Patients with cancer are divided on their expectations with checkpoint inhibitors, according to findings from a patient survey that were presented during the 47th Annual Oncology Nursing Society Congress.

The findings revealed that 27% of patients believe that their immunotherapy treatment will “help [them] live longer,” while 19% believe the therapy will “cure the cancer,” and 15% believe it will “improve [their] life quality.”

Over one-quarter of patients expressed conviction that this treatment strategy would be “effective” against their disease, while another 25% felt it would be “very effective.” Fifteen percent were unsure if it would be effective, 14% percent thought it would be somewhat effective, and 11% had no expectations.

Other patients responded that they believed the treatment would allow them “to have less side effects than chemotherapy,” “to stop the tumor from growing,” and “to delay the need for stronger chemotherapy.”

In terms of symptoms, tiredness was found to be the most commonly adverse event (AE). For those who experience an AE, calling the oncologists was the most common response (21%). However, 15% of patients responded by calling their oncology nurse, 10% discussed the AE with their family, and 9% chose to manage the AE by themselves. Eight percent of patients reported that they ignored their symptoms.

“We believe that the findings of this study well help improve the management of immunotherapy side effects and inform immunotherapy patient education and side effect reporting,” Maryellen Potts, PhD, University of Kansas School of Nursing, explained in a poster presentation of the findings.

Potts said that since the advent of immunotherapy, many studies have been designed to assess the efficacy of the agents. However, there is insufficient research documenting the patient experience while undergoing this treatment.

While checkpoint inhibitors have been reported to extend survival outcomes for patients with cancer, immune-related AEs have been known to compromise quality of life and it is necessary to understand patient expectations of treatment and of AEs in order to better communicate with patients, Potts said.

Therefore, investigators launched a cross-sectional survey querying patients about their knowledge regarding treatment, their expectations, their side effect experience and response, and information-seeking strategies. The free text responses were analyses with a content analysis.

A total of 294 patients responded to the survey. Among these, 31.1% had a lung cancer diagnosis, 17.2% had melanoma, and 14.4% had renal cancer. Of note, 34% were receiving pembrolizumab (Keytruda).

A component of the survey assesses how AEs were interfering with patients’ daily activities of living, which showed that 64% of participants experienced AEs. Nineteen percent of patients had tiredness, 10% had shortness of breath, 8.7% had feelings of sickness, 7% had pain, 7% had diarrhea, and 7% had other.

More than half of patients experienced AEs that did not immediately clear up and lasted for months. Among those experiencing debilitating AEs, 67.2% relied on their spouse or partner for support, but 13.6% reported that they did not have anyone to rely on.

In terms of education, 74% of patients learned about immunotherapy from their oncologist, while, among those who learned about immunotherapy from media, 66.7% percent reported that they found the information useful. Four percent of patients learned about immunotherapy from their oncology nurse, 3% from a physician assistant, 3% from media, 3% from the Internet, 3% from a nurse practitioner, 2% from a primary care doctor, and 2% from a primary care physician. Over half of patients described the conversation regarding immunotherapy with their health care provider as “very helpful.”

“Because these were predominantly older adults who were educated and had access to an National Cancer Institute–designated cancer center for treatment, exploring how these questions might be answered by those who are younger, not as educated, or without a regular access to a cancer center may be helpful,” Potts concluded.

Moving forwards, investigators hope to expand their research across a wider demographic and involve other institutions.

Potts M, Fleer R, Dionisi L, Wulff E, et al. Immunotherapy patient experience: a cross-sectional survey of patient knowledge, expectations, and information seeking strategies. Presented at: 47th Annual Oncology Nursing Society Congress; April 27-May 1, 2022; Anaheim, CA. Abstract P312.

Articles

Patients with cancer were reported to have mixed expectations with immunotherapy as part of their oncology treatment. 

Patients With Cancer Share Mixed Experiences With Immunotherapy

The use of catheters instead of injection needles to administer intravenous immunotherapy is linked with increased comfort and satisfaction for patients and infusion nurses alike, according to results of a study presented at the 

“The BD Saf-T-Intima butterfly catheter is specifically geared towards subcutaneous administration of medications,” Georgina Rogers, BSN, RN, OCN, NE-BC, of Cleveland Clinic Taussig Cancer Institute, said in a poster presentation during the conference. “The nice thing about this particular piece of equipment is that once it is inserted into the patient, you remove the needle stylet– making it needle-less once you remove it from the patient, and what is left in the patient is a flexible catheter for administration.”

Compared with traditional infusion via an injection needle, the use of a catheter was associated with a lack of occlusion, an overall reduction in injection site complications, and reports of nurse satisfaction and comfort with the procedure. Specifically, nurses can attach a syringe to the end of the catheter, creating more space between the patient and nurse and, in turn, increasing the nurses’ comfort. In addition, because the catheter allows for slower infusion times, the injection site stability was increased and absorption was enhanced.

Multiple large volume intravenous infusion immunotherapies have recently been converted to large volume subcutaneous formula infusions comprising of 15 mL and whose administration time lasts up to 8 minutes. The therapy is administered with hyaluronidase to enhance absorption; however, erythema, edema, pruritus, itching, and rash at the injection sites continue to represent potential complications, which can occur up to 24 hours following injection. The large volume and duration time, as well as the difficulty of maintaining needle stability for 8 minutes and the lack of safety cause multiple nurses to voice their concerns.

At the institution where the implementation was rolled out, nurses were experiencing complications in administering rituximab (Rituxan).

Investigators therefore consulted their pharmacy teams about the possibility of using different equipment. Specifically, there were concerns surrounding mitigating any potential risks related to altering the medical integrity of the trials. After identifying the BD Saf-T-Intima butterfly catheter as an appropriate piece of equipment, the study authors then consulted national nursing guidelines to develop appropriate corresponding protocol. Finally, the nurses began implementing nurse education, training, and provision of appropriate supplies.

Overall, the rollout of the catheter utilization was met with nurse satisfaction.

“You are able to apply a transparent dressing over the catheter so that there is a limited movement of that catheter within the subcutaneous tissue, and the nurse can easily, with a little bit of space between them, attach the syringe and administer the medication,” Rogers said.

To ensure that the patient receives all their medication, the nurses conduct a 0.5 flush of the catheter prior to administration and a post-administration flush of 0.5, she noted. However, since implementation, there were no increased instances of occlusion or administration site complications.

Since implementation of this catheter, the FDA has approved additional agents for subcutaneous administration. In addition to rituximab, daratumumab and hyaluronidase-fihj (Darzalex Faspro), and Phesgo (pertuzumab [Perjeta], trastuzumab [Herceptin], and hyaluronidase–zzxf) are also now approved for subcutaneous administration.

The team has therefore implemented additional catheter rollouts, which were described as “relatively seamless,” Rogers noted. In addition, they have created visual aids to help nurses administer subcutaneous administration with pre- and post-procedure instructions.

“When clinical trials are being designed, investigators may not be aware of all of the equipment that may be available for safe administration,” Rogers concluded. “For example, in this case, catheters were used for subcutaneous injection, rather than metal needles. We want to encourage our oncology nurses to advocate for safe medication practices as they play a significant role in safe administration of the medications that are used for cancer treatment.”

Colvin C, Rodgers G. A novel approach to subcutaneous immunotherapy administration. Presented at: 47th Annual Oncology Nursing Society Congress; April 27-May 1, 2022; Anaheim, CA. Abstract P25.

Oncology nurses found that the use of a flexible catheter for subcutaneous immunotherapy is linked with increased safety and satisfaction.  

Catheter Represents Preferred Administration Equipment Vs Injection Needle for Subcutaneous Immunotherapy Infusions

Treatment with the CD40 agonist sotigalimab (APX005M) in addition to pembrolizumab (Keytruda) elicited immunologic changes that yielded positive clinical responses in patients with unresectable stage III or IV metastatic melanoma, according to phase 1/2 findings (NCT02706353) presented during the 2022 AACR Annual Meeting.

Furthermore, the agent was found to have a favorable safety profile. Investigators also identified broad immune activity in both local and distant lesions through biomarker analysis.

In addition to evaluating the safety of sotigalimab, investigators determined the maximum-tolerated dose, the recommended phase 2 dose (RP2D), and objective response rate (ORR).

Among the total evaluable patients (n = 30), the ORR was 50% and was comprised of complete (17%) and partial responses (33%). Seventeen percent reported stable disease and 33% reported disease progression. The disease control rate was 67% and the response rate at the RP2D was 55%, said Bentebibel. Responses were also seen across PD-L1 and lactate dehydrogenase (LDH) levels.

By the data cutoff of December 30, 2021, 30 patients had been enrolled, said lead author Salah-Eddine Bentebibel, PhD. In the phase 1 portion of the study, 14 patients who were immune checkpoint inhibitor–naïve received an initial dose of intratumoral sotigalimab (0.1 mg) and intravenous pembrolizumab (2.0 mg/kg). This was followed by 4 increasing doses of sotigalimab at 0.5 mg, 1.0 mg, 3.0 mg, and 10 mg. Pembrolizumab was administered at 2.0 mg/kg across the escalation.

At the conclusion of phase 1, it was determined that the RP2D should be sotigalimab at 10 mg and pembrolizumab at 2 mg/kg. The phase 2 portion of the study is underway and will seek to enroll approximately 20 patients.

Investigators had hypothesized that sotigalimab could harness the CD40 pathway and activate innate and adaptive immunity. This is especially important because “many patients do not respond to [checkpoint inhibitor] therapy or develop resistance after initial tumor regressions, and new combinations are needed to improve the benefit risk profiles,” Bentebibel, an instructor in the Department of Melanoma Medical Oncology–Research at The University of Texas MD Anderson Cancer Center in Houston, Texas, said during the presentation of the data.

The majority of patients were male (n = 26; 87%) and were a median age of 65 years (range, 32-81). ECOG performance status was either 0 (57%) or 1 (43%). Fifty-seven percent had stage IV disease and 54% were 

 negative. Most patients (47%) had low LDH levels but 30% had very high LDH levels. PD-L1 status was unknown or negative in 37% of patients, respectively, and 8 patients (27%) were PD-L1 positive.

Biomarker analysis was conducted using blood and tumor samples obtained from local and distant lesions at baseline and at 24 hours post sotigalimab. Upregulation of genes and CD40 activation were noted by the investigators. “We saw robust upregulation of genes associated with antigen-presenting cells [APCs] and also engagement of MAP kinase and nuclear factor ĸB, a regulator of innate immunity,” Bentebibel said. In addition to the early time points of upregulated APCs, the investigators also reported T-cell response at later time points. “So [taken] together, these data suggest that sotigalimab engages the CD40 pathway,” Bentebibel said.

Further immune activity observed included an increase in macrophage, T cells, CD8+ T, and cytotoxic gene signatures in responding patients and the combination resulted in an increase in T-cell infiltration and clonality in local and distant lesions.

Regarding safety, investigators reported zero study discontinuations or death due to treatment-related adverse events (TRAEs). The most common TRAEs were injection-site reactions and 6 patients (20%) reported grade 3 immune-related AEs. Zero dose-limiting toxicities were observed for any dose level of sotigalimab.

Investigators concluded that the combination of sotigalimab and pembrolizumab showed encouraging antitumor activity and that the combination could induce immune activity in both local and distant lesions.

Bentebibel S-E, Johnson D, Amariae R, et al. Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors in metastatic melanoma. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT039.

The CD40 agonist sotigalimab in combination with pembrolizumab yielded promising outcomes in patients with unresectable stage III or IV metastatic melanoma.

Sotigalimab/Pembrolizumab Jumpstarts Immune Activity, Ignites Clinical Responses in Metastatic Melanoma

Second-line treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) outperformed ipilimumab alone by statistically improving progression-free survival (PFS) in previously treated patients with stage III unresectable or stage IV melanoma, according to findings from the phase 2 SWOG S1616 trial (NCT03033576) that were presented during the 2022 AACR Annual Meeting.

At a median follow-up of 28.3 months, the median PFS was 3.0 months (90% CI, 2.8-5.3) with the combination vs 2.7 months (90% CI, 2.5-2.9) with ipilimumab alone (HR, 0.63; 90% CI, 0.41-0.97; 

 = .037). The estimated 6-month PFS rates were 34% (90% CI, 25%-44%) and 13% (90% CI, 4%-27%), respectively.

“Subgroups that appear to have done particularly well with the combination therapy include patients with stage IV disease, patients with no prior adjuvant therapy, and patients who received less than 6 months of anti–PD-1 therapy prior to enrollment,” lead study author Ari VanderWalde, MD, MPH, vice president of Clinical Development, Precision Oncology Alliance, Caris Life Sciences, and research faculty at the West Cancer Center & Research Institute, said in the presentation.

The optimal use of immunotherapy is not well defined in melanoma. Available frontline options, such as the combination of ipilimumab and nivolumab, may be too toxic for all patients, and although PD-1 inhibitors have a high response rate, patients will ultimately develop resistance.

As such, the SWOG S1616 trial was designed to understand whether treatment with a CTLA-4 inhibitor alone or in combination with continued PD-1 inhibition can couldreverse primary resistance to PD-1/PD-L1 inhibition in metastatic melanoma.

The study enrolled patients with unresectable stage III or IV melanoma with disease progression on prior PD-1/PD-L1 inhibition. Patients must have achieved a confirmed partial response (PR) or complete response (CR) prior to progression. Patients who progressed on a PD-1/PD-L1 inhibitor in the adjuvant setting were not excluded from enrollment.

Additional eligibility criteria stipulated that patients must have measurable disease per RECIST version v1.1 criteria; a Zubrod performance status of 2 or belowlower; no prior exposure to a CTLA-4 inhibitor;, no history of clinically significant autoimmune disease; and no active central nervous system metastases.

Patients underwent a pretreatment biopsy and were randomized 1:3 to 3 mg/kg of ipilimumab every 3 weeks for 4 doses (n = 24) or the same schedule of ipilimumab plus 1 mg/kg of nivolumab every 3 weeks for 4 doses followed by 480 mg of nivolumab every 4 weeks (n = 70). Additional blood samples and biopsies were taken on days 28 through 35.

Patients underwent tumor assessment every 12 weeks for 1 year. Treatment was continued with clinical benefit, and patients were followed for 2 years.

PFS served as the primary end point of the study. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and the difference in T-cell infiltrate between on-study biopsy samples of responders vs nonresponders.

Between July 2017, and July 2020, 91 eligible patients were treated across 35 sites in the United States.

A total of 23 patients received ipilimumab and 68 received ipilimumab plus nivolumab.

The study arms were well balanced for significant baseline factors. Most patients were male, White, had a performance status of 0, less than 6 months of prior PD-1 therapy, no prior adjuvant therapy, and prior PD-1 therapy only for metastatic disease.

Additional results demonstrated that the ORR was 9% (n = 2; 90% CI, 2%-25%) with ipilimumab alone vs 28% (n = 19; 90% CI, 19%-38%) with the combination (

 = .05). In the ipilimumab arm, there were 0 CRs, 2 PRs (9%), 3 cases of stable disease (13%), and 18 cases of progressive disease (78%). In the combination arm, there were 6 CRs (9%), 13 PRs (18%), 14 cases of stable disease (20%), and 35 cases of progressive disease (51%); 1 patient was not evaluable for response.

The median duration of response was not reached (NR) with ipilimumab vs 18.9 months with the combination. Response was ongoing in 9% of patients on ipilimumab (100% of responders) vs 12% of patients on the combination (42% of responders).

Post-progression therapy for patients from both arms included pembrolizumab (Keytruda; n = 6; 8%), a PD-1 inhibitor (n = 5; 6%), ipilimumab (n = 6; 8%), another immunotherapy (n = 16; 21%), targeted therapy (n = 12; 15%), cytotoxic chemotherapy (n = 4; 5%), and radiation (n = 12; 15%). No significant differences were seen in post-progression therapy between treatment arms; any differences were above the threshold for significance (

At a median follow-up of 27.3 months, the median OS was 21.7 months (90% CI, 15.4-32.4) with the combination vs 25.7 months (90% CI, 8.1-NR) with ipilimumab, failing to reach the threshold for statistical significance (HR, 0.93; 90% CI, 0.54-1.60; 

 = .408). The 12-month OS rates were 63% (90% CI, 52%-72%) and 57% (90% CI, 38%-71%), respectively.

Regarding safety, any-grade adverse effects (AEs) were reported in 87% (n = 20) of patients on ipilimumab vs 93% (n = 63) of patients on the combination. Grade 1 through 3 AEs occurred in 74% (n = 17) of patients in the ipilimumab arm vs 85% (n = 58) of patients in the combination arm. Grade 4 and 5 AEs occurred in 13% (n = 3) of patients vs 7% (n = 5) of patients, respectively.

Grade 3 or greater higher AEs that occurred in at least 5% of patients in the ipilimumab and/or combination arms, respectively, included diarrhea (13% each), aspartate aminotransferase increase (7% each), alanine aminotransferase (7% each), rash (4% vs 6%), fatigue (4% vs 6%), anemia (0% vs 6%), hypotension (0% vs 6%), and hyponatremia (4% vs 6%).

A total of 16% (n = 4) and 23% (n = 16) of patients in the ipilimumab and combination arms, respectively, did not complete all 4 doses of ipilimumab because of an AE.

Correlative analysis demonstrated that the combination led to an increase in CD8+ cells in the tumor and at the boundary in responsive tumors.

“Nivolumab plus ipilimumab is an appropriate next-line treatment in patients without response to anti–PD-1 alone,” VanderWalde concluded.

VanderWalde A, Moon J, Bellasea S, et al. Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti-PD-1 therapy. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT013.

An improved progression-free survival benefit was observed in patients with stage III unresectable or stage IV melanoma who received nivolumab plus ipilimumab.

Nivolumab/Ipilimumab Elicits Promising PFS in Second-Line Metastatic Melanoma

Frontline treatment with carboplatin/etoposide and atezolizumab (Tecentriq) plus the anti-TIGIT immunotherapy tiragolumab did not significantly improve progression-free survival in patients with extensive-stage small cell lung cancer (ES-SCLC), according to updated findings form the phase 3 SKYSCRAPER-02 trial (NCT04256421).

The treatment regimen, therefore, did not reach its co-primary endpoint.

In addition, the other co-primary endpoint of the study was also not met at the interim analysis and is not anticipated to reach statistical significance by the planned final analysis. Although overall survival (OS) and PFS data were not positive, the combination was associated with acceptable tolerability and no new safety signals.

A more extensive analysis of the interim findings will be presented at an upcoming medical conference, according to Roche.

“Today’s outcome is disappointing as we had hoped to continue building on the advances of [atezolizumab] in ES-SCLC, which remains difficult to treat,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release.

An immune checkpoint inhibitor with an intact Fc region, tiragolumab was designed to selectively bind to TIGIT, which is known to suppress the response of the immune system to cancer. Preclinical data have indicated that the agent can serve as an immune amplifier when paired with other immunotherapeutic agents.

Although the TIGIT pathway is distinct to the PD-L1/PD-1 pathway, it is also complementary. Investigators have hypothesized that the combination of tiragolumab and an immunotherapy like atezolizumab could serve to overcome immune suppression and essentially restore response.

The global, placebo-controlled, double-blinded SKYSCRAPER-02 trial enrolled patients with histologically or cytologically confirmed ES-SCLC who have not previously received systemic treatment.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, acceptable hematologic and end-organ function, and they needed to be treatment free for at least 6 months since their last chemoradiation.

If patients had symptomatic or actively progressing central nervous system metastases, malignancies other than SCLC within 5 years before randomization, active or a history of autoimmune disease or immune deficiency, or human immunodeficiency virus, active hepatitis B or C virus, or severe infection at the time of randomization, they were excluded.

A total of 490 patients were enrolled to the trial, and they were randomized 1:1 to receive intravenous (IV) tiragolumab at 600 mg on day 1 of each 21-day cycle plus atezolizumab and carboplatin/etoposide or placebo plus atezolizumab and carboplatin/etoposide. All patients received IV atezolizumab at 1200 mg on day 1 of each 21-day cycle, IV carboplatin on day 1 of each 21-day cycle for 4 cycles followed by etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for 4 cycles.

The co-primary end points of the trial were OS and PFS in the primary analysis set, which was comprised of all randomized patients whose cancer had not spread to the brain. Important secondary end points included OS and PFS in all randomized patients and safety.

Previously, tiragolumab was granted a breakthrough therapy designation from the FDA for use in combination with atezolizumab in the first-line treatment of patients with metastatic NSCLC whose tumors are PD-L1 high and do not harbor any 

The phase 2 CITYSCAPE trial (NCT03563716) enrolled treatment-naïve patients with stage IV non–small cell lung cancer (NSCLC) who had 

 wild-type disease. To participate, patients needed to have a PD-L1 tumor proportion score (TPS) of 1% or higher per 22C3 immunohistochemistry and local or central assay.

A total of 135 patients were randomized 1:1 to receive IV tiragolumab at 600 mg every 3 weeks in combination with IV atezolizumab at 1200 mg every 3 weeks (n = 67), or IV placebo at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 68). Treatment was administered until progressive disease or clinical benefit was lost. Key stratification factors included PD-L1 TPS (1% to 49% vs more than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no).

The co-primary end points of this research were objective response rate (ORR) and PFS. Secondary end points included duration of response, OS, and safety.

At a median follow-up of 30.4 months, the combination produced a median PFS of 5.6 months (95% CI, 4.2-10.4) per investigator assessment vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone in the intention-to-treat (ITT) population. The median OS in the investigative and control arms was 23.2 months (95% CI, 14.1-31.5) and 14.5 months (95% CI, 9.6-20.4), respectively.

At the time of the primary analysis, which had a data cutoff date of June 30, 2019, and a median follow-up of 5.9 months, the tiragolumab combination produced a clinically meaningful improvement in ORR and PFS in the ITT population vs atezolizumab monotherapy. That benefit was maintained with the additional follow-up, with a greater magnitude of improvement noted in the patient subset who had a PD-L1 TPS of 50% or less.

The phase 3 SKYSCRAPER-01 trial (NCT04294810) is currently ongoing to confirm the results yielded in CITYSCAPE. Here, the safety and efficacy of tiragolumab plus atezolizumab is being compared with atezolizumab alone in patients with previously untreated locally advanced, unresectable or metastatic PD-L1–selected NSCLC without an 

“We look forward to seeing additional data from the upcoming phase 3 trial in PD-L1–high NSCLC based on encouraging results from the CITYSCAPE study,” Garraway added.

Ad hoc announcement pursuant to Art. 53 LR Roche provides update on phase III SKYSCRAPER-02 study in extensive-stage small cell lung cancer. News release. Roche; March 30, 2022. Accessed March 30, 2022. 

A study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer (SKYSCRAPER-02). ClinicalTrials.gov. Updated March 17, 2022. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04256421

Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche; January 5, 2021. Accessed March 30, 2022. 

Cho BC, Rodriguez-Abreu S, Hussein M, et al. LBA2 updated analysis and patient-reported outcomes (PROs) from CITYSCAPE: a randomised, double-blind, phase II study of the anti-TIGIT antibody tiragolumab + atezolizumab (TA) versus placebo + atezolizumab (PA) as first-line treatment for PD-L1+ NSCLC. 

. 2021;32(suppl 7):S1428. doi:10.1016/j.annonc.2021.10.217

A study of tiragolumab in combination with atezolizumab compared with placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (SKYSCRAPER-01). ClinicalTrials.gov. Updated December 7, 2021. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04294810

This article was published on OncLive as “Tiragolumab Plus Atezolizumab/Chemo Misses PFS End Point in Extensive-Stage SCLC"

An update from the phase 3 SKYSCRAPER-02 trial found that tiragolumab to atezolizumab did not significantly improve progression-free survival in extensive-stage small cell lung cancer. 

Tiragolumab/Atezolizumab Fails to Improve PFS in Extensive-Stage SCLC 

Most, but not all, immunotherapy-related adverse events (irAE) occur throughout the first 12 weeks of treatment, and can affect any organ, according to La-Urshala Brock, FNP-BC, CNM, RNF, a clinical instructor specializing in breast and gynecologic cancers at the Nell Hodgson Woodruff School of Nursing with Emory University.

 Miami Breast Cancer Conference® about immunotherapy-related adverse event management, in a lecture titled, “Immunotherapy Adverse Effects,” which focused specifically on toxicities associated with pembrolizumab (Keytruda).

In July 2021, the PD-L1 inhibitor pembrolizumab was 

 to treat patients with triple-negative breast cancer (TNBC) in the neoadjuvant meeting in conjunction with chemotherapy, to be continued as an adjuvant monotherapy after surgery.

The approval for pembrolizumab was supported by findings from the randomized, multicenter, double-blind, placebo-controlled KEYNOTE-522 trial (NCT03036488).

 Results demonstrated a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; 

 = .00031).The recommended dose for intravenous pembrolizumab is 200 mg every 3 weeks.

Notably, this approval also marked the first immunotherapy to treat patients with high-risk early-stage TNBC. However, the introduction of the agent also opens the door for more toxicity management education for nurses who care for patient with breast cancer.

“Immunotherapies present with a novel spectrum of AEs that differ in important ways from those associated with chemotherapy and targeted agents,” said Brock. “When you're using immunotherapy, truly any organ can be affected. The median onset is 4 to 5 weeks [after beginning treatment], but adverse events can happen as early as when you start the treatment.”

Atezolizumab (Tecentriq), a PD-L1 inhibitor, was 

 for TNBC to be given every 3 weeks with weekly nab-paclitaxel (Abraxane) in 2019, but this agent was withdrawn from market, since it was not shown to improve survival in patients with locally unresectable metastatic, PD-L1–positive disease.

In her discussion, Brock highlighted a wide range of toxicities that are associated with immune checkpoint inhibitiors (ICI)—particularly for patients with TNBC receiving pembrolizumab. Toxicities of interest include dermatitis, endocrine effects, adrenal insufficiencies, lung effects, colitis, hepatotoxicity, and ocular side effects, in addition to a couple rarer immune-related AEs (irAEs).

ICIs may induce low-grade rashes in many patients. This can include reticular erythema, papules, and plaques. In more rare cases, Stevens-Johnson syndrome or toxic epidermal necrolysis, palmar–planta dysesthesia may also occur.

Effective management of skin-related toxicities involve frequent photo documentation of the toxicity and follow-up photos to track potential changes, as well as consulting a dermatologist to obtain a biopsy. For low-grade toxicities, symptomatic treatment with antihistamines typically prove to be effective. However, for high-grade toxicities, treatment with topical or oral steroids may be appropriate. In addition, if symptoms progress to grade 3, treatment should be withheld, and if symptoms worsen to grade 4, treatment should be discontinued.

“We hold at this point,” said Brock. “You could think about using rituximab [Rituxan] for treatment. You want to continue steroids until the blisters have resolved completely and then [once] the blisters have resolved, you want to slowly taper the steroids.”

Endocrine toxicities occur in approximately 10% of patients receiving pembrolizumab. Nurses should watch for vision changes, weight gain or weight loss, dizziness, constant chilliness or feeling cold, constipation, and hair loss. Other signs of endocrine toxicities include increased headaches or changes in headache patterns, increased heartbeat, increased urination, increased tiredness, increased thirst or appetite, changes in mood, and increased sweating.

Patients suspected to be experiencing these toxicities should have their thyroid-stimulating hormone (TSH) and free thyroxine (FT4) checked every 4 to 6 weeks with complete blood count (CBC) and comprehensive metabolic panel (CMP).

Adrenal insufficiency, or Addison’s disease, means that the adrenal glands produce insufficient amounts of the hormone cortisol, Brock explained. Signs and symptoms include extreme fatigue, darkening skin or hyperpigmentation, low blood pressure or fainting, abdominal pain, muscle or joint pain, salt craving, weight loss, depression or behavioral changes, and nausea, vomiting, or diarrhea.

For primary adrenal insufficiency, the workup should include assessing morning cortisone and adrenocorticotropic hormone (ACTH) levels, as well as CMP to assess sodium, glucose, potassium, and carbon dioxide.

If a patient has elevated TSH levels but normal or low FT4, then hypothyroidism is the cause. So long as the toxicity remains a grade 1 (TSH < 10 ml U/L or asymptomatic), they may continue receiving the checkpoint inhibitor with continued TSH and FT4 monitoring.

For hypophysitis, or inflammation of pituitary gland, the workup should include assessing morning cortisone as well as ACTH, TSH, FT4, testosterone in men, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen in premenopausal women, and an MRI of the brain with or without contrast with pituitary cuts.

If the hypothyroidism progresses to a grade 2 (TSH > 10 mIU/L or symptomatic), the ICI should be withheld, an endocrinologist should be consulted, and a thyroid hormone supplementation should be implemented. The patients will continue to require TSH and FT4 checks every 6 weeks, but if the severity reduces to a grade 1 event, they may continue treatment.

In the event of grade 3/4 hypothyroidism, the ICI should be withheld until symptoms resolve to baseline with thyroid supplementation.

If a patient has low TSH and high, normal, or elevated FT4 levels, then this person is experiencing hyperthyroidism. As long as the toxicity remains at grade 1, they may continue receiving the ICI with continued TSH and FT4 checks every 2 to 3 weeks.

If the hyperthyroidism progresses to a grade 2, the ICI should be withheld until symptoms return to baseline and an endocrinologist should be consulted. A beta blocker might also be considered.

For grade 3/4 hyperthyroidism, the ICI will need to be withheld until symptoms resolve to baseline with thyroid supplementation. In addition, at this grade, hospitalization may be required if thyroid storm occurs. Prednisone should be considered at a dosage of 1 to 2 mg/kg daily and then put on a tapering schedule.

“With hyperthyroidism, what I want to mention here is that if someone is experiencing symptoms, we can use a beta blocker, but we also still want to be consulting endocrinology,” Brock highlighted. “One of the risk factors here when we get to grade 4 is the risk for thyroid storm. That is why it is important to have endocrinology involved.”

In less than 1% of patients, ICI-mediated endocrinopathy type 1 diabetes mellitus may occur with rapid onset anytime following therapy initiation.

Management for this toxicity involves monitoring serum glucose at baseline and prior to each cycle of ICI. An endocrinologist should be consulted, and generally, lifelong insulin therapy will be required. Once blood sugar is well controlled, the ICI therapy can be restarted.

Pneumonitis equates to inflammation of the lung parenchyma. This irAE occurs between 0% to 10% of patients, but the odds increase when patients receive combination therapy as opposed to monotherapy, as well as if there has been previous thoracic radiation.

 The onset time for lung toxicity can range from 2 to 24 months, however, the median onset time is 3 months.

Cough, fever, dyspnea, and chest pain should be evaluated when monitoring for lung toxicity. Patients who experience these symptoms will need a chest x-ray and CT scan. The threshold for obtaining a CT scan of the chest and a pulmonary consultation should be low, noting that CT findings typically lag patient symptoms.

Management includes routine pulse oximetry checks in addition to potential CT scans, as well as administration of high-dose steroids, starting at 1 to 2 mg/kg daily, and tapering across 45 to 60 days. If symptoms return, the steroids may require retapering.

If within 72 to 96 hours of steroid initiation there is no symptom relief, patients should receive infliximab-axxq (Avsola) at 5 mg/kg. In most cases, the addition of immunosuppressants will help to resolve the issue.Infectious workup should include a nasal swab for potential viral pathogens, including COVID-19.

Notably, lung toxicity has been associated with immune checkpoint inhibitors but is an uncommon AE; less than 5% of patients experience this irAE, and less than 1% report high-grade lung toxicity while receiving this type of immunotherapy. In comparison, lung toxicity tends to present more in patients receiving ipilimumab (Yervoy) plus nivolumab (Opdivo), explained Brock.

Colitis occurs in approximately 8% to 27% of patients receiving ICIs. Onset of GI toxicities typically appear about 5 to 10 weeks after treatment begins but can occur months after treatment with the ICI has stopped.

Initial workup for colitis should include CBC, CMP labs to assess TSH, c-reactive protein (CRP), HIV, hepatitis A and B; whereas interferon gamma release assay should be used to look for tuberculosis (TB). In addition, stool cultures to identify C. diff, CMB, ova, and parasites are recommended; lactoferrin should identify inflammation of digestive tracts and calprotectin can determine immune bowel disease (≤80 ug/g) vs inflammation (levels on 80 ≥ 1, 60 ug/g); and a CT scan.

At grade 1 severity, the ICI can either continue or be temporarily withheld. Providers should discuss dietary changes with their patients and review hydration strategies, and antdiarrheal administration may also be effective.

If the inflammation progresses to grade 2 level, the ICI should be withheld until symptoms return to grade 1 or less. A GI specialist should be consulted for an EGD/colonoscopy and prednisone should be administered at a dosage of 1 mg/kg daily. In addition, stools should be checked for inflammatory markers, such as lactoferrin and calprotectin. Once the symptom returns to grade 1, the steroids should be tapered across 4 to 6 weeks.

Grade 3 inflammation requires a hold on the ICI. Hospitalization may be required if there is electrolyte imbalance and dehydration. Providers should rule out CMV via colonoscopy and consult a GI specialist. Corticosteroids given at a dosage of 1 to 2 mg/kg day or infliximab at a dosage of 5 to 10 mg/kg daily should be administered.

“With colitis, there could be another rebound,” said Brock. “Someone could resolve back to a ready to a grade 1; if that occurs then, of course, we restart the steroids or increase the steroids and start again—slowly tapering once the symptoms improve.”

If the severity level reaches a grade 4, it is now life-threatening, and treatment should be discontinued permanently.

Hepatotoxicity or immune-mediated hepatitis occurs in approximately 2% to 10% of patients receiving pembrolizumab and onset usually occurs between 6 to 12 weeks after treatment initiation. Symptoms include drowsiness, jaundice, right-sided abdominal pain, severe nausea or vomiting, increased bleeding, or bruising, decreased appetite, and abnormal liver blood tests (aspartate aminotransferase [AST], alanine transaminase [ALT], and bilirubin).

For grade 1 inflammation (AST or ASLT > upper limit of normal [ULN] to 3.0 and/or total bilirubin 1.0 ULN > 1.5 ULN), ICI treatment may continue but liver function should be monitored 1 to 2 times weekly. For grade 2 inflammation (ASR or ALT > 3.0 ULN to 

 5.0 and/or total bilirubin 1.0 ULN to 3.0 ULN with symptoms), the ICI should be held until severity resolves to a grade 1.

In addition, the liver should be monitored every 3 days if the patient is symptomatic. If the symptom reaches statistical significance, after 3 to 5 days they can receive corticosteroids at a dosage of 0.5 to 1.0 mg/kg daily. This will require tapering over 1 month. Lastly, any hepatoxic medication should be halted.

For grade 3 inflammation (ASR or ALT 5 x 20 x ULN and/or total bilirubin >3-10 x ULN with symptoms such as biopsy-fibrosis or cirrhosis), the ICI should be discontinued permanently, and the patient should be monitored every 1 to 2 days. Corticosteroids should be administered at a dosage of 1 to 2 mg/kg/day, and the patient should be referred to a hepatologist.

If the symptom progresses to grade 4 (ASR or ALT >20 x ULN and/or total bilirubin > 10 x ULN, with symptoms such as ascites or encephalopathy), they will need to be hospitalized with daily lab monitoring and consultation from a hepatitis. They should receive methylprednisone at a dosage of 2 mg/kg daily.

Ocular symptoms typically occur in less than 1% of patient receiving PD-1/PD-L1 inhibitors alone or in combination. Symptoms include eyelid swelling, blurred vision, double vision, or color vision changes, photophobia, painful eye movement, scotomas, proptosis or bulging eyes, and visual field changes.

La-Urshala Brock, FNP-BC, CNM, RNFA, discusses effective toxicity management for patients with breast cancer receiving pembrolizumab. 

Checkpoint Inhibitors Present Unique Adverse Events, Require Careful Management Strategies in Breast Cancer

The FDA has approved neoadjuvant nivolumab (Opdivo) plus chemotherapy to treat patients with resectable non–small cell lung cancer (NSCLC). Notably, this combination now represents the first available neoadjuvant immunotherapy combination option for this patient population, according to a news release.

The approval is supported by findings from the CheckMate 816 trial (NCT02998528), which showed that the combination elicited a significantly improved survival outcomes in patient with resectable NSCLC. Patients who received this combination experienced a 37% reduction in the risk of progression, recurrence, or death (HR 0.63; 95% CI, 0.45-0.87; 

= .0052) compared with those who received chemotherapy alone.

Furthermore, patients in the nivolumab/chemotherapy cohort also reached a median event-free survival (EFS) of 3.6 months (95% CI, 30.2-not reached) compared with 20.7 months (95% CI, 14.0-26.7) in the control group.

In addition, at the 2021 AACR Annual Meeting, data were presented that demonstrated a significantly improved pathological complete response rate with the combination compared with those who received chemotherapy alone (24% vs 2.2%, respectively).

 The combination was not associated with an increase in overall toxicity or surgery delays.

Moreover, surgical outcomes revealed that the definitive surgery rates were 83% with nivolumab plus chemotherapy compared with 75% with chemotherapy alone, according to findings presented at the 2022 ASCO Annual Meeting.

 Reasons for surgery cancellation included disease progression, adverse events (AEs), as well as patient refusal, unrespectability, and poor lung function.

“Given the rates of disease recurrence in patients with resectable NSCLC, additional treatment options are needed that can be given before surgery to help improve the chance of successful surgical treatment and support the goal of reducing the risk of cancer returning,” study investigator Mark Awad, MD, PhD, clinical director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, said in a statement. “The approval of nivolumab with platinum-doublet chemotherapy marks a turning point in how we treat resectable NSCLC, and it enables us to use immunotherapy and chemotherapy as neoadjuvant treatment for patients before surgery. Today’s announcement reinforces the need to increase the rates of NSCLC screening and early detection, and for patients to discuss treatment options with their providers.”

The recommended dose is 360 mg of nivolumab along with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles.

The most frequently observed adverse events included nausea, constipation, fatigue, decreased appetite, and rash. Notably, the combination did not elicit more delays or cancellations of surgery; the median length of hospital stays following surgery were also found to be similar between both study arms.

U.S. Food and Drug Administration approves Opdivo (nivolumab) with chemotherapy as neoadjuvant treatment for certain adult patients with resectable non-small cell lung cancer. News release. Bristol Myers Squibb. March 4, 2022. Accessed March 7, 2022. https://bit.ly/3INrdQA

Neoadjuvant nivolumab plus chemotherapy increased pathological complete response rate in CheckMate-816 lung cancer trial. American Association for Cancer Research. April 10, 2021. Accessed February 28, 2022. 

Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). 

. 2021;39(supp 15; abstr 8503). doi:10.1200/JCO.2021.39.15_suppl.8503

FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. FDA. News release. March 4, 2022. Accessed March 7, 2022. https://bit.ly/3Myicx2

Nivolumab combined with chemotherapy is now approved in the resectable non–small cell lung cancer setting. 

Neoadjuvant Nivolumab Plus Platinum-Doublet Chemotherapy Is Now Approved for Resectable NSCLC 

Nivolumab (Opdivo) plus ipilimumab (Yervoy) was associated with better maintained health-related quality of life (HRQOL) compared with sunitinib (Sutent) across multiple sub-groups of patients with advanced renal cell carcinoma (RCC), according to a 5-year follow-up analysis of the CheckMate 214 trial (NCT02231749), which was presented during the 2022 Genitourinary Cancers Symposium.

Furthermore, the benefit was observed across multiple definitions and subgroup population analyses, suggesting that the combination is linked with favorable long-term health-related QOL (HRQOL) outcomes. The data were presented during the 2022 Genitourinary Cancers Symposium.

When compared with sunitinib, nivolumab/ipilimumab was associated with least square (LS) mean longitudinal changes from baseline, a longer time to confirmed deterioration, and less bothersome adverse events (AEs). These findings were consistent across both the all-randomized and intermediate-/poor-risk populations.

“Nivolumab plus ipilimumab continued to demonstrate HRQOL benefits with extended follow-up vs sunitinib, with significant differences in scale scores between the treatment arms favoring nivolumab plus ipilimumab,” lead author David Cella, FASCO, PhD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and coinvestigators, wrote in a poster presentation of the findings.

The FDA approved nivolumab plus ipilimumab in April 2018 as a frontline treatment for intermediate- and poor-risk patients with RCC, based on earlier findings from the phase 3 CheckMate-214 trial.

CheckMate-214 enrolled 1096 patients with previously untreated advanced clear cell RCC. Eligible participants needed a Karnofsky performance status of at least 70. Participants were randomized 1:1 to receive either 3 mg of nivolumab plus 1 mg of ipilimumab every 3 weeks for 4 cycles, followed by 3 mg of nivolumab every 2 weeks, or to receive oral sunitinib at 50 mg once daily for 6 cycles on a 4-weeks-on/2-weeks-off schedule.

Patients received treatment until progression or unacceptable toxicity. A 2017 amendment to the study design permitted patients receiving sunitinib to switch over to the nivolumab/ipilimumab cohort. The amendment also permitted discontinuation of any study treatment after 2 years.

At the 5-year follow-up, patients who received nivolumab/ipilimumab demonstrated favorable overall survival (OS) rates compared with those who received sunitinib in both the intermediate-/poor-risk subgroup (HR, 0.68; 

 <.0001) and in the intent-to-treat (ITT) group (HR, 0.72; 

Also with the longer follow-up, the median duration of response was not reached (NR) among those receiving the combination compared with 19.7 months with sunitinib in the intermediate-/poor-risk subgroup (HR, 0.46; 

 < .0001) and NR and 24.8 months, respectively, in the ITT population (HR, 0.49; 

To assess HRQOL, patients were administered 3 different patient-reported outcome (PRO) instruments: the Functional Assessment of Cancer Therapy–Kidney Symptom Index 19 (FACT-KSI19), the Functional Assessment of Cancer Therapy- General (FACT-G), and the 3-level version of the EuroQol-5 Dimension (EQ-5D-3L).

Assessment responses were collected at baseline, on day 1 of weeks 1 and 4 of the first 2 cycles, on day 1 of weeks 1 and 5 of the next 2 cycles, and on day 1 week 1 of all subsequent cycles.

Baseline characteristics were well-balanced between the 2 treatment arms. Across all populations, PRO completion rates were high at baseline (>90%) and remained as such throughout treatment (>75%).

FKSI-19 and FACT scores were initially comparable with the general US population at baseline, indicating that patients began treatment with relatively low symptom burden and good functioning scores. In comparison, although EQ-5D-3L indicated good health status, they were also lower than the general population they were compared against, which was the UK general population.

A mixed model for repeated measures (MMRM) was utilized to assess longitudinal changes in PRO scores spanning from baseline through week 235. Time was treated as a continuous variable.

In both the ITT and intermediate-/poor-risk populations, nivolumab/ipilimumab elicited superior overall changes from baseline to 59 months.

For FKSI-19 total scores, nivolumab/ipilimumab induced a 0.45 LS mean (LSMean) change compared with –2.53 with sunitinib (LSMean change difference, 2.98; 95% CI, 2.04-3.92) in the ITT population.

FKSI-19 Disease-Related Symptoms (DRS) scores showed a –0.17 and a –0.93 LSMean change with nivolumab/ipilimumab vs sunitinib, respectively (LSMean change difference, 0.76; 95% CI, 0.36-1.16). DRS-P LSMean changes were 0.13 vs –1.17 (LSMean change difference, 1.30; 95% CI, 0.73-1.87), and FWB changes were 0.01 vs –0.58 (LSMean change difference, 0.58; 95% CI, 0.29-0.88), respectively.

FACT total score changes were 0.76 with nivolumab/ipilimumab vs –2.29 with sunitinib (LSMean change difference, 3.05; 95% CI, 1.55-4.55). Psychological well-being (PWB) changes were –0.73 vs –2.28, respectively (LSMean change difference, 1.55; 95% CI, 1.11-1.99) and FWB changes were 0.04 and –0.93, respectively (LSMean change difference, 0.97; 95% CI, 0.38-1.57).

EQ-5D-3L VAS changes were 2.82 vs 0.39 with nivolumab/ipilimumab and sunitinib, respectively (LSMean change difference, 2.44; 95% CI, 0.42-4.46), and the UK Utility Index score changes were 0.01 vs –0.03 (LSMean change difference, 0.04; 95% CI, 0.03-0.06).

In the intermediate-/poor-risk population, for FKSI-19 total scores, nivolumab/ipilimumab induced a 0.96 LSMean change compared with –2.43 with sunitinib (LSMean change difference, 3.39; 95% CI, 2.31-4.47). FKSI-19 DRS scores showed LSMean changes of –0.03 and–0.90 with nivolumab/ipilimumab and sunitinib, respectively (LSMean change difference, 0.87; 95% CI, 0.40-1.33). DRS-P LSMean changes were 0.40 vs –1.16, respectively (LSMean change difference, 1.56; 95% CI, 0.91-2.21), and FWB changes were 0.11 vs –0.58, respectively (LSMean change difference, 0.69; 95% CI, 0.35-1.03).

The immunotherapy combination of nivolumab and ipilimumab elicited favorable health-related quality of life responses compared with sunitinib in patients with advanced renal cell carcinoma. 

Immuno-Oncology