Immunotherapy (IO) has revolutionized the head and neck squamous cell carcinoma (HNSCC) space, but there are still avenues to explore to offer benefit to all patients, according to Ranee Mehra, MD.

 CFS®, Mehra, who is director of head and neck medical oncology and professor of medicine at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, reviewed data from KEYNOTE-048 (NCT02358031) in HNSCC highlighting that PD-L1 positive patients have better outcomes with IO therapy of pembrolizumab (Keytruda), as either monotherapy, or with chemotherapy. She also touched on new data for IO in combination with radiation, which has not been as effective as investigators had hoped.

® following the presentation, Mehra recounted the main takeaways from her talk—underscoring the advantages and limitations of IO therapy in HNSCC, and where the field is continuing to focus.

“[Data from KEYNOTE-048 have] completely changed the course of the disease for patients,” Mehra said, adding that although not all patients derive benefit, clinicians are seeing more patients living longer with a good quality of life and without excessive toxicity. Moving forward, the field needs better biomarkers for monotherapy selection and better combination data, both upfront and in the refractory setting.

Interestingly, there may be opportunities in combining targeted therapies and IO therapies; however, these avenues have not been adequately explored, she noted. There has been interest in combining IO with targeted therapy and kinase inhibitors, such as lenvatinib (Lenvima) plus pembrolizumab is a regimen currently under exploration. Moreover, because many patients with HNSCC (up to 30%) exhibit 

 alterations, other research is focused on inhibitors in this space. It also crucial to recognize that not all patients will benefit from IO, she added, and that investigators continue to learn about the molecular biology of the different genomic profiles to provide more options to patients.

She concluded by noting that PD-L1 expression is a key factor in determining a frontline regimen for patients whether its chemotherapy alone, in combination with IO, or IO monotherapy.

“Involving the patient individual factors is important in the initiation of treatment as well as in [making] decisions about whether [a regimen] needs to be added—or reduced [because of] toxicity,” she summarized.

Burtness B, Rischin D, Greil R, et al. Pembrolizumab alone or with chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048: subgroup analysis by programmed death ligand-1 combined positive score. 

. 2022;40(21):2321-2332. doi:10.1200/JCO.21.02198

Videos

Ranee Mehra, MD, discusses the link between PD-L1 expression and increased immunotherapy efficacy in head and neck squamous cell carcinoma, and what future treatment options may look like for patients in this space. 

Mehra Details the Importance of PD-L1 Expression in HNSCC Treatment Selection 

Several immunotherapy agents have received FDA approval across numerous malignancies since ipilimumab (Yervoy) a decade ago and, in many ways, the effect of immunotherapy in certain populations is equitable to magic, according to Melinda S. Weber, DNP, APN, AOCN-C. However, the unique mechanism of action associated with immunotherapy is also linked to adverse events (AEs) for patients receiving treatment.

In a presentation during the Nursing track at the 

 Weber who is the director of care transformation and a charge APN in the Skin and Sarcoma Division at John Theurer Cancer Center at Hackensack University Medical Center Weber, touched on the marked success of the treatment in the field in melanoma and outlined the tenets of early recognition, appropriate grading, and best management practices for these immune-related adverse events (irAEs).

Immunotherapeutic Agents Usher in a Wave of Hope

“Prior to the advent of ipilimumab [Yervoy] in 2011, [a diagnosis of] metastatic melanoma was a death sentence,” said Weber in an interview with 

 ahead of a presentation. “No radiation touched [the melanoma], no chemotherapy touched it, [and approximately] less than 1% of patients might survive [treatment with] high-dose IL-2 therapy, but that was very rare.”

In November 2022, approved immune-checkpoint inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), cemiplimab-rwlc (Libtayo), dostarlimab-gxly (Jermperli), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). Each of these regiments are approved across multiple indications.

Weber said that the efficacy that immunotherapy wielded in certain populations has been nothing short of astounding, and that it drastically changed her clinical practice.

“They’ve changed the face of oncology…I never thought in a million years that I would see PET scans, that were once lit up like a Christmas tree, become normal and stay normal over months, and then years. Now we have people that are survivors 10 years [or longer]….Our focus for those patients [with] late-stage disease was about palliative care, preserving their dignity, and optimizing their comfort. It was very sad.”

Weber said that the availability of these drugs is exciting because they are helping many patients achieve remission, and for those who do not, immunotherapeutic agents may help individuals reach partial remission, prolonged duration of responses, and superior overall survival rates.

“I never take for granted when we bring in our patients for follow-up visits, because I will never forget what it was like before these drugs,” Weber said. “To see people now go on to live their lives, enjoy their families, watch their children and grandchildren grow, is incredible.”

However, Weber noted the start of the immunotherapy integration was not a smooth journey and shared that when immunotherapy first hit the scene, she had patients who chose not to continue treatment because the irAEs were so severe. According to Weber, as clinicians, you must do everything in your power to avoid that possibility, because patients could be forfeiting a chance at a partial or full remission.

The most common irAEs associated with immune-checkpoint inhibitors include fatigue, asthenia, musculoskeletal pain, decreased appetite, diarrhea, nausea, vomiting, pyrexia, cough, dyspnea, constipation, abdominal pain, rash, peripheral neuropathy, mucosal inflammation, alopecia and stomatitis.

Additionally, immune-checkpoint inhibition is also associated with pneumonitis, colitis, hepatitis, encephalitis, endocrinopathies, dermatologic adverse events, nephritis, renal dysfunction, solid organ transplant rejection, infusions-related reactions, and embryo-fetal toxicity.

According to the National Comprehensive Cancer Network (NCCN), a comprehensive baseline assessment of a patient’s current emotional, physical, and spiritual status, with attention to a patient’s social determinants of health, financial toxicity burden, and health literacy are important for early recognition and prompt intervention for irAEs. These factors may influence how and when patients report irAEs, and can influence whether a patient needs to be admitted following the emergence of irAEs. 

According to Weber, the key with irAEs is to catch them early and intervene as soon as possible, because the sooner that the reactions dissolve and therapy can continue, the greater the outcome the patient can expect to achieve.

Weber noted that nurses today may be able to leverage novel technologies such as mobile applications or software programs to track irAEs. Prior to the advent of these applications, research nurses would carry around binders with the common terminology criteria for adverse events (CTCAE) information when assessing patients.

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only, intervention not indicated.

Gradw 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL).

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.

Grade 4: Life-threatening consequences; urgent intervention indicated.

Although CTCAE provides this broad overview of irAE grading, Weber also provided an example of what the clinical presentation looks like for a common irAE, diarrhea.

Grade 1: Increase of < 4 stools per day over baseline; mild increase in ostomy output compared with baseline.

Grade 2: Increase of 4 to 6 stools per day over baseline; moderate increase in ostomy output compared with baseline; limiting instrumental ADL.

Grade 3: Increase of > 7 stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared with baseline limiting self-care ADL.

According to Weber, CTCAE criteria offer clear guidance into appropriate handling of various irAEs, and with early intervention, management is possible. However, she repeatedly stressed that these irAEs are not to be taking lightly, as they can represent a serious barrier to treatment for many patients.

“If I can get anything across, it is that irAEs represent real suffering. [They are] different from chemotherapy adverse reactions,” Weber said. “For example, immunotherapy-induced colitis is horrific, and patients, depending on the grade, may be frightened to leave their homes. Besides the abdominal cramping, the discomfort, the risk of dehydration malnutrition, for many patients, there may be embarrassment or fear of living a normal life, and they may not want to leave their house.”

Moreover, irAEs are different from chemotherapy-related toxicities, because they can occur at unexpected time intervals. These toxicities have varying onset times—they can appear as early as within the first 2 weeks of treatment, or 12 weeks in, they can even occur over 22 months past the last cycle of immunotherapy. Thus, the gravity of these toxicities, the threat they pose to patients, and the need for patient education, cannot be overemphasized.

“irAEs are profoundly debilitating for many, many patients,” she added. “Our job as nursing professionals, besides [providing] great patient education, must be knowing the patient’s baseline to where they are right now, teaching patients to call us early when anything is out of ordinary that’s didn’t not occur before these drugs to call us, and intervening as swiftly as possible.”

Nurses Play a Vital Role in irAE Management

Therefore, when a patient is embarking on immunotherapy, the oncology nurse adopts a unique role as a patient cheerleader.

“We have to be the person who provides knowledge and comfort to that patient,” Weber said. She noted that patients are often afraid of the AEs of their treatments, but nurses can help reassure them and let them know that there is a plan to manage their irAEs.…We tell patients ‘We are going to get you through this,’” Weber said. She added that she likes to tell patients that immunotherapy makes their immune system similar to hungry sharks.

“It’s important for patients to understand what’s happening to them and how we are going to intervene,” she said. “We use a multidisciplinary group, we need our nutritionist, our psychotherapist, we need [individuals] that can provide globally comprehensively care for that patient.”

When it comes to symptom management, there is an arsenal of strategies that clinicians can utilize to help their patients; however, the most important thing, according to Weber, is recognizing the effect these symptoms can have on a patient’s quality of life and reassure them that it can be diminished.

“You can do old-fashioned things. For example, with diarrhea you can [advise patients] to use the BRAT diet, given its within your institutions policies. You can give Imodium [loperamide], Lemotil [atropine and diphenoxylate], Bentyl [dicycloverine], etc. Teach them appropriate dosing of prednisone as ordered, and to get the [irAE] behind them so they can move on.

Weber stressed that there must be awareness alongside action. Nurses have a responsibility to recognize the anguish, pain, and sometimes embarrassment, that patients experienced with these therapies. In managing the patients’ physical symptoms, it is important to recognize the turmoil they can induce on the whole person.

“They are not just clinical symptoms; they really change the face of the patient’s and the family member’s perception of their treatment,” Weber emphasized. “We have to really inspire hope that it's not going to be this way forever,” she said.

Weber MS. Monitoring and managing toxicities associated with immune checkpoint inhibitors. Presented at: 

 CFS®; November 9-11, 2022; New York, NY.

Clinical practice guidelines in oncology. National Comprehensive Cancer Network. Management of Immune-Related Toxicities. Version 1.2022 February 28, 2022. Accessed November 9, 2022. bit.ly/3UK0VnZ

Common terminology criteria for adverse events (CTCAE) v5.0. November 27, 2017. Accessed November 9, 2022. bit.ly/3TlJF7n 

Articles

Immunotherapy has changed the face of cancer treatment, but requires appropriate irAE management to reach full potential. 

Maximizing Potential of Immunotherapy Requires Appropriate irAE Management

Following treatment with chemoradiotherapy (CRT), patients with locally advanced nasopharyngeal carcinoma (NPC) may derive clinical benefit with adjuvant capecitabine, according to phase 3 findings published in 

. The results showed that the adjuvant treatment prolonged failure-free survival (FFS) in a pool of patients with NPC who presented with at least 2 high risk factors.

In the open-label, randomized clinical trial (NCT02143388), 180 Chinese patients were assigned to capecitabine or observation following CRT. Investigators found that those in the capecitabine group (n = 90) had superior FFS to those assigned to observation at 3 years (83.3% vs 72.2%) and 5 years (78.5% vs 65.9%; HR, 0.53; 95% CI, 0.30-0.94; 

NPC is a unique head and neck cancer endemic to East Asia and Southeast Asia and associated with Epstein-Barr virus (EBV). Most patients present with locally advanced disease and metastatic recurrence in the bones, liver, and lungs is common.

Previous findings have demonstrated that capecitabine monotherapy has efficacy in recurrent metastatic NPC, and the agent has shown promise in combination with induction chemotherapy. Investigators in this trial sought to determine if capecitabine plus CRT improved FFS in the locally advanced patient population. These results were collected after a median follow-up of 58.0 months after patients received a full dose of capecitabine for 6 months.

Eligible patients aged 18 to 70 years were required to have histologically confirmed, newly diagnosed, nonkeratinizing NPC; Karnofsky performance status of at least 80 points, TNM stage III-IVb disease, and the presence of at least 1 unfavorable prognostic factors: T3-4N2 or T1-4N3; plasma EBV DNA titer higher than 20,000 copies/mL; primary gross tumor volume greater (GTV) than 30.0 cm

; a maximum standard uptake value of primary GTV higher than 10.0 on fluorodeoxyglucose F18 PET/CT, or multiple nodal metastases and at least 1 larger than 4.0 cm. Patients were not allowed to have received prior radiotherapy, chemotherapy, or surgery except for diagnostic investigations.

 intravenous cisplatin every 3 weeks for 2 to 3 cycles depending on the duration of radiotherapy. Patients randomly assigned to the experimental arm (n = 90) then received 8 cycles of 1000 mg/m

 twice-daily oral capecitabine for 14 days every 21 days beginning 4 weeks after CRT. Investigators modified chemotherapy doses based on the nadir blood counts and acute toxic effects of the preceding cycle.

Investigators determined that pretreatment clinical characteristics were comparable between groups. Fourteen patients (15.6%) in the experimental group had 1 unfavorable risk factor, 31 (34.4%) had 2 risk factors, and 45 (50.0%) had 3 or more risk factors. In the control group, 10 (11.1%) had 1 unfavorable risk factor, 42 (46.7%) had 2 risk factors, and 38 (42.2%) had 3 or more risk factors.

The median patient age was 46 years (range, 39-55) in the capecitabine group vs 48 (range 41-55) in the control group. Most patients in both arms (81.1% vs 77.8%, respectively) were male.

Eighty-five (94.4%) patients received capecitabine, 71 (78.9%) of whom completed all 8 cycles of treatment.The median relative dose intensity of capecitabine was 100% (interquartile range, 84.7%-100%).

The rates for 3-year overall survival (OS) were 93.3% for the capecitabine group vs 87.8% for the control group (HR, 0.62; 95% CI, 0.29-1.32). The rates for 3-year distant metastasis-free survival also favored the experimental arm at 85.5% vs 80.4% in the control arm (HR, 0.69; 95% CI, 0.35-1.35). Rates for 3-year locoregional relapse-free survival were 97.5% for the capecitabine group vs 84.1% for the control group (HR, 0.28; 95% CI, 0.10-0.76).

Investigators observed no interaction between high-risk factors and treatment. However, the addition of adjuvant capecitabine favored the subgroup of patients who had risk factors with a maximum standard uptake value higher than 10.0, a primary GTV larger than 30.0 cm

, and an EBV DNA titer higher than 20,000 copies/mL.

Seventy-eight (86.7%) patients in the capecitabine arm had complete response and 12 (13.3%) had partial response compared with 79 (87.8%) and 10 (11.1%), respectively, in the control arm. One patient in the control arm could not be assessed.

Nineteen (21.1%) patients required capecitabine dose reductions, 11 because of hand-foot syndrome, 4 because of gastrointestinal adverse events, 2 because of recurrent myelosuppression, 1 because of fatigue, and 1 because of treatment noncompliance.

Fifty-four (60.0%) patients in the experimental arm experienced grade 3 treatment-related adverse events (TRAEs) compared with 46 (51.1%) in the control arm. The most common grade 3 TRAEs were xerostomia (18.9% vs 10.0%, respectively), mucositis (23.3% vs 16.7%, respectively), and anorexia (8.9% vs 4.4%, respectively). One patient in each group experienced grade 4 TRAEs.

Nine of 83 (10.8%) patients in the experimental arm experienced delayed grade 3/4 TRAEs compared with 7 of 81 (8.6%) in the control arm. Investigators said incidence of any-grade delayed TRAEs was comparable between the 2 groups except for a higher incidence of ototoxicity (69.9% vs 58.0%) and grade 1 xerostomia (59.0% vs 49.4%) in the experimental arm.

Miao J, Wang L, Tan SH, et al. Adjuvant capecitabine following concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: a randomized clinical trial. 

. Published online October 13, 2022. doi:10.1001/jamaoncol.2022.4656

At a 5-year follow-up, the failure-free survival rate with capecitabine was 83.3% vs 72.2% with observation.

Chemoradiotherapy Plus Capecitabine Delivers Superior Failure-Free Survival in High-Risk Nasopharyngeal Carcinoma

Nearly 50% of patients with high-risk neuroblastoma achieved a response following treatment with a 4-drug combination of irinotecan, temozolomide, dinutuximab (Unituxin), and granulocyte-macrophage colony-stimulating factor (GM-CSF), according to retrospective findings published in the 

In total, 48.6% (n = 71) of patients achieved an objective response, including a complete response (CR), partial response (PR), and minor response in 29%, 14%, and 5% of patients, respectively. This includes 47% of the 133 patients with metastatic soft tissue and bone disease. Additionally, investigators detected a marrow response in 73% of the 58 patients with available posttreatment bone marrow data.

“Data regarding response timing and duration will aid clinicians in balancing the risks and benefits of continuing treatment of [irinotecan/temozolomide/dinutuximab/GM-CSF] in patients with relapsed [high-risk neuroblastoma],” lead study author Benjamin J. Lerman, MD, MS, of the Children’s Hospital of Philadelphia and the University of Pennsylvania, and colleagues, wrote in the journal article. “The survival outcomes described in this study provide a new point of reference for evaluating novel therapeutics in relapsed [high-risk neuroblastoma].”

This retrospective study sought to describe response and progression-free survival (PFS) in patients with relapsed high-risk neuroblastoma who received the regimen of irinotecan, temozolomide, dinutuximab, and GM-CSF.

To be eligible, patients needed to be under 30 years old at diagnosis of high-risk neuroblastoma and received at least 1 cycle of irinotecan/temozolomide/dinutuximab/GM-CSF for progressive disease (PD) or relapsed disease. Patients also needed to have an objective response or stable disease after standard initial frontline therapy.

Patients were excluded if they had primary refractory disease and progressed through induction therapy. Those who received the combination for suboptimal response to induction treatment were also excluded.

In total, 146 patients were analyzed in this study, which included those who received at least 1 cycle of irinotecan/temozolomide/dinutuximab/GM-CSF outside the context of a clinical trial from January 1, 2015, to June 1, 2020. The study regimen consisted of intravenous (IV) irinotecan at 50 mg/m2 once daily, temozolomide at 100 mg/m2 once daily on days 1 though 5, IV dinutuximab at 17.5 mg/m2 once daily on days 2 through 5, and subcutaneous GM-CSF at 250 µg/m2 once daily on days 6 through 12 of a 21-day cycle.

Regarding patients who received the combination for multiple distinct relapse events, the study only used data related to the first relapse event treated with the combination.

Patients received a median of 4.5 cycles of study treatment (interquartile range, 2-7; range, 1-31) over a median of 87 days. Of the 23% (n = 34) patients who received concurrent treatment at some point during their time on the combination, 5 received surgery, 23 received radiation, 2 received meta-iodobenzylguanidine therapy, and 5 received another anticancer therapy.

The median age of patients at diagnosis was 51 months (interquartile range, 31-72), and 58.2% (n = 85) were male. A total of 67.8% (n = 99) of patients received the study treatment after their first relapse or progression. In addition, 63.0% (n = 92) of patients had measurable disease at relapse or progression, and 55.5% (n = 81) had received anti-GD2 therapy prior to study treatment.

In total, 50 (37%) of the 134 patients had known tumor MYCN status, and 43 of those patients (32%) had tumors with 

 amplification. Additionally, 94 patients had known tumor 

 status, and 21 of those patients (22%) had tumors with 

A total of 58.2% (n = 85) of patients discontinued study treatment because of stable disease (SD) or PD, 13.0% (n = 19) discontinued because of unacceptable acute or chronic toxicity, 23.3% (n = 34) discontinued because of a transition to another anticancer therapy, and 19.9% (n = 29) discontinued because of planned treatment completion. Patients who stopped treatment with the combination because of toxicity received a median of 3 cycles (range, 1-15) before discontinuing. At the time of data collection, 4 patients were still on the study therapy.

The primary end point was the proportion of patients with objective response after receiving the combination, which was defined as CR, PR, or minor response on a disease evaluation after initiation of study treatment; PFS; and duration of response (DOR) after objective response. Investigators sought to evaluate timing and durability of response and to identify molecular and clinical factors associated with PFS in these patients.

Patients who achieved an objective response received a median of 2 cycles (range, 1-9) from the beginning of study treatment to their first disease evaluation showing objective response. One patient required over 6 cycles to reach a first objective response; this patient received 9 cycles of treatment.

The median time between diagnosis and first relapse was 26 months (range, 17-38) in patients who achieved an objective response vs 18 months (range, 12-35) in those who did not respond (

 = .04). Additionally, White patients were most likely to respond, as 71.2% (n = 40) of White patients responded and 53.3% (n = 51) did not respond (

 = .03). Responders were also more likely to have received prior anti-GD2 therapy, at 64.8% (n = 46) vs 46.7% (n = 35; 

 = .03) in those who did not respond, and tumor 

 aberrations were less frequent in responders, at 11.3% (n = 8) vs 17.3% (n = 13; 

Furthermore, the median age of responders (54 months; range, 33.0-80.5) was older than that of non-responders (44 months; range, 30.5-64.5; 

 = .15), and more responders had stage M disease, at 97.2% (n = 69) vs 89.3% (n = 67; 

 = .13). Responders were also less likely to have measurable disease at the time of receiving study therapy, at 56.3% (n = 40) vs 69.3% (n = 52; 

Although all the above distinctions met the criteria for inclusion in the multivariate model, after multivariate adjustment, only the comparison between White and non-Black and non-White patients retained statistical significance. No covariates were independently associated with PFS.

Of the total population, 21% (n = 31) had SD, and 30% (n = 44) progressed on the study treatment. Of the 79 patients who initially had SD, minor response, or PR, 72% (n = 57) achieved their best response by the first disease evaluation. Of the 22% of patients with SD or better at first post–study treatment disease evaluation who experienced an improvement in response designation in a subsequent evaluation, 5 had initial SD, 3 had initial minor response, and 14 had initial PR.

In the overall study population, the median PFS was 13.1 months (95% CI, 9.8-16.5), the 6-month PFS rate was 62% (95% CI, 55%-71%), the 1-year PFS rate was 51% (95% CI, 43%-60%), and the 2-year PFS rate was 28% (95% CI, 20%-40%).

In all patients who had an objective response, the median DOR was 15.9 months (95% CI, 14-not available [NA]), the 6-month PFS rate was 86% (95% CI, 78%-95%), the 1-year PFS rate was 68% (95% CI, 57%-81%), and the 2-year PFS rate was 44% (95% CI, 32%-61%).

Additionally, 21 patients who achieved an objective response discontinued study treatment and received no further anticancer therapy, with a median additional PFS of 10.4 months (95% CI, 7.4-NA). Of those patients, 14 had CRs and 7 had PRs. Of these patients, the 6-month PFS rate was 73% (95% CI, 54%-99%), and the 1-year PFS rate was 26% (95% CI, 10%-67%).

In total, 108 patients relapsed or progressed 0 to 30 months after initiating study treatment. Of these, 56% (n = 60) experienced relapse while actively receiving study treatment, 31% (n = 33) relapsed after transitioning from study treatment to another anticancer therapy, and 14% (n = 15) relapsed after discontinuation of study treatment without additional therapy.

Bone was the most common site of relapse (76.9%; n = 83), followed by metastatic soft tissue 54.6% (n = 59) and lymph nodes in 54.6% (n = 59), bone marrow in 30.6% (n = 33), lung in 16.7% (n = 18), and brain in 5.6% (n = 6).

“These data establish a new baseline of response and survival for comparison during future trials in patients with relapsed/progressive neuroblastoma in the chemoimmunotherapy era,” the study authors concluded.

Lerman BJ, Li Y, Carlowicz C, et al. Progression-free survival and patterns of response in patients with relapsed high-risk neuroblastoma treated with irinotecan/temozolomide/dinutuximab/granulocyte-macrophage colony-stimulating factor. 

 Published online October 7, 2022. doi:10.1200/JCO.22.01273

Among 71 patients with neuroblastoma, 48.6% achieved an objective response and 29% achieved a complete response with a 4-drug combination. 

Chemoimmunotherapy Yields Promising Objective Responses in Patients With High-Risk Neuroblastoma 

Xevinapant in addition to chemoradiotherapy reduced the risk of death in patients with unresectable locally advanced head and neck squamous cell carcinoma (HNSCC) significantly more than placebo/chemoradiotherapy in a 5-year follow-up of a phase 2 study (NCT02022098). Moreover, the results, which were presented during the 2022 ESMO Congress, showed that the increased efficacy was not tied to increased toxicities.

The results showed that xevinapant plus chemoradiotherapy (n = 48) nearly doubled the 5-year overall survival (OS) rate vs chemoradiotherapy alone (n = 48), at 53% vs 28%, respectively. At a median follow-up of 60.1 months (range, 7.1-70.5) in the xevinapant arm and 39.2 months (range, 4.8-71.2) in the placebo arm, the median OS was not reached (95% CI, 40.3-not estimable [NE]) vs 36.1 months (95% CI, 21.8-46.7), respectively (HR, 0.47; 95% CI, 0.27-0.84; 

“This is the first study in decades to improve the cure rate by adding a new treatment to standard-of-care cisplatin and radiotherapy,” lead study author Jean Bourhis, MD, PhD, of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and coauthors, wrote in the presentation.

Xevinapant is a first-in-class, potent, oral, small molecule IAP inhibitor believed to restore cancer cell sensitivity to apoptosis, leading to improved efficacy with chemoradiotherapy.

The study enrolled patients with unresected, locally advanced, stage III, IVA, or IVB HNSCC of the oral cavity, oropharynx, or larynx who had a greater than 10 pack-year smoking history. Per the TNM staging system, patients had to have a tumor score of at least 2, node score between 0 and 3, and a metastasis score of 0.

Patients were randomly assigned to 200 mg/day of oral xevinapant on days 1 through 14 plus 100 mg/m2 of intravenous cisplatin every 3 weeks for 3 cycles and 70 Gy of intensity-modulated radiation therapy (IMRT) administered at 2 Gy/day, 5 days a week for 7 weeks, or matched placebo plus cisplatin and IMRT in the same schedule.

The primary end point was the 18-month local-regional control (LRC) rate from the end of chemoradiotherapy. Secondary end points included progression-free survival (PFS), OS, duration of response (DOR), and safety.

Prior findings showed a significant improvement in the 18-month LRC rate with xevinapant vs placebo, meeting the primary end point of the study (odds ratio, 2.74; 95% CI, 1.15-6.53; 

 = .0232). Additionally, the 3-year PFS rate favored the use of xevinapant over placebo, at 72% vs 36%, respectively (HR, 0.33; 95% CI, 0.17-0.67; 

Notably, findings from the updated analysis showed that xevinapant improved OS and DOR across all prespecified subgroups, including nodal involvement (N0-N1 vs N2-N3), primary tumor type (oropharynx vs hypopharynx vs larynx vs oral cavity), TNM stage (III vs IVA vs IVB), smoking history (former vs current), and alcohol consumption (current vs none).

Additional findings showed that xevinapant prolonged DOR, leading to a median DOR that was not reached (95% CI, NE-NE) compared with 17.3 months (95% CI, 5.0-NE) with chemoradiotherapy. The 3-year DOR rate was 79% with xevinapant vs 36% with chemoradiotherapy (HR, 0.21; 95% CI, 0.08-0.54; 

Responses with xevinapant consisted of 31 complete remissions (CRs) and 6 partial remissions (PRs) vs 26 CRs and 9 PRs with chemoradiotherapy alone.

A total of 16 (33.3%) patients in the xevinapant arm received subsequent anticancer therapy vs 19 (40.4%) in the placebo arm, consisting of surgery (31.3% vs 31.6%), radiotherapy (37.5% vs 21.1%), or systemic therapy (75.0% vs 84.2%).

With regard to systemic therapy, most patients in the xevinapant arm received cetuximab (Erbitux) with (66.7%) or without chemotherapy (66.7%) compared with a checkpoint inhibitor (41.7%). Most patients in the placebo arm received cetuximab with or without chemotherapy (68.8%) or a checkpoint inhibitor (62.5%) compared with chemotherapy (50.0%).

In keeping with prior findings, the safety profile, including late-onset adverse effects (AEs), was comparable between arms. The rate of all-grade and grade 3 or greater late-onset AEs was 81.3% and 27.1% with xevinapant vs 70.2% and 25.5% with placebo.

Toxicities in order of frequency included dry mouth, dysgeusia, trismus, fibrosis, dysphagia, ear pain, chronic kidney disease, tinnitus, laryngeal edema, weight decrease, anemia, dysphonia, mucosal inflammation, deafness, lymphedema, edema, hypoacusis, and odynophagia.

No patients in the xevinapant arm died because of treatment-related AEs vs 2 (4.3%) patients in the placebo arm, resulting from asphyxia and multiple organ dysfunction syndrome.

Early treatment discontinuation occurred in 8 patients (16.7%) in the xevinapant arm vs 7 patients (14.6%) in the placebo arm.

Based on these results, the confirmatory phase 3 TrilynX trial (NCT04459715) will move forward as planned, enrolling patients with unresected, locally advanced HNSCC.

Bourhis J, Tourneau CL, Calderon B, et al. 5-year overall survival (OS) in patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase 2 study. 

. 2022;33(suppl 7):S1400. doi:10.1016/j.annonc.2022.08.030

Sun X-S, Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study. 

. 2020;21(9):1173-1187. doi:10.1016/S1470-2045(20)30327-2

Bourhis J, Sun X, Le Tourneau C, et al. 3-years follow-up of double-blind randomized phase II comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. 

. 2020;31(suppl 4):S1168. doi:10.1016/j.annonc.2020.08.2269

A presentation at the 2022 ESMO Congress found that xevinapant plus chemoradiotherapy decreased the risk of death by twice that of placebo for patients with unresectable, locally advanced head and neck squamous cell carcinoma.

5-Year Findings Support Xevinapant Plus Chemotherapy in Locally Advanced Head and Neck Cancer 

Pembrolizumab (Keytruda) continued to outperform cetuximab in extending overall survival (OS) among patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to a follow-up of the 3-arm, phase 3 KEYNOTE-048 trial (NCT02358031). At 4-years follow-up, the benefit was observed both alone and in combination with chemotherapy.

Investigators randomly assigned 882 patients to pembrolizumab monotherapy (n = 301), pembrolizumab-chemotherapy (n = 281) or cetuximab-chemotherapy (n = 278). Investigators evaluated efficacy in PD-L1 combined positive score (CPS) greater than or equal to 20, CPS greater than or equal to 1, and total populations, with no multiplicity or alpha adjustment.

At a median follow-up of 45.0 months (interquartile range, 41.0-49.2), pembrolizumab improved OS in the PD-L1 CPS greater than or equal to 20 (HR, 0.61; 95% CI, 0.46-0.81) and CPS greater than or equal to 1 subgroups (HR, 0.74; 95% CI 0.61-0.89). The PD-1 inhibitor was noninferior in the total population (HR, 0.81; 95% CI, 0.68-0.97).

The pembrolizumab-chemotherapy combination improved OS in the PD-L1 CPS greater than or equal to 20 (HR, 0.62; 95% CI, 0.46-0.84) and CPS greater than or equal to 1 subgroups (HR, 0.64; 95% CI, 0.53-0.78). The combination also improved OS in the total population (HR, 0.71; 95% CI, 0.59-0.85).

These updated findings are in keeping with prior data from KEYNOTE-048, which showed that pembrolizumab alone significantly improved OS compared with cetuximab plus chemotherapy in the subsets of patients with a PD-L1 CPS greater than or equal to 20 and 1 or higher, and noninferior OS in the total population. Pembrolizumab plus chemotherapy also improved OS vs the control arm in the entire study population.

In June 2019, the FDA approved pembrolizumab alone or with chemotherapy for frontline treatment of patients with HNSCC based on these results.2

Results from the phase 1b KEYNOTE-012 trial (NCT01848834) previously demonstrated that pembrolizumab alone produced a higher overall response rate (21% vs 6%; 

 = .023) and a longer median OS (10 months vs 5 months; 

 = .008) in those with PD-L1 CPS greater than or equal to 1 vs a CPS of less than 1.3

Patients enrolled to KEYNOTE-048 had recurrent and/or metastatic squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx who had an ECOG performance status of 0 or 1 with tissue available for PD-L1 testing, and who had not received prior chemotherapy or systemic therapy for their recurrent or metastatic disease. Patients were stratified by PD-L1 expression, p16 status, and performance status.

Patients were randomly assigned to 200 mg of pembrolizumab alone every 3 weeks for 2 years, 200 mg of pembrolizumab plus platinum-based chemotherapy and 5-fluorouracil (5-FU), or the EXTREME regimen of cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2, plus cisplatin at 100 mg/m2 or carboplatin at area under the curve 5 given every 3 weeks, plus 5-FU at a daily dose of 1000 mg/m2 on days 1 through 4 of each 3-week cycle for a maximum of 6 cycles.

The objective response rate (ORR) on second course pembrolizumab was 27.3%. Investigators found that pembrolizumab-chemotherapy resulted in a numerically higher ORR compared with cetuximab-chemotherapy in the PD-L1 CPS greater than or equal to 20 population and similar ORRs in the CPS greater than or equal to 1 and total populations.

The ORR was 43.7% for pembrolizumab-chemotherapy vs 38.2% for cetuximab-chemotherapy in the PD-L1 CPS greater than or equal to 20 population. In the CPS greater than or equal to 1 group, the ORR was 37.2% for the chemoimmunotherapy combination vs 35.7% for cetuximab-chemotherapy and 36.3% vs 36.3% in the total population.

Median duration of response was numerically longer with pembrolizumab-chemotherapy in all populations.

Progression-free survival on next-line therapy (PFS2) improved with pembrolizumab in the PD-L1 CPS greater than or equal to 20 (HR, 0.64; 95% CI, 0.48-0.84) and CPS greater than or equal to 1 (HR, 0.79; 95% CI, 0.66-0.95) populations. Pembrolizumab-chemotherapy also improved PFS2 in the PD-L1 CPS greater than or equal to 20 (HR, 0.64; 95% CI 0.48-0.86), CPS greater than or equal to 1 (HR 0.66; 95% CI, 0.55-0.81), and total (HR, 0.73; 95% CI, 0.61-0.88) populations.

Investigators found that PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes. In contrast, PFS2 was shorter following pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes.

Seventeen percent of patients in the monotherapy group experienced grade 3 or higher treatment-related adverse effects (TRAEs) compared with 71.7% in the pembrolizumab-chemotherapy group, and 69.3% in the cetuximab-chemotherapy group.

Harrington KJ, Burtness B, Greil R, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study. 

. Published online October 11, 2022. doi:10.1200/JCO.21.02508

FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma. FDA. June 10, 2019. Accessed October 14, 2022. 

Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. 

. 2018;119(2):153-159. doi:10.1038/s41416-018-0131-9

The overall survival benefit associated with pembrolizumab for patients with head and neck cancer continued to be observed at a 4-year follow-up of the KEYNOTE-048 trial.  

Pembrolizumab Continues to Boost Overall Survival in Patients with Head and Neck Cancer at 4-Year Follow-Up

Transformative solutions in nursing are ones that are sustainable, according to Linda Laskowski-Jones, MS, APRN, ACNS-BC, CEN, NEA-BC, FAAN. To come up with a transformative solution, leaders need to engage their employees and see how new strategies affect their working environment.

“Transformation oftentimes [is a] term bantered about and used freely in healthcare institutions today across the board but without understanding what it means, what it looks like, and how much time it takes—because it's not a short walk,” Laskowski-Jones said. She added, “as an oncology nurse, I think you can advocate best through helping to enable others to grow and when you do that you grow yourself and you also learn to take risks in your profession.”

®, Laskowski-Jones, who is editor-in-chief of 

 and president of the Delaware Emergency Nurses Association, and who has spent nearly 4 decades working in trauma and emergency nursing, as well as served as a manager, director and vice president in her hospital’s trauma and emergency departments, discussed how meeting problems with transformative solutions can help improve the working conditions of nurses across a unit.

Understanding the problem: Nursing Shortages

In her presentation, Laskowski-Jones highlighted that, although there are 4.3 million nurses in the US, because of new roles, more jobs, retirements, better staffing ratios, and RN’s leaving the profession, 11 million more nurses are needed to avoid shortages. Moreover, RN employment is projected to be the occupation requiring the most growth through 2026.

The effect of the COVID-19 pandemic on the nursing landscape paired with outside pressures as well as internal elements such as workloads, expectations, and patient factors, have left the field needing transformative solutions to address the causes of turnover along with burnout. Based on geography and specialty, the average turnover of nursing staff ranges from 8.8% to 37% and the American Nurses Association declared the nursing shortage a national crisis on September 1, 2021, to the Department of Health and Human Services.

In speaking about the nursing shortage, Laskowski-Jones noted that the “great resignation” had already begun in 2019, before the COVID-19 pandemic. “In 2019 there was this uptake of resignations across the board in all professions—not just in healthcare…. hospitals were starting to ratchet down on staffing. They were trying to cut corners and reduce resource utilization, [even though] we had organizations saying: we expect high patient experience scores.”

Laskowski-Jones noted that hospitals were being held to higher standards as the patient experience scores are publicly reported and with that came pressure. Additionally, an increase of violence in health care, and lawsuits piled on.

Of course, in 2020, the pandemic compounded these issues, and by 2021, many nurses were burnt out.

“In 2020, we had the pandemic, and everybody was engaged because nurses rise to the challenges, we always rise to the challenges, they’re all in; they’re being battered with what they’re dealing with between the personal protective equipment needs, the complex patients, potentially being pulled to a unit where they never worked before, having to learn new skills, and dealing with devastating situations in many cases,” Laskowski-Jones said.

“[However,] 2021 was a different story,” she said. “Even with vaccines, the pandemic had not ended. The biggest thing was that there was this latent demand in the community for services [because some patient’s] cancer wasn't diagnosed or their heart disease wasn't diagnosed and now they were all coming in where they had been too afraid to even use the hospital [before].” 

With a large increase in patients coming to hospitals, nurses were working in environments that were at overcapacity and nurses “did not feel that they were being supported, they were valued, and they were starting to see shortages that weren't necessarily being addressed.”

While issues were still active, travel nurses had a large positive affect in care, but this impacted the dynamic in the hospital as travel nurses receive high contract pay which may have led some nurses who had been at institutions for a long time to feel undervalued and leave.

In her presentation, Laskowski-Jones noted that creating a healthy workplace environment is a crucial solution in beginning to rebuild the nursing field. The root causes for burnout, turnover and unhappiness must be addressed, and nurses should not be expected to be able to handle everything with a lack of support; psychological safety must be developed. Key points under that umbrella include developing non-defensive listening skills, promoting a clear vision with team alignment, innovation, respectful communication, and generating a culture across the organization of effective teamwork.

Transformative is a broad term, but it essentially refers to solutions that are sustainable, according to Laskowski-Jones. She highlighted some examples of unsustainable solutions vs sustainable ones.

“Transformation means going from this vision of what you think should be to sustainably getting there.” Laskowski-Jones gave the example, “let’s say there is a directive that when the patient comes in staff have only a specified amount of time to get a certain type of work done (eg, their admission process, or their discharge process, etc.).

In this hypothetical example, Laskowski-Jones said, someone looked at data and determined that all patients should be discharged in 6 hours. All nurses are trying to get patients discharged within a 6-hour time-frame. However, if they are struggling to do it, are exhausted, and are consequently cutting corners, that would be an unsustainable goal as currently performed.

Sustainable solutions should make work easier and more effective, Laskowski-Jones noted. This means that when new strategies are implemented, leaders should be asking employees how they feel about the change, and whether it is making things better.

Laskowski-Jones’s presentation emphasized the importance of creating a healthy work culture and assessing one’s own style and reputation to encourage positive change in the environment. Emotional intelligence is key in the workplace and establishing trust to build relationships with coworkers and teams is crucial while being mindful of short- and long-term goals that are set.

When discussing issues in the workplace, Laskowski-Jones said that she encourages nurses to come-up with solutions to the problems that they pose to her.

“If you bring me a problem,” she said, “and I don’t care what it is, you need to bring me your idea of what the solution is... If we make this change that you recommend, how is that going to affect other people?”

Lastly, Laskowski-Jones emphasized that leadership must value their staff.

“You have to show empathy,” she said. “Value is not just giving somebody a little gift… or some sort of recognition day, value is being able to have a conversation where you witnessed someone having a difficult day or a challenging patient,” she said. “It’s when a manager says ‘I was impressed with how you handled that.’ Or that must have been difficult for you, do you want to talk about it? I am here to listen, I’ve been there, and I know how hard this is.” 

Laskowski-Jones L. Finding your voice: how nurses can create a healthy work culture to enhance a thriving work environment. Presented at: ONS Bridge; September 13-15, 2022; virtual.

Linda Laskowski-Jones, MS, APRN, ACNS-BC, CEN, NEA-BC, FAAN, discusses how oncology nurse leaders can help improve working environments for their staff. 

Nurse Leaders Must Foster Change to Develop a Healthy Workplace Environment

Over the past few decades, the number of advanced practice providers (APPs) in oncology has increased dramatically and the role they play expanded greatly. One reason for this is that there are more patients who need oncologists in the US than there are physicians practicing the specialty. According to the American Society of Clinical Oncology, the nation will see a shortage of more than 2200 oncologists by 2025 and an increase of 40% in demand for cancer treatment during the next 6 years.

 This growth in demand is driven not only by new patients, but by those who have completed active treatment and require follow-up care. Thanks to advanced therapies, better outcomes are being achieved and survival rates are improving. Cancer survivors—even with complex comorbidities—are living longer than ever before.

Survivorship care can readily be performed by APPs, given their wide breadth of expertise and training. A closer look at how these highly skilled professionals deliver survivorship care will provide some insight into why they areideally suited to lead these programs, meeting a critical need that will only grow in the future.

In many practices, APPs are the backbone of survivorship programs, playing a key role in their planning and execution. They are well suited to lead these programs because of their extensive education, training, and scope of practice.

They also develop strong relationships with patients and caregivers during active treatment. As trusted members of the care team, it makes sense for them to discuss the key elements of survivorship with patients, some of which—like lifestyle changes and advance care planning—can be difficult to talk about.

Many patients are under the misconception that survivorship doesn’t begin until they have finished active treatment. According to the National Cancer Institute, however, a patient is considered to be a survivor from the time of diagnosis until the end of life.

APPs can help patients understand that survivorship encompasses everything from diagnosis onward—be they undergoing treatment, in remission, or facing recurrence.

Advanced practice providers are the future of survivorship care because of the tremendous value they offer to the practice and its patients. 

Head and Neck Cancers