutaneous agents at a higher rate. A retrospective cross-sectional study examining treatment in the US vs Canada noted that subcutaneous and IV drugs are coded, managed, and billed differently in the US. The study included data from the acute palliative care units of The University of Texas MD Anderson Cancer Center in Houston and Princess Margaret Cancer Centre in Toronto, Ontario—centers that practice care for patients with cancer at the end of life similarly.

When examining administration, data revealed that of patients receiving care in Canada (n = 191) vs the US (n = 198), patients received subcutaneous agents only (55.5% vs 0.0%), IV only (4.7% vs 99.5%), and both (39.8% vs 0.5%), respectively.

Turning to the Logistics: Administration and Assessment of Performance Status

When examining the subcutaneous route with at-home administration and telemedicine visits that will take place, Nieva noted that data from wearable fitness monitors and smartphones can be a way to gather fitness information on patients. He added, “Using as many tools at your disposal to try to get an accurate assessment of your patients’ performance status is going to be important, and I believe it can be done by telemedicine. Trying to leverage some other orthogonal information that informs patient performance is a key feature of providing good telemedicine visits for your patients.”

“The biggest problem with telemedicine is it’s very hard to assess performance status and functionality of the patients because you don’t get to see the patient move in telemedicine as cameras tend to be fixed,” Nieva said. “In this clinical trial, we have a dashboard that gives us patient-derived information such as vital signs, weight, results from patient-reported outcome survey questionnaires, and other metrics of health and well-being that we can look at to provide optimal care for patients. That’s something that we’ve custom designed for this clinical trial. [For] other telemedicine appointments, I don’t currently have that dashboard created, so we have to do more in terms of questioning patients [and] sometimes doing things such as asking the camera to be repositioned and having the patient get up and walk around a little bit in the room while I watch them walk.”

In addition to keeping a close eye on assessing performance status during telemedicine visits, a key component of the trial will include the nurses administering the subcutaneous atezolizumab to patients. Nieva noted that currently USC has contracted with Mobile Medical LA, which provides at home nursing services across a broad range of indications. The nurses will travel throughout Southern California to deliver atezolizumab to patients.

“They’re not specifically research nurses, but they follow the research protocol in terms of delivering the medications. The key logistics, and probably the most important logistical challenges, are making sure that the medicine is shipped to the patient’s home and that it’s shipped cool,” Nieva noted. “We have the nurse open the shipping container rather than the patient to ensure that there’s no temperature variance that would lead to instability of the product. That works out well, but it does require a bit of coordination on our end and [for] our pharmacy to go from the order [of] administering the medicine after the results of laboratory studies are obtained to having the medicine shipped to the patient’s home, and then coordinating that with the arrival of the nurse.”

Delving Into the Next Steps With Telemedicine

Furthermore, the National Cancer Institute Telehealth Research Centers of Excellence (TRACE) is funding multiple centers focused on improving lives. Ways the centers are taking action include developing evidence-based telehealth approaches across cancer care, and evaluating the changing policy and payment environment as well as its impact on delivery of telehealth for cancer care, among others. The University of Pennsylvania TRACE is 1 of 4 TRACE centers, and it uses lung cancer care as a model for telehealth across the care continuum.

As telemedicine and subcutaneous delivery of agents continues to expand, the at-home study conducted by USC remains open to enrollment for patients with NSCLC. Patients will receive atezolizumab and rHuPH20 subcutaneously for 3 to 8 minutes on day 1 with cycles repeating every 3 weeks for 1 year for those with early-stage disease or up to 2 years for those with late-stage disease until disease progression or unacceptable toxicity.

“Patients who have high copays or who have difficulty with health maintenance organization coverage of these checkpoint inhibitors for lung cancer [treatment] are welcome to contact us, and we’d be happy to determine if they are eligible for clinical trial participation,” Nieva said.

Study explores the future of at-home cancer treatment. News release. Keck Medicine of USC. March 28, 2024. Accessed
May 8, 2024. bit.ly/3wrUv6q

Tecentriq. Prescribing information. Genentech Inc; 2024.
Accessed May 8, 2024. bit.ly/3ycReZr

US Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and
hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 8, 2024. bit.ly/4dyDtUO

Harvey MJ, Zhong Y, Morris E, Beverage JN, Epstein RS, Chawla AJ. Assessing the transition from intravenous to subcutaneous delivery of rituximab: benefits for payers, health care professionals, and patients with lymphoma. 

. 2022;17(1):e0261336. doi:10.1371/journal.pone.0261336

Tang M, Abdelaal M, Lau J, et al. Subcutaneous vs intravenous administration of medications and fluids for patients with cancer in the US and Canada. 

. 2023;9(5):717-719. doi:10.1001/jamaoncol.2023.0239

TRACE overview. NCI Telehealth Research Centers of Excellence (TRACE). Accessed May 8, 2024. bit.ly/3JW66Op

Subcutaneous atezolizumab for the treatment of non-small cell lung cancer. ClinicalTrials.gov. Updated February 13, 2024. Accessed May 8, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05340309

Articles

The integration of telehealth and subcutaneous immunotherapy is being explored in a pioneering clinical trial for non–small cell lung cancer (NSCLC). This trial aims to administer atezolizumab subcutaneously at patients' homes, leveraging telemedicine and wearable technology for remote monitoring. The subcutaneous route offers flexibility, cost savings, and ease of administration compared to intravenous therapy. The trial also addresses logistical challenges, such as medication delivery and performance status assessment, and highlights the potential for broader adoption of at-home cancer treatments.

Jorge J. Nieva, MD, details the role of telemedicine for patients with non–small cell lung cancer and a first-of-its-kind study examining atezolizumab given subcutaneously at home.

Addressing the Logistics of At-Home Cancer Care With Subcutaneous Administration of Immunotherapy

Non–small cell lung cancer (NSCLC) comprises approximately 80% to 85% of all lung cancer diagnoses, with 1% to 4% of these patients’ disease harboring mutations in 

, a tyrosine kinases receptor that plays an important role in cell growth and differentiation. The longtime standard of care in the space, chemotherapy, has produced a median progression-free survival (PFS) of only approximately 4 months historically, underscoring the need for more effective treatment options in the space (

“For patients with metastatic lung cancer, PD-L1 expression, as well as broad molecular profiling, is recommended. Currently, we have 11 types of molecular alterations that we are looking for in lung cancer; we are making our treatment decisions based on those alterations, and the 

 mutation is one of those alterations,” Lyudmila A. Bazhenova, MD,

®, a panel of expert clinicians in NSCLC discussed the treatment landscape of 

-mutantNSCLC. They highlight the current roles of antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) in the treatment arsenal, as well as touching on the unmet needs that remain in the space.

The ADC that has made the most waves in the HER2-positive (HER2+) NSCLC space is fam-trastuzumab-nxki deruxtecan (Enhertu), which first gained significant traction in treatment of HER2+ breast cancer. Following preliminary antitumor activity in the first-in-human study (NCT02564900), the HER2-directed ADC was evaluated in patients with 

-mutant NSCLC that was refractory to standard treatment exclusively in the phase 2 DESTINY-Lung01 trial (NCT03505710). The primary end point was objective response rate (ORR); secondary end points included PFS, duration of response (DOR), overall survival (OS), and safety.

“ADCs are a relatively new area for NSCLC,” Edward S. Kim, MD, MBA, said. “We’re now seeing these ADCs becoming approved in the clinic, [which] first started with HER2+ metastatic breast cancer and then HER2-low metastatic breast cancer, which was a quite an achievement—you have evenHER2+ stomach cancer. What we’re observing is that the utilization of chemotherapy and some of these other agents just don’t work very well in these [patients with 

-mutant disease], so finding alternatives to treat these folks is going to be very important.”

At a median follow-up of 13.1 months (range, 0.7-29.1), findings from the primary analysis of DESTINY-Lung01 demonstrated that patients who received trastuzumab deruxtecan 6.4 mg/kg (n = 91) achieved a centrally confirmed ORR of 55% (95% CI, 44%-65%) and a median DOR of 9.3 months (95% CI, 5.7-14.7). In terms of survival outcomes, the median OS and PFS were 17.8 months (95% CI, 13.8-22.1) and 8.2 months (95% CI, 6.0-11.9), respectively. “DESTINY-Lung01 was the backbone of the development of trastuzumab deruxtecan in relapsed or refractory NSCLC,” Edgardo Santos, MD, FACP, FCCP, FASCO, noted.

“We did see toxicities; it’s an ADC, so it’s a chemotherapy-like molecule,” Bazhenova said. “The most common toxicities were nausea, vomiting, fatigue, and [approximately] half of the patients had alopecia. One adverse effect that gave us a little bit of a pause, at least initially, was pneumonitis; approximately 26% of patients were reported to have interstitial lung disease [ILD] or pneumonitis.”

“If [a patient] gets pneumonitis, that’s really bad news, especially if it’s higher grade. But some other patients have just felt extremely fatigued. Depending on [a patient’s] reserve, most individuals can probably cope with it. But if a patient has no reserve to cope with a bump in the road, we shouldn’t forget that this is just a relatively sophisticated chemotherapy,” D. Ross Camidge, MD, PhD, added.

In another phase 2 trial, DESTINY-Lung02 (NCT04644237), investigators evaluated trastuzumab deruxtecan at 2 different dose levels, 6.4 mg/kg and 5.4 mg/kg, in patients with 

-mutant NSCLC who previously received platinum-based therapy. The primary end point was ORR per blinded independent central review, and patients were randomly assigned 2:1 to the 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50) arms.

The confirmed ORR in the 5.4 mg/kg and 6.4 mg/kg groups was 49.0% (95% CI, 39.0%-59.1%) and 56.0% (95% CI, 41.3%-70.0%), respectively. The median DOR was 16.8 months (95% CI, 6.4-not estimable [NE]) and NE (95% CI, 8.3-NE), respectively. At respective median follow-ups of 11.5 months (range, 1.1-20.6) and 11.8 months (range, 0.6-21.0), the median PFS was 9.9 months (95% CI, 7.4-NE) and 15.4 months (95% CI, 8.3-NE), respectively, and the median OS was 19.5 months (95% CI, 13.6-NE) and NE (95% CI, 12.1-NE), respectively.

“It’s going to be interesting to see whether the dose-adjusted patients actually have worse outcomes,” Martin Dietrich, MD, PhD,

said. “There is sort of a confidence about dose adjusting these patients. Those 2 data sets were relatively congruent, which helped us to confirm that 5.4 mg/kg of body weight [should be] the standard here.”

Trastuzumab deruxtecan was granted accelerated approval at a recommended dose of 5.4 mg/kg given intravenously every 3 weeks by the FDA in August 2022 for the treatment of adult patients with 

-mutant NSCLC, as detected by an FDA-approved test, who were previously treated with systemic therapy. The regulatory decision made trastuzumab deruxtecan the first agent approved for 

-mutant NSCLC and was supported by findings from DESTINY-Lung02.

“In [terms of efficacy and toxicities] including ILD, the confidence intervals overlap, but there was enough of a trend all heading in the same direction to say that the efficacy looks about the same, but the lower dose seems to be better tolerated. This is really the key to the accelerated approval of trastuzumab deruxtecan; [the] bigger data set followed up with saying, ‘This is the dose.’ This is the poster child for the FDA’s Project Optimus,” Camidge said.

Then, in April of this year, the FDA granted another accelerated approval to trastuzumab deruxtecan for adult patients with any unresectable or metastatic HER2+ solid tumors who have received previous systemic therapy and do not have any treatment alternatives. The approval was supported by findings from DESTINY-Lung01, DESTINY-PanTumor02 (NCT04482309), and DESTINY-CRC02 (NCT04744831).

Following the positive phase 2 findings observed with trastuzumab deruxtecan in 

-mutant NSCLC, investigators initiated the phase 3 DESTINY-Lung04 trial (NCT05048797). DESTINY-Lung04 is comparing trastuzumab deruxtecan with standard of care chemotherapy with either cisplatin or carboplatin in combination with pemetrexed (Alimta) and pembrolizumab (Keytruda) in adult patients with unresectable, locally advanced, or metastatic nonsquamous NSCLC with 

To be eligible for DESTINY-Lung04, patients must be treatment naive in the locally advanced or metastatic setting and have measurable disease per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 1 or less. The primary end point is PFS per blinded independent central review; secondary end points include PFS per investigator assessment, ORR, DOR, OS, and safety.

“We’ve been seeing consistent outcomes throughout the different lines of therapy, so hopefully we’ll see similar things [in DESTINY-Lung04],” Kim said. “This trial does allow patients with brain metastases, but they needed to have completed local therapy for it. We hope to see a similar safety profile and a similar efficacy profile [as observed in DESTINY-Lung01 and DESTINY-Lung02].”

Although there are currently no HER2-directed TKIs approved by the FDA in NSCLC, investigators are examining the HER2-selective TKI zongertinib (formerly BI 1810631) in the phase 1a/1b Beamion LUNG-1 trial (NCT04886804) in patients with 

-mutant solid tumors. Zongertinib binds covalently to wild-type and mutant HER2, including 

 exon 20 insertion mutations, and spares EGFR signaling.

Beamion LUNG-1 is examining zongertinib at a starting dose of 15 mg twice daily, with successive cohorts receiving increasing doses until at least 1 level above the estimated therapeutic dose is reached. The primary end point of the nonrandomized trial in phase 1a is safety by dose-limiting toxicities (DLTs) and determining the maximum tolerated dose (MTD), as well as ORR in phase 1b.

During the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer in September, study authors presented preliminary efficacy and safety findings from Beamion LUNG-1. In phase 1a (n = 46), patients received twice-daily doses of zongertinib from 15 mg to 150 mg or once-daily doses between 60 mg and 360 mg. Phase 1b (n = 42) included patients with pretreated, 

 tyrosine kinase domain (TKD)–mutant NSCLC (cohort 1); treatment-naive, 

 TKD–mutant NSCLC (cohort 2); NSCLC with a non–

 TKD mutation (cohort 3); NSCLC with active brain metastases (cohort 4); and NSCLC previously treated with a HER2-directed ADC (cohort 5).

At the July 17, 2023, data cutoff, the MTD had not yet been reached; on-treatment DLTs consisted of grade 2 edema (n = 1; 60 mg twice daily), grade 2 diarrhea (n = 1; 150 mg twice daily), grade 3 platelet count decrease (n = 1; 360 mg once daily), grade 3 alanine aminotransferase increase (n = 1; 180 mg once daily), grade 2 blood bilirubin increase (n = 1; 180 mg once daily), and grade 2 aspartate aminotransferase increase (n = 1; 180 mg once daily). The ORR in phase 1a was 41.3%, including 50.0% in patients with NSCLC (n = 34); all responses were partial. Efficacy-evaluable patients in phase 1b who received 2 to 5 treatment cycles (n = 23) achieved an ORR of 73.9% (95% CI, 53.5%-87.5%).

“More data are still needed. It’s [a] very small but very promising data set and we know that in an active TKI/driver mutation setting, it doesn’t take a lot of patients to show efficacy. Hopefully, this is a sign of better things to come. But I think everybody’s still waiting because of the prior data that we’ve seen with this type of class of agents,” Kim commented.

Updated data from phase 1a of Beamion LUNG-1, including PFS findings, are expected to be presented during this year’s American Society of Clinical Oncology Annual Meeting (ASCO 2024) in June.

“I’m excited to see where the drug is being taken forward and excited to see the first-line data because we’ve had discussions that trastuzumab deruxtecan does have toxicity,”Bazhenova said. “How [is] the field going to shake up if we see efficacy [with a] TKI in [the] first line, and how are we going to decide what goes first and what goes second? It remains to be seen.”

-mutant NSCLC is the oral agent BAY2927088, which selectively targets both HER2 and EGFR driver mutations, including exon 20 insertions; this preferential activity indicates a potentially wide therapeutic window for the agent. In the phase 1/2 trial SOHO-01 (NCT05099172), BAY2927088 is being examined in patients with advanced NSCLC with 

 mutations following disease progression after at least 1 systemic therapy. The coprimary end points are safety, tolerability, pharmacokinetics, and MTD. Secondary end points include ORR and determining the recommended phase 2 dose.

Preliminary findings presented during the 2023 European Society for Medical Oncology Congress in October showed that the ORR among all efficacy-evaluable patients (n = 69) was 26.1% (95% CI, 16.3%-38.1%), including 1 patient who achieved a complete response (CR). Among those with 

 exon 20 insertions (n = 20), the ORR was 60.0% (95% CI, 36.1%-80.9%) with 1 CR. In the overall population (n = 76) most patients experienced a treatment-related adverse effect (TRAE; 86.8%), there were 5 DLTs, and no patients were forced to discontinue treatment due to TRAEs.

In February 2024, Bayer announced that the FDA had granted BAY2927088 breakthrough therapy designation for the treatment of patients with NSCLC harboring 

activating mutations who received a previous systemic therapy. Additional safety and efficacy findings from an expansion cohort of SOHO-01 are expected to be presented during ASCO 2024.

“The most important thing is recognizing the role of HER2 as an oncogenic driver,” Dietrich said in conclusion. “These mutations look unfamiliar, and they come in many flavors, so it’s important to identify them properly. Oftentimes, we forget mutations that have been identified in the first-line setting to utilize them in a second-line setting. There’s a growing portfolio of clinical trials that are available for patients. HER2 needs to be recognized and channeled accordingly. HER2 is going to get more complex when we have the expression data. The inclusion of HER2 immunohistochemistry at some point in the treatment paradigm is going to be helpful. But [I am] very excited about the field of HER2 developing and finally getting ready for clinical application.”

Zhang J, Han W, Guo J, et al. Efficacy of immunotherapy in HER2-mutated non-small cell lung cancer: a single-arm meta-analysis. 

. 2024;150(2):42. doi:10.1007/s00432-023-05509-0

Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in 

. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431

Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with 

-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. 

. 2023;41(31):4852-4863. doi:10.1200/JCO.23.01361

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 16, 2022. Accessed May 8, 2024. bit.ly/3ycj8Vv

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed May 8, 2024.
bit.ly/3UUaNyg

Li BT, Ahn MJ, Goto K, et al. Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04). 

. 2022;40(suppl 16):TPS9137. doi:10.1200/JCO.2022.40.16_suppl.TPS9137

Heymach J, Opdam F, Barve M, et al. A phase I, open-label, dose confirmation, escalation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations. 

. 2023;24(2):e65-e68. doi:10.1016/j.cllc.2022.10.008

Yamamoto N, Opdam F, Barve M, et al. Beamion Lung-1, a phase 1a/b trial of the HER2 TKI, zongertinib (BI 1810631), in patients with advanced solid tumors with HER2 aberrations. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract MA13.08.

Heymach J, Opdam F, Barve M, et al. Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2-specific tyrosine kinase inhibitor (TKI), in patients (pts) with HER2 aberration-positive solid tumors: updated phase Ia data from Beamion LUNG-1, including progression-free survival (PFS) data.

.2024;42(suppl 16):8514. doi:10.1200/JCO.2024.42.16_suppl.8514

Loong HHF, Daniele G, Yang TY, et al. Early evidence of efficacy in patients (pts) with non-small cell lung cancer (NSCLC) with HER2 exon20 insertion (ex20ins) mutations treated in a phase I study with BAY 2927088. 

. 2023;34(suppl 2):S761-S762. doi:10.1016/j.annonc.2023.09.2409

Bayer receives U.S. FDA breakthrough therapy designation for BAY 2927088 for non-small cell lung cancer harboring HER2 activating mutations. News release. Bayer. February 26, 2024. Accessed May 10, 2024. bit.ly/4bfTSfw

Girard N, Kim TM, Kim HR, et al. Safety and anti-tumor activity of BAY 2927088 in patients with 

-mutant NSCLC: results from an expansion cohort of the SOHO-01 phase I/II study.

.2024;42(suppl 17):LBA8598. doi:10.1200/JCO.2024.42.17_suppl.LBA8598

Non–small cell lung cancer (NSCLC) with HER2 mutations represents a small subset of lung cancer cases. Traditional chemotherapy has limited efficacy, prompting exploration of new treatments like antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs). Trastuzumab deruxtecan has shown promising results in clinical trials, leading to its accelerated FDA approval. Ongoing research is evaluating other HER2-targeted therapies, including zongertinib and BAY2927088, which have demonstrated early efficacy. The evolving treatment landscape emphasizes the importance of molecular profiling and personalized therapy in managing HER2-mutant NSCLC.

A panel of expert clinicians discuss the treatment landscape of HER2-mutant non–small cell lung cancer, highlighting the current roles of ADCs and TKIs, and unmet needs that remain in the space.

ADCs and TKIs Look to Carve Out Their Place in the HER2-Mutant NSCLC Treatment Paradigm

It is surely widely appreciated that the quality of life (QOL) experienced by patients with cancer is a critically relevant measure of the care provided. Further, in the therapeutic clinical trials domain, enhancing QOL and improving survival are frequently cited as primary end points or secondary end points that define a favorable outcome.

Yet, when one considers the establishment of a clinical team within an organized cancer program, or even a large oncology practice group, where the focus will be on maximizing QOL, it may be difficult to define the objective goals of this effort. In fact, even agreeing on the clinical membership of the initiative may be problematic.

Despite an internal understanding of a variety of potentially beneficial strategies to maintain and enhance the QOL of the cancer patient population, the reality of the current American health care payment model, which in most circumstances fails to recognize the effort required to provide these essential services, may realistically negatively affect the development of a fiscally viable program.

In addition, although some may choose to disagree, in the opinion of this commentator the terminologies and metrics designed to carefully and objectively demonstrate the favorable influence of interventions on survival are far easier to define, be agreed upon, measure, and ultimately be accepted by the cancer community and others (eg, regulators, payers) as being clinically meaningful than currently available outcomes employed to assess individual or group perceptions of the quality of care experienced during the cancer journey.

For example, even a high-level descriptive term such as “survivorship,” which is designed to foster hope, develop assisting programs, and generally support a positive approach to potentially difficult future events and feelings, has not been without controversy.

Supportive care, or a frequently employed alternative name, palliative care, is terminology designed to emphasize necessary efforts to optimize outcomes involving multiple clinical and nonclinical domains that may substantially influence an individual patient’s QOL, especially in the setting of advanced cancers.

Trial-based experiences have confirmed that a variety of novel approaches (eg, follow-up telephone calls after hospital discharge, easy-to-use online patient portals, etc) designed to quickly recognize and effectively manage signs of serious cancer or treatment-related adverse effects may favorably affect patient well-being, medically related costs (emergency department visits, unplanned hospitalizations), and even survival.

Yet, if one inquires as to what services are required/essential to establish an effective supportive or palliative care team, what services might be considered optional, what is the optimal organizational and leadership structure of such an effort, and what should be the anticipated costs vs revenue of the program, responses and current experiences are almost certain to vary greatly.

Does supportive care include behavioral and nutrition services, social work, financial counselors, pastoral care, and discharge planners, all of which are surely relevant to many individual patients’ well-being? Does a “survivorship” program, however this effort is defined, belong within the organizational domain of supportive care, and if not, where should such an initiative be placed?

Conversely, although likely not a popular notion, when limited available resources are necessarily considered, might supportive care as a specific cancer program rationally be defined far more narrowly? Should it perhaps focus on pain management, effective transition to end-of-life care and use of hospice services, and strategies to optimize safe and efficient hospital discharge?

The difficulty in providing clear answers to these questions is highlighted by the reported outcomes of trials at least partially designed to help define and further objectively document the utility of palliative/supportive in cancer management and patients with other serious but nonmalignant medical conditions.

For example, in a recently reported randomized study of palliative care provided in the perioperative setting involving 359 patients with gastrointestinal cancers undergoing an attempt at curative surgery, investigators were unable to demonstrate a difference in either survival or prospectively defined patient-reported health-related QOL measures.

 One might suggest an alternative interpretation of the study results was that the inclusion criteria were excessively broad, and perhaps a different result might have been obtained if participants were restricted to individuals at high risk of experiencing a poor outcome due to nutritional concerns or the presence of relevant comorbid conditions.

Investigators in another randomized study involving “seriously ill hospitalized patients” explored the utility of a default palliative care consult order and failed to demonstrate a reduction in the length of hospital stay, the primary study end point.

 Although perhaps a disappointing result, it is reasonable to inquire if the declared end point, while surely a rational fiscal goal, exceeded what could have possibly been expected for a palliative care consult intervention.

Conversely, a recently reported analysis of the ADAPT trial (NCT02713347), which explored a nurse/social worker effort within the Veterans Health Administration in individuals with serious lung and heart disease, demonstrated a statistically significant improvement in QOL compared with “usual care,”

 but although clinically meaningful, one can certainly appreciate this end point may not by itself result in such a program being granted high priority within an organization dealing with the reality of limited resources.

There has been no intent in writing this commentary to achieve closure on this complex topic. Rather, the goal has been to stimulate essential discussions to ensure that supportive/palliative care efforts achieve recognition as an 

essential core component of any cancer program

, regardless of our current societal difficulties in defining exactly what that “core” entails and how it will be funded.

Astrow AB. Cancer survivorship and beyond. 

. 2012; 308(16):1639-1640. doi:10.1001/jama.2012.13258

Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. 

. 2010; 363(8):733-742. doi:10.1056/ NEJMoa1000678

Temel JS, Greer JA, El-Jawahri A, et al. Effects of early integrated palliative care in patients with lung and GI cancer: a randomized clinical trial. 

. 2017;35(8):834-841. doi:10.1200/ JCO.2016.70.5046

Basch E, Deal AM, Dueck AC, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. 

. 2017; 318(2):197-198. doi:10.1001/ jama.2017.7156

Basch E, Deal AM, Kris MG, et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. 

. 2016; 34(6):557-565. doi:10.1200/ JCO.2015.63.0830

Basch E, Schrag D, Henson S, et al. Effect of electronic symptom monitoring on patient-reported outcomes among patients with metastatic cancer: a randomized clinical trial. 

. 2022; 327(24):2413-2422. doi:10.1001/ jama.2022.9265

Kayastha N, LeBlanc TW. Why are we failing to do what works? Musings on outpatient palliative care integration in cancer care. 

. 2022;18(4):255-257. doi:10.1200/OP.21.00794

Aslakson RA, Rickerson E, Fahy B, et al. Effect of perioperative palliative care on health-related quality of life among patients undergoing surgery for cancer: a randomized clinical trial. 

. 2023;6(5):e2314660. doi:10.1001/ jamanetworkopen.2023.14660

Courtright KR, Madden V, Bayes B, et al. Default palliative care consultation for seriously ill hospitalized patients: a pragmatic cluster randomized trial. 

. 2024;331(3):224-232. doi:10.1001/ jama.2023.25092

Bekelman DB, Feser W, Morgan B, et al. Nurse and social worker palliative telecare team and quality of life in patients with COPD, heart failure, or interstitial lung disease: the ADAPT randomized clinical trial. 

. 2024;331(3):212-223. doi:10.1001/ jama.2023.24035

Quality of life (QOL) is a critical measure in cancer care, often cited as a primary or secondary endpoint in clinical trials. However, defining objective goals and establishing a clinical team focused on QOL can be challenging. The current American healthcare payment model often fails to support these essential services, impacting program viability. Metrics for survival are easier to define and measure compared to QOL outcomes. Despite trial-based evidence supporting novel approaches to enhance QOL, the optimal structure and funding for supportive/palliative care programs remain contentious and variable.

Defining the goals of a clinical team within a cancer program or oncology practice group, where the focus will be on maximizing QOL, may be difficult.

Oncologic Supportive Care Is Absolutely Critical—But How Do We Define It?

After I elucidate the intricacies and potential risks of the Whipple procedure to my patients with pancreatic cancer, they invariably pose the crucial question, “What can I expect afterward?” Their query underscores the primary aim of this surgical intervention—to extend life. Regrettably, I often find myself without a definitive answer. Despite remarkable advancements in cancer care, we remain uncertain about the postoperative survival rates for patients with pancreatic cancer.

Patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC), which constitutes approximately 90% of pancreatic cancers, exhibit varying survival outcomes.

 Although average survival figures differ across study data, investigators of 1 study reported that 3-year survival rates ranged from 20% to 34% for patients with successfully resected tumors.2 Notably, the 5-year survival rate for Whipple surgery after pancreatic cancer is 20% to 25%.

 The challenge lies in predicting where an individual patient will fall within this spectrum. Will they experience an early recurrence, nullifying the surgical benefits, or will they become a long-term survivor? The absence of reliable prognostic data compels us to approach most nonmetastatic cases uniformly with a combination of chemotherapy and surgery.

The field of pancreatic cancer prognostication is severely constrained, which is particularly concerning given that pancreatic cancer is poised to become the second leading cause of cancer-related deaths in the United States by 2030.

 This research deficit manifests in our clinical approach to patients with pancreatic cancer, which lacks the complexity and individualization seen in breast cancer management, as breast cancer is a field that benefits from extensive research funding. Unlike breast cancer treatments—which are tailored based on various factors such as patient age, tumor characteristics, and molecular profile—pancreatic cancer treatments remain largely homogeneous across stages I through III, with minor variations. This oversimplified approach stems from our inability to effectively stratify patients based on long-term prognosis.

In a recent study, we evaluated the predictive accuracy of existing models that incorporate clinicopathologic factors and biomarkers, such as CA 19-9 levels and tumor stage. Findings from our analysis, conducted across 6 high-volume academic centers in the United States, revealed that these models possess approximately a 60% accuracy rate in predicting survival following pancreatectomy.

Such limited predictive capability carries serious implications. In a retrospective study at our institution examining 66,326 patients undergoing the Whipple procedure across 1500 US cancer centers, data showed that approximately 25% of patients died within 1 year post diagnosis, despite under- going surgery. Given that patients with metastatic disease typically survive for up to 1 year with chemotherapy alone, surgery conferred no survival advantage for a significant subset of patients. Clearly, there is an urgent need for improvement.

Two major obstacles hinder the development of more accurate predictive models: data availability and analytical methodologies employed in previous studies. In our ongoing research, funded by the National Cancer Institute, we are leveraging machine learning techniques to analyze electronic health record (EHR) data from over 80 centers in the United States. Although EHRs offer extensive longitudinal patient information ideal for studying cancer outcomes, they also have limitations. Our current efforts involve incorporating additional biological and socioeconomic variables known to influence outcomes.

Over the past 2 years, in collaboration with University of Wisconsin informatics teams and funded by the Pancreas Cancer Task Force, we have established a unique data registry for patients with PDAC. This repository integrates EHR data from University of Wisconsin Health, socioeconomic data from the American Community Survey, surgical outcomes from the National Surgical Quality Improvement Program, genomic data, and cancer-specific information from the North American Association of Central Cancer Registries. Hosted on a cloud-based platform, the registry facilitates interdisciplinary pancreatic cancer research beyond prognostic modeling.

We are expanding this registry to encompass pathology, radiology, and other pertinent markers, and invite collaborators to join us in address-
ing these research questions. Furthermore, we plan to extend this pioneering registry to multiple academic sites, aiming to create the most comprehensive digital database specific to PDAC.

Our overarching goal is to devise a risk-stratification method capable of identifying distinct disease trajectories in patients with PDAC. This stratification will facilitate more informed treatment decisions, enhance clinician-patient communication, and pave the way for personalized treatment strategies tailored to individual patient needs.

: This piece features references to unpublished data.

Stoffel EM, Brand RE, Goggins M. Pancreatic cancer: changing epidemiology and new approaches to risk assessment, early detection, and prevention. Gastroenterology. 2023;164(5):752- 765. doi:10.1053/j.gastro.2023.02.012

Spore LM, Dencker EE, Kvanner EA, et al. Perioperative factors associated with survival following surgery for pancreatic cancer – a nationwide analysis of 473 cases from Denmark. BMC Surg. 2024;24(1):76. doi:10.1186/s12893-024-02369-4

Whipple surgery for pancreatic cancer. UPMC Hillman Cancer Center. Accessed May 6, 2024. bit.ly/44zuxKT

Rosenzweig A. New paper highlights urgent need for pancreatic cancer progress. Pancreatic Cancer Action Network. April 7, 2021. Accessed May 6, 2024. bit.ly/3JQ4tSh

Marcinak CT, Parker WF, Parikh AA, et al. Accuracy of models to prognosticate survival after surgery for pancreatic cancer in the era of neoadjuvant therapy. J Surg Oncol. 2023;128(2):280-288. doi:10.1002/jso.27287

Despite advancements in cancer care, predicting postoperative survival rates for pancreatic cancer patients remains challenging. The Whipple procedure, a common surgical intervention for pancreatic ductal adenocarcinoma (PDAC), shows varied survival outcomes, with 3-year survival rates ranging from 20% to 34% and 5-year rates at 20% to 25%. Current prognostic models, which incorporate clinicopathologic factors and biomarkers, have limited accuracy. Ongoing research aims to improve predictive capabilities using machine learning and comprehensive data registries, ultimately striving for personalized treatment strategies and better patient outcomes.

Partner Perspective

Zyed Nabeel Zafar, MD, MPH, explores the nuances of postoperative considerations in pancreatic cancer treatment. 

Exploring the Nuances of Postoperative Considerations in Pancreatic Cancer

 fusion–positive non–small cell lung cancer (NSCLC) is a rare but important lung cancer subtype, constituting 1% to 3% of all reported lung cancer cases. These alterations also occur in other solid tumors such as cholangiocarcinoma, glioblastoma, angiosarcoma, and ovarian cancer. Over 50 

 fusion partners have been identified, each influencing subcellular localization, signaling, metastasis, and drug sensitivity.

 fusions are rare but important events,” Stephen V. Liu, MD, explained in an interview with 

. “These types of cancers don’t respond particularly well to immunotherapy. They can respond to chemotherapy, but for years our standard of care has been targeted therapy.”

Despite the array of effective agents targeting ROS1/NTRK within the current armamentarium, these tyrosine kinase inhibitors (TKIs) have limitations that may affect the durability and efficacy of the therapeutic response. These include limited central nervous system (CNS) penetrance, an inability to treat on-target resistance, and TRK-associated neurologic and gastrointestinal toxicities.

Investigators are hoping to address key limitations and toxicity concerns associated with available ROS1/TRK inhibitors for patients with 

-positive tumors through the development of the selective ROS1 inhibitor zidesamtinib (NVL-520), which is being evaluated in the phase 1/2 ARROS-1 study (NCT05118789).

“A selective ROS1 inhibitor is certainly something that we need [in lung cancer],” Liu emphasized in the interview. “It may be more potent, may even be more effective with longer durability, and could have better activity in the brain, but more importantly, it should have a better safety profile. When designing the perfect ROS1 inhibitor, we want one that’s able to overcome resistance mutations, has few toxicities, and has excellent CNS penetration. NVL-520 was designed with this in mind.” Liu is an associate professor of medicine at Georgetown University, as well as the director of thoracic oncology and head of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Current Arsenal of ROS1-Targeted TKIs: Advantages and Limitations

Several TKIs are approved for the treatment of patients with 

 fusion–positive NSCLC. Crizotinib (Xalkori) was the first agent to be approved for patients with 

fusion–positive metastatic NSCLC in March 2016.

 This was followed by the March 2019 accelerated FDA approval of entrectinib (Rozlytrek) for the treatment of adult and pediatric patients 12 years or older with solid tumors that harbor an 

 fusion, as well as adults with TKI-naive, 

“Crizotinib proved to be a very effective agent in this setting. It often [produced] periods of disease control measured in years, with [data from] some studies quoting a progression-free survival [PFS] of just over 1 year,” Liu continued. He added, “The ROS1/NTRK inhibitor entrectinib has supplanted crizotinib as my own favored ROS1 inhibitor. Entrectinib shows a similar PFS [to that of crizotinib in this setting] but in a slightly newer, more modern population, and has the advantage of being more effective within the brain. If you [look at] the outcomes with entrectinib and crizotinib in their best-performing studies, the numbers look similar. [However,] we must keep in mind that crizotinib was studied at a time when sequencing and testing for ROS1 was done in a very different way.”

More recently, the FDA approved repotrectinib (Augtyro) in locally advanced or metastatic 

 fusion–positive NSCLC on November 15, 2023.

 The approval was based on findings from the phase 1/2 TRIDENT-1 trial (NCT03093116), in which patients with 

-positive NSCLC in the phase 2 dose-expansion cohorts experienced high response rates regardless of prior exposure to a TKI.

“When you look at entrectinib and repotrectinib, they have a few things in common,” Liu continued. “They’re CNS penetrative and effective in the brain, and they’re very potent—they can work for years. Both [agents] have activity for ROS1 and TRK. It turns out there’s a fair amount of homology between those 2 kinases.”

Other options in this space include lorlatinib (Lorbrena), which the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology lists as a treatment option for TKI-pretreated 

 Investigational TKIs such as taletrectinib (AB-106/DS-6051b) are also being studied for 

fusion–positive cancers, with this agent receiving an FDA breakthrough therapy designation for adult patients with advanced or metastatic 

-positive NSCLC who are ROS1 inhibitor–naive or had previously received crizotinib.

Notably, entrectinib, lorlatinib, taletrectinib, and repotrectinib are all inhibitors of both ROS1 and TRKA/B/C. Although the use of these ROS1/NTRK–targeted TKIs allows for the use of the same treatment for patients harboring either alteration, Liu cautioned that there can be significant gastrointestinal and neurologic adverse effects (AEs) associated with TRK inhibition that can be dose limiting and negatively affect quality of life. TRKB inhibition in particular has been associated with cognitive impairment, mood/sleep disturbance, dizziness, ataxia, orthostasis, and weight gain.

“TRK is responsible for proprioception and plays an important role in gait stability and coordination,” Liu explained. “When we inhibit TRK, it can often lead to dizziness, gait instability, ataxia, and lightheadedness. Although it is [an advantageous] feature if you have an 

-driven cancer, it is otherwise quite a flaw. By [giving patients with] 

-positive cancer a drug that also inhibits TRK, that’s mediating toxicity but not really helping in terms of cancer control.”

Stephen V. Liu, MD, details the phase 1/2 ARROS-1 study evaluating the selective ROS1 inhibitor zidesamtinib in patients with ROS1 fusion–positive non–small cell lung cancer.

Vol. 25 No. 8 | Oncology Live®

Addressing the Logistics of At-Home Cancer Care With Subcutaneous Administration of Immunotherapy

ADCs and TKIs Look to Carve Out Their Place in the HER2-Mutant NSCLC Treatment Paradigm

Oncologic Supportive Care Is Absolutely Critical—But How Do We Define It?

Exploring the Nuances of Postoperative Considerations in Pancreatic Cancer

ARROS-1 Trial of Zidesamtinib Aims to Address Current TKI Limitations in ROS1+ NSCLC

Exploiting the Vulnerabilities of High-Grade Serous Ovarian Cancer Through WEE1 Inhibition