OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Advances in the treatment of solid tumors and hematologic malignancies have resulted in the development of thera-peutic regimens that can be administered at various points in a patient’s care. However, as patients’ disease progresses, adverse effects (AEs) from initial standards of care or second- or later-line may limit the ability of a patient to pursue addi-tional treatments. Neutropenia is a common complication of chemo-therapy that increases the risk of serious infections and fever and may require adjustments to patients’ chemotherapy schedules, potentially affecting their early and long-term outcomes. “It can be quite challenging in clinics to [treat], prevent, anticipate, and then keep patients on track in terms of their curative chemotherapy or therapy that’s helping to extend life and keep their symptoms under control,” Rita Nanda, MD, said during a recent 

Nanda was joined by a panel of breast cancer experts to discuss this high-stakes complication, which may be encountered more frequently in patients with breast cancer than other tumor types as risk of neutropenia tends to increase with increas-ing treatment lines. “We see it in breast cancer because we’re [treating] patients in the sixth-, seventh-, or eighth-line setting,” Tiffany A. Traina, MD, explained. During their discussion, the panelists shared their experiences with chemotherapy-induced neutropenia (CIN) and provided insights on its risk factors, when to intervene, use of granulocyte colony-stimulating factors (G-CSFs), and the unique challenges associ-ated with these agents.

A patient is generally considered to have CIN when their absolute neutrophil count (ANC) count is less than 2000 cells/µL.

 This toxicity is then further classified into grades based on severity (TABLE 1

). Nanda said she considers CIN to be any ANC level that would preclude her from providing a patient with their planned treat-ment. In most cases, she said this is an ANC level of 1000 cells/µL or less. It is at this threshold when the most severe form of neutropenia, febrile neutropenia, may manifest.3 The National Cancer Institute’s Common Terminology Criteria for Adverse Events version 5.0 characterizes chemother-apy-induced febrile neutropenia (CIFN) as an ANC level less than 1000 cells/µL and a single temperature of higher than 38.3 °C (101 °F) or a sustained temperature of at least 38 °C (100.4 °F) for more than 1 hour.

“It’s not always entirely predictable in whom [CIN] is going to occur,” William J. Gradishar, MD, said. He explained that there can be variability, even among patients receiving the same treatments. Nevertheless, he said that some regimens may increase the risk of CIN, including dose-dense anthracycline-based regimens and docetaxel and other taxanes, particularly when administered as part of a combination regimen.

Traina noted that there are many patient- and disease-related risk factors for CIN, including older age (≥ 65 years), compromised organ function (eg, elevated bilirubin levels), low body surface area or low body mass index, low baseline white blood cell counts, presence of more advanced disease and/or more compromised bone marrow, and increasing treatment lines. “There is literature around certain SNPs [single nucleotide polymorphisms] that may predispose to neutropenia, depending on the regimen being used,” she said. 

For example, in a study of patients with breast cancer who were treated with 5-fluorouracil, epirubicin, and cyclophosphamide in the phase 3 SUCCESS-A trial (NCT02181101), 3 SNPs in 

 were found to be significantly associated with neutropenia.

 All 3 of these SNPs were transexpression quantitative trait loci for the expression of 

, encoding the cytokine B-cell activating factor. However, Traina said that SNP findings are not yet actionable but the hope is that they may eventually lead to the identification of biomarkers predictive of CIN risk.

The panelists noted that although CIFN is uncommon in their practices, it still occurs. A risk factor for CIFN is the use of corticosteroids, with longer-term use and more recent use of these agents reported to increase the risk of CIFN 3-fold and 2-fold, respectively.

 Additionally, certain dermatologic and mucosal conditions (eg, gastritis, dermatitis, psoriasis), as well as the use of intravenous antibiotics, but not oral antibiotics, before chemotherapy, have been associated with a higher risk of CIFN during the first chemotherapy cycle. It has been suggested that these factors should be considered in prophylaxis use and CIFN prediction modeling.

The National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients with solid tumors and nonmyeloid malignancies be evaluated for their risk of CIFN before their f irst chemotherapy cycle.

 The risk assessment should consider patients’ disease; chemotherapy regimen, including intensity (eg, high-dose, dose-dense, or standard-dose therapy); individual patient risk factors; and treatment intent (ie, curative vs palliative). Based on these findings, patients are classified into a high-, intermediate-, or low-risk category, which guides the use of William J. Gradishar, MD prophylactic G-CSFs (TABLE 2

Traina explained that these are recommendations for primary prophylaxis. “Obviously, we’re all very comfortable once you’ve gone to treat a patient on, say, day 1 of a cycle, and they present with limiting neutropenia, then incorporating growth factor in that secondary prophylaxis setting, [which] is often preferred to keep patients on schedule at an appropriate dose and intensity,” she said.

Though the NCCN guidelines provide guidance on preventing CIFN following the first round of chemotherapy, they do not address CIFN risk after patients start chemotherapy. “It’s important for us to understand when patients are at their greatest risk for CIN, which is after they start chemotherapy. That’s something our patients also want to know, in terms of what their risk is if they’re going to travel or work,” Hope S. Rugo, MD, FASCO, said. 

Rugo explained that with most regimens neutropenia occurs 7 to 10 days after chemotherapy is administered, though risk of CIN may be prolonged when drugs with a longer half-life are used, such as platinum agents. “We worry a lot about infections when [a patient] has grade 4 neutropenia with a neutrophil count fewer than 500 per µL, whereas we’ll see patients with a neutrophil count of 980 per µL, which is fewer than 1000 per µL but not worrisome….There’s some risk, but with fewer than 500 per µL there’s an even greater risk,” she said. 

Nanda said clinicians should have a low threshold on when to integrate prophylaxis into their regimens, particularly during the COVID-19 pandemic. “In this era of COVID-19, we need to be aggressive about trying to prevent neutropenia and neutropenic fevers because hospitals are not great places for our patients to be right now, and emergency departments are even more challenging [environments]. Preventing neutropenia and preventing neutropenic fevers is even more critical for our patients,” she emphasized.

Using Growth Factors in Clinical Practice

The panelists explained that the supportive measures used today, such as growth factors, have helped eliminate or at least significantly reduce the risk of many of the toxicities observed in the past, such as mouth sores and typhlitis. “The most common symptoms we see are the sequalae from the chemotherapy, low-grade fevers, or flu-like symptoms,” Gradishar said. “The typical AEs that would have been more common at the early part of our careers are infrequent.” Nevertheless, he warned that there are rare patients who may still experience profound neutropenia in the immediate period after chemotherapy before their blood counts recover, which can be catastrophic. 

Traina recently encountered such a patient, a woman in her late 60s treated with docetaxel/cyclophosphamide (TC) in the adjuvant setting. She said the patient was hospitalized with neutropenic colitis after her first treatment cycle. Based on her experience, Traina said she is very sensitive to risk factors and using growth factors as prophylaxis for any patient with a high-risk feature.

Gradishar agreed and indicated that, although chemotherapy regimens have improved and become more tolerable overall, there are still regimens that warrant the use of G-CSF prophylaxis, including some requiring a long-acting G-CSF such as pegfilgrastim (Neulasta). “With TC we [give pegfilgrastim]. With AC [doxorubicin hydrochloride/cyclophosphamide], we [give it] every other week. [With] weekly paclitaxel, we don’t. We don’t use TAC [docetaxel/ doxorubicin hydrochloride/cyclophosphamide],” he explained. 

The panelists also noted differences in their G-CSF prophylaxis practices in the curative/adjuvant setting vs the metastatic setting. Rugo said she still tends to use growth factors in the metastatic setting “to keep [patients] on schedule in part because they do better and secondly because it’s a nightmare to reschedule everybody all the time,” but that they might change the schedules to every other week. 

Gradishar and Traina both said they tend to be less rigid about patients staying on their chemotherapy schedules in the metastatic setting because the focus is more on palliation. “There’s a real inconvenience aspect [to] self-injection or having to come into the clinic for daily growth factor injection,” Traina said. “In the palliative setting, that’s not where I want my patients spending their time. I don’t want them to be in the hospital or the clinic. I’m with [Dr Gradishar], adjusting schedules and doses perhaps a little more liberally in that setting.”

Nanda said that she also considers patients’ past experiences to determine the need for G-CSF in the metastatic setting. “If I have patients who’ve been on chemotherapy drugs that generally aren’t associated with needing growth factor but they needed it, then a lot of times I will preventively use it when they move on to subsequent lines of therapy,” Nanda said. “There are cases in which I’ll even preventively use it in the advanced cancer setting, particularly for patients who have a heavy disease burden and have struggled with therapies in the past that most [patients] don’t struggle with.”

Mitagating Challenges Associated with G-CSF Treatments

Although treatment with G-CSFs is generally well tolerated, they are associated with several toxicities, including bone pain. Rugo explained that bone pain is more common in patients with naïve bone marrow but that some patients “seem to get it all the time.” In patients with bone pain, an important step is for clinicians to determine its cause, including whether it is related to the patient’s chemotherapy regimen or to the growth factor support, especially because bone pain can be mistaken for a myocardial infarction or other complications and lead to unnecessary hospitalizations and procedures. 

“I have a patient who has von Recklinghausen neurofibromatosis and a bunch of other things, including...ER [estrogen receptor]–positive early-stage breast cancer,” Rugo said. “She has had severe bone pain and went to the emergency department, where [she received a diagnosis of] pericarditis. I pointed out that she didn’t have that, but they didn’t believe me—she just had this drug-induced pain. Consequently, we’re working around that, but it can be a big issue for patients.” 

Once it is determined that the bone pain is induced by the growth factor support, Gradishar said he will treat his patients with a course of steroids or antihistamines, as these can be helpful in resolving the pain in some cases. Rugo agreed and said that she usually prescribes nonsedating antihistamines. Although they work variably, and the mechanisms by which they improve bone pain remains unclear, she said these agents have “little downside” because they are “cheap and nontoxic.” 

Because bone pain from G-CSFs usually occurs quickly after their administration, Nanda said that she forewarns her patients about this complication and advises them to take over-the-counter (OTC) anti-inflammatory medications if they notice any pain. Then, if the OTC treatment does not work, they are advised to call the office so that they can be prescribed steroids. Another challenge the panelists discussed is delivery of G-CSF via an on-body device. Although these devices spare patients from returning to their doctor’s office the day after their infusion, they come with other restrictions. Traina noted that patients with such devices can’t have imaging done, which may lead to other care challenges and make it difficult to travel if they need to fly. Additionally, the on-body devices do not provide flexibility in dosing and there may be drug delivery issues in some patients. 

“Clinicians would often give different amounts of pegfilgrastim if [patients] didn’t need the full dose, but with the on-body device, we can’t do that,” Rugo said. “Additionally, I’ve had a very overweight patient for whom I don’t think the drug was delivered. She kept getting profound neutropenia, and then as soon as we switched to the injection, on day 2 it went away.”

Ba Y, Shi Y, Jiang W, et al. Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association. Cancer Biol Med. 2020;17(4):896-909. doi:10.20892/j.issn.20953941.2020.0069

Sapkota B, Shrestha R, Chapagai S, Shakya DK, Bista P. Validation of risk of chemotherapy-induced neutropenia: experience from Oncology Hospital of Nepal. Cancer Manag Res. 2020;12:3751-3758. doi:10.2147/CMAR.S243916 

Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. National Cancer Institute. November 27, 2017. Accessed November 22, 2021. bit.ly/3nFlRPp 

Bidadi B, Liu D, Kalari KR, et al. Pathway-based analysis of genome-wide association data identified SNPs in HMMR as biomarker for chemotherapy-induced neutropenia in breast cancer patients. Front Pharmacol. 2018;9:158. doi:10.3389/ fphar.2018.00158 

Family L, Li Y, Chen LH, Page JH, Klippel ZK, Chao C. A study of novel febrile neutropenia risk factors related to bone marrow or immune suppression, barrier function, and bacterial f lora. J Natl Compr Canc Netw. 2018;16(10):1201-1208. doi:10.6004/jnccn.2018.7051 

NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic growth factors, version 4.2021. Accessed November 23, 2021. bit.ly/2Zg5teH

Articles

Oncology Live®

Advances in the treatment of solid tumors and hematologic malignancies have resulted in the development of thera-peutic regimens that can be administered at various points in a patient’s care.

Investigators Navigate the Complicated Treatment Landscape of Chemotherapy-Induced Neutropenia 

The immune checkpoint TIM-3 is shaping up to be a viable target for designing therapies for patients with non–small cell lung cancer (NSCLC) and other malignancies, according to a growing body of early scientific and clinical data. Investigative efforts so far are focusing on pairing novel agents directed at TIM-3 activity with PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy.

The research involving TIM-3 comes amid continuing efforts to boost the efficacy of ICI immunotherapy. Although PD-1/PD-L1 ICIs have improved outcomes for patients in a range of tumor types, primary and acquired resistance represents a significant unmet need. Investigators are exploring ICI combinations, including regimens involving novel immune checkpoints such as TIM-3, as a means of increasing response rates.

The potential for leveraging TIM-3 for anticancer therapy is being tested in early studies in several solid malignancies, with many of the trials exploring dual combination of ICIs aimed at TIM-3 and PD-1/PD-L1 immune checkpoints. Other approaches include bispecific antibodies that simultaneously target TIM-3 and PD-1.

In NSCLC, TIM-3 is among the intriguing emerging targets in development, accord-ing to experts who participated in Molecular Targets on the Horizon in Non–Small Cell Lung Cancer OncLive

 Scientific Interchange & Workshop, a panel discussion held on September 27.

“The theory here is that you can overcome I/O [immuno-oncology] resistance with a combination of a TIM-3 antibody with a PD-1/PD-L1 antibody,” Fred R. Hirsch, MD, PhD, said during the program. “We don’t have advanced clinical data…but I think we will see more and more of this target in the future.”

Hirsch, a longtime biomarker expert in the lung cancer field, is executive director at the Center for Thoracic Oncology in The Tisch Cancer Institute at Mount Sinai and the Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology) at Icahn School of Medicine at Mount Sinai, both in New York, New York.

Prognostic Implications of TIM-3 Expression

TIM-3, which stands for T-cell immunoglobulin and mucin domain 3, is a member of a family of coinhibitory receptors that help regulate immune responses. First described in 2002, TIM-3 is a cell-surface glycoprotein that can be expressed both on tumor cells and multi-ple types of immune cells.

 Hirsch noted that TIM-3 particularly is expressed on CD4-positive and CD8-positive T cells and often is coexpressed with other immune checkpoints such as PD-1 and TIGIT.

Investigators have identified 4 ligands that interact with TIM3: galectin-9, phos-phatidylserine, HMGB1, and CEACAM1.

 Galectin-9 is considered TIM-3’s main ligand

; binding of TIM-3 with this ligand inhibits an immune response by promoting cell death in TIM3-expressing T cells.

 TIM-3 also is upregulated on regulatory T cells, which hampers effector T cell functions. Specifically, TIM-3 overexpression contributes to T-cell exhaustion, which is characterized by a loss of T-cell effector functions, expression of inhibitory receptors, and alterations in transcriptional functions.

Hirsch noted that TIM-3 expression has a “complex biology” that negatively affects the immune system. “It is demonstrated preclinically that TIM-3 expression leads to dysfunctional lymphocytes and a dysfunc-tional immune reaction,” he said.

Findings from a meta-analysis published in 

 in August 2020 illustrate the prognostic impact of TIM-3 expression, according to Hirsch. “TIM-3 protein expression is related to poor over-all survival, poor outcomes, and increased capacity of metastasis,” he said. “And that is certainly a bad prognostic indicator.”

The meta-analysis was based on findings involving 3072 patients with solid tumors who were treated during 21 studies reporting results from 2012 to 2019 from China, Japan, Korea, and Poland. Thirteen tumor types were represented in the study populations. TIM-3 protein expression was evaluated via immunohistochemistry (IHC) on tumor cells and/or tumor-infiltrating lymphocytes (TILs).

For the entire study population, TIM-3 overexpression correlated with poor overall survival (HR, 1.73; 95% CI, 1.39-2.15; 

 < .001). Additionally, TIM-3 expression was associated with positive lymph node metastases (N+ vs N–; OR, 1.59; 

 = .013), higher tumor grade (G2-3 vs G1; OR, 1.68; 

 = .002), and PD-L1 expression (PD-L1 high vs PD-L1 low; OR, 3.26;

In terms of tumor types, elevated TIM-3 protein expression was a negative predictor of overall survival (OS) for patients with NSCLC, gastric cancer, esophageal squamous cell carcinoma, and other cancers but not for participants with breast cancer. In a further analysis, investigators analyzed data on TIM-3 mRNA expression for patients with NSCLC, gastric cancer, and breast cancer from a public database and found that the results aligned with their findings on the prognostic impact based on protein expression. High TIM-3 mRNA expression was significantly correlated with poor OS outcomes in patients with NSCLC (HR, 1.46; 

 = .0038) but not breast cancer (HR, 0.79; 

Investigators also examined the impact of TIM-3 protein expression on disease-free survival (DFS) outcomes based on findings from 7 studies involving 1243 patients. For the overall population, the data showed that TIM-3 expression did not correlate with DFS (HR, 1.39; 95% CI, 0.75-2.57; 

 = .297). However, elevated TIM-3 expression was significantly associated with shorter DFS in patients with NSCLC (HR, 2.40; 

Another study finding showed a differ-ence in the impact of TIM-3 expression on tumor cells vs TILs. TIM-3 overexpression was significantly associated with worse OS outcomes on tumor cells (HR, 2.10; 

Investigators noted that TIM-3 expression on tumor cells appears to have greater prognostic value than levels on TILs but that further research is needed to verify this signal. The authors also said that because most of the participants whose data were examined live in East Asia, similar analyses should be conducted on results from European patients. Another limitation involved the calculation of TIM-3 IHC expression; the antibodies and cut-off values differed among studies included in the meta-analysis.

In 2010, investigators established the negative impact on the immune system of upregulated TIM-3 and PD-L1 coexpression on melanoma specimens and suggested that a combination blockade strategy would be effective.

 Both TIM-3 and PD-L1 overexpression are markers of T-cell exhaustion; inhibiting both may result in a restoration of T-cell proliferation and cytokine production, thus generating an immune response.

Results of in vitro studies show that combining TIM-3 inhibition with a PD-1/ PD-L1 antibody increases production of interferon γ.

 “If you combined a blockade of TIM-3, which is the same mechanism as with PD-1/PD-L1, you actually see quite a lot of synergy,” Hirsch said. “…You see improvement of lymphocyte function and penetration and immune capacity.”

Early data from several clinical trials are encouraging, investigators say. In 2018, investigators reported the first findings from combination therapy with a TIM-3directed antibody and a PD-1 ICI, cobolimab (TSR-022) and dostarlimab-gxly (Jemperli), respectively, for patients with NSCLC who participated in the first-in-human multicohort phase 1 AMBER study (NCT02817633).

At the time of data cutoff, 39 patients with NSCLC whose disease had progressed after anti–PD-1 therapy had received cobolimab at either 100 mg or 300 mg plus a fixed dose of dostarlimab at 500 mg. Of the 14 patients who received the lower dose of cobolimab, 11 were evaluable for response; 1 had a confirmed partial response by immune-related RECIST criteria and 3 had stable disease. Of the 25 patients who received the higher dose of cobolimab, 20 were evaluable for response; 3 had confirmed partial responses and 8 had stable disease. All objective responses were among patients with PD-L1 tumor proportion scores of 1% or more.

Overall, the AMBER study, which seeks to enroll 369 participants, includes 2 parts. Part 1 comprises 8 experimental arms evaluating cobolimab as monotherapy and in combination with dostarlimab, the PD-1 inhibitor nivolumab (Opdivo), the antiLAG-3 antibody TSR-033, or chemotherapy in patients with advanced solid tumors. In part 2, there are separate cohorts testing cobolimab as monotherapy or in combination with dostarlimab in patients with NSCLC, melanoma, and colorectal cancer.

Investigators said the combination regimen was well tolerated across multiple dosing levels and that the responses showed the strategy is worth pursuing.

 However, they recommended increasing the dose of cobolimab to 900 mg for the NSCLC expansion cohort after analysis demonstrated that the 300-mg dose was inadequate for maintaining a maximal pharmacodynamic effect.

Meanwhile, triplet therapy with cobolimab plus dostarlimab and docetaxel is being evaluated in patients with advanced NSCLC in the phase 2/3 COSTAR Lung study (NCT04655976). Another experimental cohort is testing dostarlimab plus docetaxel, and the comparator arm is evaluating docetaxel monotherapy.

As these trials continue, dostarlimab has moved into the ranks of approved therapies. In separate decisions in 2021, the FDA granted dostarlimab accelerated approvals for adult patients with mismatch repair– deficient recurrent/advanced solid tumors or endometrial cancer that has progressed on or following prior treatment who have no satisfactory alternative treatment options.

In other early findings, investigators reported that the combination of sabatolimab (MBG453), a TIM-3 antibody, and spartalizumab (PDR001), a PD-1 ICI, generated partial responses lasting between 12 and 27 months among 6% of 86 patients with advanced solid tumors who received the regimen in an ongoing phase 1/2 study (NCT02608268). The responders included 2 patients with colorectal cancer and 1 each with NSCLC, malignant perianal melanoma, and small cell lung cancer. No responses were observed with sabatolimab monotherapy. The most common treatment-related adverse effect was fatigue, which was reported in 9% of those who received monotherapy and in 15% who had the combination.

Another experimental TIM-3 antibody, LY3321367, was tested as monotherapy and in combination with LY3300054, a PD-L1 inhibitor, in patients with advanced cancers during a phase 1 study (NCT03099109). In April 2021, investigators reported that the agent had an acceptable safety profile but exhibited “only modest antitumor activity.” In the NSCLC monotherapy expansion cohort, the objective response rate (ORR) was 0% among 23 patients who were refractory to PD-1/PD-L1 therapy and 7% among 14 prior ICI responders. In the combination expansion cohorts, the ORR was 4%.

 The study is active but no longer recruiting participants, according to ClinicalTrials.gov.

From the roster of novel regimens in development, Hirsch highlighted an ongoing phase 1/2 study (NCT03744468) testing the novel TIM-3 antibody BGB-A425 in combination with tislelizumab, a PD-1 inhibitor.

In the phase 1 dose-escalation phase, patients with locally advanced or metastatic unresectable solid tumors will receive BGB-A425 IV at increasing dosing levels ranging from 2 mg to 800 mg plus tislelizumab at 200 mg IV. The primary end points are safety, tolerability, and the identification of the recommended phase 2 dose.

In the phase 2 stage, the combination will be tested in separate cohorts of patients with recurrent or metastatic head and neck squamous cell carcinoma, extensive-stage NSCLC, or advanced gastric/gastroesophageal junction cancer. The primary end point is the objective response rate.

Investigators are seeking to recruit up to 42 patients from Australia and the United States to participate in phase 1 of the study. To be eligible, patients must have previously received standard systemic therapy, if available, or been unable or unwilling to undergo such treatment. The goal for phase 2 is to enroll up to 120 patients from Asia, Australia, and the United States. For these disease-specific cohorts, patients must have advanced or metastatic disease with 1 or more measurable lesions that has progressed after the most recent treatment.

Although BGB-A425 is a novel agent, tislelizumab is becoming an established part of anticancer therapy. Tislelizumab is approved in China for 5 indications including several first-line NSCLC settings, according to BeiGene Ltd, a pharmaceutical company based in Beijing, China, that is developing both drugs in the regimen.

 The company is collaborating with Novartis to develop tislelizumab in North America, Europe, and Japan.

 In the United States, the FDA is reviewing a biologics license application for tislelizumab for treating patients with unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma after prior systemic therapy. The agency is scheduled to decide on the application by July 12, 2022.

In hematologic malignancies, investigators are studying whether there is a role for combining TIM-3 inhibitors with other agents besides ICIs. In May 2021, the FDA granted a fast-track designation for sabatolimab in combination with hypomethylating agents for the treatment of adult patients with myelodysplastic syndromes (MDS) defined as high or very high risk on the Revised International Prognostic Scoring System.

Novartis, the company developing the drug, is exploring the efficacy of sabatolimab as part of different combination therapies in patients with MDS and acute myeloid leukemia (AML). The development program includes the phase 2 STIMULUSMDS1 (NCT03946670) and STIMULUS-MDS3 (NCT04812548) studies and the phase 3 STIMULUS-MDS2 (NCT04266301) study in MDS, as well as the phase 2 STIMULUSAML1 study (NCT04150029) in AML.

The studies of combination TIM-3 and PD-1/PD-L1 inhibitors underway in NSCLC are recruiting patients who already have received at least 2 lines of therapy. Paul A. Bunn Jr, MD, who served as moderator for the 

 program, wondered about the rationale for not testing the combination in upfront settings, where the regimen might be more effective. He also questioned whether a patient who progressed on ICI therapy would respond to repeat administration of an ICI with an added therapy.

 award winner in the lung cancer category, is the James Dudley Chair in Cancer Research and a distinguished professor of medicine-medical oncology at the University of Colorado School of Medicine in Aurora.

Hirsch agreed that the combination therapy is a candidate for first-line settings but that investigators are still seeking to establish “acceptable safety data” with early-phase studies. “The primary goal so far in this drug development has been to overcome I/O resistance,” he said. “…First-line studies are traditionally in later lines. We might see it in the future when we have a clear picture of the safety and the doses.”

With regard to biomarkers, Hirsch said IHC scoring approaches are “still on a very premature level of development” compared with other immunotherapies and that much more work is needed.

Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. 

. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911

Friedlander A, Addeo A, Banna G. New emerging targets in cancer immunotherapy: the role of TIM3. 

. 2019;4(suppl 3):e000497. doi:10.1136/esmoopen-2019-000497

Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. 

. 2017;168(4):707-723. doi:10.1016/j.cell.2017.01.017

Velcheti V, Schalper K. Basic overview of current immunotherapy approaches in cancer. 

. 2016;35:298-308. doi:10.1200/EDBK_156572

Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. 

. 2020;20(3):173-185. doi:10.1038/s41577-019-0224-6

Solinas C, De Silva P, Bron D, Willard-Gallo K, Sangiolo D. Significance of TIM3 expression in cancer: from biology to the clinic. 

. 2019;46(4-5):372-379. doi:10.1053/j.seminoncol.2019.08.005

Qin S, Dong B, Yi M, Chu Q, Wu K. Prognostic values of TIM-3 expression in patients with solid tumors: a meta-analysis and database evaluation. 

. 2020;10:1288. doi:10.3389/fonc.2020.01288

Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. 

. 2010;207(10):2175-2186. doi:10.1084/jem.20100637

Desai J, Meniawy T, BeagleB , et al. Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: a phase I/II trial in progress. 

. 2020;38:(suppl 15):TPS3146. doi:10.1200/JCO.2020.38.15_suppl.TPS3146

TESARO announces immuno-oncology data presentations at SITC 2018 Annual Meeting. News release. TESARO, Inc. November 9, 2018. Accessed November 22, 2021. https://bit.ly/3CJWvUO

Davar D, Boasberg P, Eroglu Z, et al. A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042 (anti-PD-1) in patients with colorectal cancer and post-PD-1 NSCLC and melanoma. 

. 2018;6(suppl 1):O21. doi:10.1186/s40425-018-0423-x

Jemperli. Prescribing information. GlaxoSmithKline; 2021. Accessed November 22, 2021. 

Curigliano G, Gelderblom H, Mach N, et al. Phase I/Ib clinical trial of sabatolimab, an anti–TIM-3 antibody, alone and in combination with spartalizumab, an anti–PD-1 antibody, in advanced solid tumors. 

. 2021;27(13): 3620-3629. doi:10.1158/1078-0432.CCR-20-4746

Harding JJ, Moreno V, Bang YJ, et al. Blocking TIM-3 in treatment-refractory advanced solid tumors: a phase Ia/b study of LY3321367 with or without an anti-PD-L1 antibody. 

. 2021;27(8):2168-2178. doi:10.1158/1078-0432.CCR-20-4405

BeiGene pipeline. BeiGene, Ltd. Updated July 13, 2021. Accessed November 22, 2021. https://bit.ly/3qZsM8d

BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed November 22, 2021. 

Novartis receives FDA fast track designation for sabatolimab (MBG453) in myelodysplastic syndromes. Novartis. May 25, 2021. Accessed November 22, 2021. 

The immune checkpoint TIM-3 is shaping up to be a viable target for designing therapies for patients with non–small cell lung cancer and other malignancies.

Novel Immunotherapy Combos Target  TIM-3 and PD-1/PD-L1 Networks

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

Early efficacy data in a phase 1 trial of the agent now known as nivolumab (Opdivo) were not enough to convince Julie Brahmer, MD, MSc, about the potential of the investigative agent.

 It was only when patients with non–small cell lung cancer (NSCLC) continued responding in readouts from the phase 2 trial that she was sure she was working on something important, an intuition confirmed by the results from the phase 3 CheckMate 057 trial (NCT01673867) and subsequent approval of the PD-1 inhibitor.

Brahmer, who is codirector of the Upper Aerodigestive Cancer Department at Johns Hopkins Medicine’s Bloomberg~Kimmel Institute for Cancer Immunotherapy in Baltimore, Maryland, has remained at the cutting edge of immunotherapy research and lung cancer treatment ever since. She has worked on dozens of trials and authored or coauthored nearly 200 papers, all while continuing to see patients in clinical practice. 

Brahmer is also a cochair of the 19th Annual Winter Lung Cancer Conference

, which will take place February 4-6, 2022, virtually and on site at the Eden Roc Miami Beach hotel in Florida. The 3-day event hosted by Physicians’ Education Resource

), LLC, will provide a practical overview of recent advances in the landscape of lung cancer treatment.

During the conference, experts will discuss trial results that have changed or have the potential to change standards of care. Leaders in thoracic oncology joining Brahmer include cochairs Rogerio C. Lilenbaum, MD, director of Banner MD Anderson Cancer Center in Phoenix, Arizona, and Mark A. Socinski, MD, executive medical director at AdventHealth Cancer Institute in Orlando, Florida. 

Faculty will discuss a wide range of recently published data from ongoing trials, debate controversial topics via Medical Crossfire

 exchanges, and open the floor to discussions that address practical strategies for treating complex clinical cases. Topics of interest include:

integrating and optimization of molecular testing throughout the continuum of disease,

leveraging the growing therapeutic armamentarium for oncogene-driven NSCLC,

navigating options for first-line immunotherapy-based regimens in metastatic NSCLC, 

applying consolidation immunotherapy in locally advanced NSCLC, and 

using surgery and radiation oncology for patients with thoracic malignancies.

Brahmer recently sat down for an interview with OncologyLive® to preview the conference in greater depth, share her thoughts about the major trends in lung cancer, and discuss some of the major work she has done over the course of her career. “This is a very exciting time in lung cancer care,” she said. “A number of significant trial results have appeared in the past year or so, and a large number of very interesting trials are under way.”

Ongoing Research Sparks New Directions in Care

Expanding PD-L1 inhibitors beyond expression

Among the most important results presented this year came from the phase 3 IMpower010 trial (NCT02486718), which supported the decision by the FDA to expand the approval of the PD-L1 inhibitor atezolizumab (Tecentriq). The agent’s indication now includes the adjuvant treatment of patients with stage II to IIIA NSCLC, whose tumors express PD-L1 following surgery and platinum-based chemotherapy. The approval is the first adjuvant indication in NSCLC for an immunotherapy.

 The FDA also approved the VENTANA PD-L1 (SP263) Assay for use as a companion diagnostic device.

Data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in June and the European Society for Medical Oncology Annual Congress 2021 in September showed that the end point of disease-free survival (DFS) was met in the all-randomized stage II to IIIA population with a benefit demonstrated for those with PD-L1 expression of at least 1%.

For those in the all-randomized stage II to IIIA population, at a median follow-up of 32.2 months (range, 0-57.5), the median DFS in patients who received atezolizumab (n = 442) was 42.3 months (95% CI, 36.0-not estimable [NE]) vs 35.3 months (95% CI, 30.446.4) in patients who received best supportive care (n = 440; HR, 0.79; 95% CI, 0.64-0.96; P = .02). The 36-month DFS rates were 55.7% vs 49.4%, respectively.

At a median follow-up of 32.8 months (range, 0.1-57.5), the median DFS for patients with PD-L1 expression of at least 1% on tumor cells who received atezolizumab (n = 248) was NE (95% CI, 36.1-NE) vs 35.8 months (95% CI, 29.0-NE) for those who received best supportive care (n = 228; HR, 0.66; 95% CI, 0.50-0.88; P = .004). 

Atezolizumab performed particularly well in patients with high PD-L1 expression. In a prespecified secondary subgroup analysis of patients with stage II to IIIA NSCLC with a PD-L1 tumor cell expression of 50% or higher (n = 229), the HR for DFS vs best supportive care was 0.43 (95% CI, 0.27-0.68). In results of an exploratory analysis, patients with a PD-L1 tumor cell expression ranging from 1% to 49% (n = 247), the HR for DFS was 0.87 (95% CI, 0.60-1.26).

The most frequently reported adverse effects were increased aspartate aminotransferase, increased blood creatinine, and increased alanine aminotransferase. Other toxicities included hyperkalemia, rash, cough, hypothyroidism, pyrexia, fatigue/ asthenia, musculoskeletal pain, peripheral neuropathy, arthralgia, and pruritus. The recommended atezolizumab dose for this indication is 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks for up to 1 year. 

“It’s great to be able to see immunotherapy [affect] patients in early-stage disease for NSCLC. It is another demonstration that lung cancer is a cancer that’s affected by the immune system and that the immune system plays a role in disease control,” Brahmer, who believes the new treatment option will be adopted quickly on the strength of the trial results, said. “It’s early on, but the data we’re seeing show increased chances of cure or at least increased disease-free survival in these patients with early-stage disease.”

Atezolizumab was not the only drug to earn a lung cancer approval in 2021. In May, the FDA granted accelerated approval to sotorasib (Lumakras) as a second-line treatment for patients with NSCLC with 

 G12C mutations based on data from the phase 2 CodeBreaK 100 trial (NCT03600883).

In published findings from CodeBreaK 100, sotorasib elicited an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%) among 124 patients with KRAS G12C–mutated NSCLC who had progressed following treatment with an immunotherapy and/ or chemotherapy. The median duration of response (DOR) with the treatment was 11.1 months (95% CI, 6.9-NE), and the disease control rate was 80.6% (95% CI, 72.6%-87.2%).7 The median progression-free survival (PFS) was 6.8 months (95% CI, 5.1-8.2), and the median overall survival (OS) was 12.5 months (95% CI, 10.0-NE). 

Findings from exploratory biomarker analyses revealed that sotorasib demonstrated clinical activity across a range of biomarker subsets, including those with PD-L1–negative or –low status, and those with tumors that exhibited 

Sotorasib is the first drug approved for patients with 

 G12C mutation in NSCLC, and Brahmer thinks it will be interesting to see when the targeted drug will be used in such patients relative to other treatment options.

“Right now, at least in patients with driver- mutated tumors who are never smokers, we typically start with the tyrosine kinase inhibitor [TKI],” she said. “Where it gets a little bit harder right now is in patients with KRAS G12C inhibitors, where immune checkpoint inhibitors as a single agent have a decent response rate, somewhere between 30% and 40%. That is where we need head-tohead comparison studies to see what is best to give these patients first,” said Brahmer, who added that there are reasons beyond treatment efficacy to prefer trying TKIs before immunotherapy.

“A lot of us are a bit hesitant when we’re giving immunotherapy first in patients who will receive TKIs next because there’s concern about increased adverse effects. It takes [time] for the immunotherapy antibody to get out of [the patient’s] system, and the effects on a patient’s immune system can last for months to years. Sometimes when we add a TKI to immunotherapy or start a TKI after immunotherapy, we can see more unusual adverse effects or increased adverse effects, and that’s always a concern.”

Managing adverse effects from immuno-therapy will be a major point of emphasis at the conference because strategies for treat-ment selection and toxicity management continue to evolve.

“For the most part, oncologists are now getting comfortable treating patients on with this class of medication, but there are always nuances in dealing with the toxicities,” Brahmer said. “The guidelines help give us a framework to treat or mitigate the adverse effects, and we’ll discuss those. I also think we’re learning more about who we can safely treat and how to best use these therapies in patients with preexisting autoimmune diseases as well. At the conference, we hope to focus on some complex cases that we see occasionally in the clinic to give the providers in attendance a framework in thinking about these toxicities.”

Molecular Testing Solidifies Role in NSCLC

Another area of emphasis at the conference will be strategies for using molecular tests to guide caregiver decisions, both before treatment and as treatment continues. The number of molecular tests has ballooned in recent years along with the number of medications targeted at new mutations.

This year, for example, the FDA approved 2 diagnostic tests designed to evaluate eligibility for 2 novel agents—amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity)—both of which were approved for patients with NSCLC with EGFR exon 20 insertion mutations (Table

). They are the first treatments for these rare mutations, which are associated with aggressive cancer growth.

The amivantamab approval—which was joined by an approval for a companion diag-nostic, the Guardant360 CDx liquid biopsy assay and the QIAGEN therascreen KRAS RGQ PCR kit—was based on data from the phase 1 CHRYSALIS trial (NCT02609776). Results showed that amivantamab elicited an ORR of 40% (95% CI, 29%-51%) among 81 pretreated patients whose NSCLC had EGFR exon 20 insertion mutations. The median DOR was 11.1 months (95% CI, 6.9-NR) with 63% of responders maintaining a response for at least 6 months.

Among those who responded to amivan-tamab, 3 achieved complete response and 29 had partial responses. Variations in EGFR exon insertion mutations that were detectable in circulating tumor DNA did not seem to affect response to treatment. The median PFS for patients who received amivantamab was 8.3 months (95% CI, 6.5-10.9), and the median OS was 22.8 months (95% CI, 14.6-NR).

Almost all participants experienced treat-ment-related adverse effects (TRAEs). Some 16% experienced TRAEs that were grade 3 or higher, 9% percent of patients reported serious TRAEs, and 4% had toxicities that resulted in discontinuation.

The mobocertinib approval—which also came with the approval of a companion diag-nostic, Thermo Fisher Scientific’s Oncomine Dx Target Test—was based on results from a phase 1/2 trial (NCT02716116) on a cohort of 114 patients with EGFR exon 20 inser-tion–positive NSCLC who had received prior platinum-based therapy.

Results showed that mobocertinib elicited an ORR of 28% (95% CI, 20%-37%) and a DOR of 17.5 months (95% CI, 7.4-20.3). The median PFS was 7.3 months (95% CI, 5.5-9.2), and the median OS was 24.0 months (95% CI, 14.6-28.8).

 Further, the ORR in the cohort of patients who received prior platinum-based therapy was 35% (95% CI, 26%-45%) with a median DOR of 11.2 months (95% CI, 5.6-NE). The confirmed disease control rate in this cohort per investigator assessment was 78% (95% CI, 69%-85%).

The most common TRAEs included diarrhea, rash, nausea, stomatitis, vomiting, and decreased appetite. The prescribing information for mobocertinib includes a box warning for heart-rate corrected QT prolongation and Torsades de pointes, in addition to warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.

“We’ll certainly be going over all of these new inhibitors that are being approved by the FDA on what almost seems like a monthly basis, focusing on some of the new FDA approvals for KRAS G12C mutations, EGFR exon 20 mutations, as well as HER2 mutations,” Brahmer said. “I’m excited to be able to offer [participants] a time to discuss some of these new treatment options and to figure out how best to integrate them into practice.”

As Brahmer spoke of the new targeted agents, she returned to the topic of molecular testing. “As targetable mutations proliferate, testing obviously becomes more important, so we want to go over testing: who to test, what tests are best,” Brahmer said. “In the metastatic setting, we always struggled with the issue of getting enough tumor tissue and in trying to get those results as quickly as possible so that we can get the patients on the right treatment as quickly as possible. Certainly, we do use blood-based cell-free DNA testing platforms in order to try to get those results more quickly.”

Early efficacy data in a phase 1 trial of the agent now known as nivolumab were not enough to convince Julie Brahmer, MD, MSc, about the potential of the investigative agent.

Vol. 22/No. 24 | Oncology Live®

Investigators Navigate the Complicated Treatment Landscape of Chemotherapy-Induced Neutropenia

Novel Immunotherapy Combos Target TIM-3 and PD-1/PD-L1 Networks

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

Predominant Lung Cancer Investigator Welcomes a New Era of Research

The Future of Cancer Care Depends on Trust in the Scientific Community

Pembrolizumab Proves Potential as New Standard of Care for RCC in Adjuvant Setting

Expansion Cohort Explores Efficacy of Novel Treatment for Waldenström Macroglobulinemia