Biologics: Role in the Management of Cancer

Educational Objectives

The goal of this program is to improve management of cancer with use of biologics. After hearing and assimilating this program, the clinician will be better able to:

1. Implement evidence-based strategies for the management of malignancies using various biologic agents.
2. Identify common adverse effects of biologic agents.
3. Manage toxicities associated with use of biologic agents in patients with cancer.

Summary

Immune checkpoint inhibitors (ICIs)

Anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody: ipilimumab and tremelimumab block CTLA-4 and T-cell interaction and are approved by the United States Food and Drug Administration (FDA) for management of solid malignancies; high-dose interleukin (IL)-2 induces durable remission in 3% to 5% of patients with metastatic melanoma; Hodi et al (2010) demonstrated an overall survival benefit with use of ipilimumab alone or in combination with gp100 vaccination in patients with advanced melanoma, compared with use of gp100 alone; toxicities — patients may develop autoimmune-like toxicities, including, eg, colitis (most common), hypophysitis (may lead to secondary endocrinopathies), rash (more common with use of programmed cell death protein 1 [PD1] inhibitors), hepatotoxicity; rashes begin after 1 or 2 cycles of immunotherapy, while diarrhea and hypophysitis occur at later stages; hepatotoxicity is fatal if not recognized early; monitor blood counts, biochemistry, and thyroid function studies; secondary hypothyroidism may occur because of hypophysitis; obtain endocrine testing for patients reporting severe fatigue; corticosteroids are beneficial to reverse several toxicities; loperamide is used for grade 1 colitis, and budesonide is used to treat colitis of at least grade 2 severity; one dose of infliximab can stop symptoms of severe colitis; obtain colonoscopy to rule out other causes of colitis; pseudoprogression — during initial rollout of the medications, several patients developed disease progression as late as 12 wk following drug initiation; while patients at high-volume centers were being screened for other trials, disease response was seen 2 to 3 wk after discontinuing treatment, and continuation of therapy led to tumor regression; it is recommended to wait for another 1 to 2 cycles prior to switching therapies

Programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors: Postow et al (2015) — evaluated the effects of nivolumab (anti-PD-1 antibody) with ipilimumab vs ipilimumab alone in patients with metastatic melanoma; 50% of patients with melanoma have a BRAF mutation which increases sensitivity to targeted therapies; results of the study demonstrated good response rate (>30%) and disease-free survival among patients who received combination therapy; tumor volume increased by ≈5.5% among patients taking ipilimumab alone, compared with a ≈68.1% volume decrease among patients prescribed combination therapy; complete response was observed with doublet therapy; doublet therapy induces greater toxicity than single-agent therapy; updated analysis by Wolchok et al (2022) — revealed an overall survival rate of ≈50% with use of nivolumab plus ipilimumab; nivolumab has received approval from the United States Food and Drug Administration (FDA) for treatment of advanced melanoma in combination with ipilimumab, or with noted disease progression following treatment with ipilimumab alone

Approved use: ICIs received FDA approval for use in the adjuvant setting for earlier-stage disease to reduce risk for postoperative recurrence of lung cancer; one study demonstrates response of renal cell cancer and melanoma following treatment with ICIs; patients with melanoma and lung cancer on chemotherapy with immunotherapy (eg, pembrolizumab) may develop vitiligo

Drug safety: PD-1 and PD-L1 inhibitors have similar toxicity profiles, compared with CTLA-4 inhibitors; compared with PD-1 and PD-L1 inhibitors, incidence of pneumonitis is reduced and incidence of grade 3 to 5 gastrointestinal toxicity is increased among patients taking CTLA-4 inhibitors; Tawbi et al (2022) — demonstrated greater progression-free survival following combination treatment with relatlimab (approved by FDA for use as a lymphocyte-activation gene 3 [LAG-3] ICI with nivolumab for advanced melanoma) and nivolumab vs nivolumab alone; 2-yr update showed improvement in clinical survival, overall survival, and activity with doublet therapy; relatlimab and nivolumab doublet therapy is well-tolerated; toxicities include pneumonitis, diarrhea, rash, and hepatitis

Financial concerns: ICIs are expensive; single-agent PD-1 ICIs are administered once every 3 wk ($200,000/yr); Saltz et al (2016) projected the cost of treating patients with colorectal cancer using immunotherapy; the American Society of Medical Oncology and European Society of Medical Oncology provide evidence-based options categorized by cost

Use in microsatellite instability-high (MSI-H) cancers: Cercek et al (2022) showed that patients with high MSI-H rectal cancer went into remission after sole use of immunotherapy; the increased production of tumor antigens in MSI-H disease may explain the enhanced efficacy of immunotherapy

Chimeric antigen receptor (CAR) T-cell therapy

Background: CARs are genetically modified T-cells derived from patients after transduction with a viral vector; once injected back into the patient, the T-cells then attack the antigens that the CAR recognizes; second-generation CAR T-cells have an extracellular domain that recognizes CD19; the ELIANA trial (Maude et al [2018]) and JULIET trial (Schuster et al [2019]) demonstrated efficacy of CAR T-cell therapy for the management of refractory B-cell acute lymphoblastic leukemia (B-ALL) and large B-cell lymphoma; CAR T-cell therapy was more effective than traditional therapies

Newer agents: axicabtagene ciloleucel recently received FDA approval for the management of lymphoma; studies showed that the T-cells persisted for ≥180 days beyond infusion (unlike the first-generation CAR T-cell agents which lasted only for a few days); toxicity — >90% of patients developed CRS, and >60% had neurotoxicity; tisagenlecleucel is much safer and effective in the outpatient setting; other agents may require 14-day inpatient hospitalization because of associated toxicities (eg, CRS, immune effector cell-associated neurotoxicity [ICAN]); the FDA requires all patients to be monitored for 10 yr

Toxicity: cytokine release syndrome — patients develop fever and hypotension; C-reactive protein and ferritin levels are elevated; the first-line agent for the management of CRS is tocilizumab, which blocks IL-6; corticosteroids are also used; neurotoxicity — CAR T-cell agents cause cognitive dysfunction; the clinician must be watchful for subtle neurologic changes within 12 hr of administration; patients may develop cerebral edema and herniation; patients with suspected ICAN must be admitted to the hospital and evaluated using electroencephalography and magnetic resonance imaging; they have to be closely monitored; management is with corticosteroids; CAR T-cell therapy for solid tumors is less effective and more toxic (eg, use of CAR T-cell therapy for targeting human epidermal growth factor receptor 2 (HER2) overexpression in sarcoma leads to pulmonary toxicity because of HER2 expression in the pulmonary parenchyma; carbonic anhydrase is overexpressed in renal cell carcinoma; carbonic anhydrase expression in the liver may cause hepatotoxicity); CAR T-cell therapy is approved for the management of lymphomas and hematologic malignancies; the stroma produced by solid tumors acts as a physical barrier to T-cells

Natural killer (NK) cell product: has been evaluated for lymphoma; recent studies show benefit with no adverse events; CAR NKs and induced NKs are being studied for the management of solid tumors, and hematologic malignancies; they may be administered in the outpatient setting

Cost: CAR T-cell therapy costs $300,000 to $450,000 per dose; outpatient monitoring adds to infrastructure costs; CRS and ICANs are most prevalent within the first 10 to 14 days

Bispecific T-cell engager (BiTE) therapy: CD3 monoclonal antibody is fused with an antibody anti-target (CD19); antitumor activity begins when the T-cell binds to the antibody and contacts the target cells; blinatumomab has been approved for use for B-ALL; studies show clinical benefit of blinatumomab over chemotherapy for patients with refractory B-ALL; blinatumomab is a short-acting agent which requires continuous venous infusion for days in the hospital; manufacturers have developed alternative therapies that do not require continuous venous infusion and hospitalization; incidence of toxicity (eg, CRS, ICAN) is lower; BiTE therapy is currently being evaluated for solid tumors, small cell lung cancer, and prostate cancer; patients with advanced uveal melanoma have gone into remission with BiTE therapy; step-up dosing for newer agents requires hospitalization for 24 to 48 hr; patients have to be monitored and managed following discharge for development of CRS and ICANs in centers with sufficient infrastructure for follow-up; studies evaluating premedication with tocilizumab to prevent CRS are underway

Readings

Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma [published correction appears in N Engl J Med. 2010 Sep 23;363(13):1290]. N Engl J Med. 2010;363(8):711-723. doi:10.1056/NEJMoa1003466; Jones L, Rittberg R, Leung B, et al. Alternate pembrolizumab dosing interval in advanced NSCLC with PD-L1 TPS ≥ 50%: 3 weekly compared to 6 weekly dosing. Curr Oncol. 2022;29(11):8686-8692. doi:10.3390/curroncol29110685; Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-17. doi:10.1056/NEJMoa1414428. Erratum in: N Engl J Med. 2018 Nov 29;379(22):2185. PMID: 25891304; PMCID: PMC5744258; Saltz LB. Value in colorectal cancer treatment: where it is lacking, and why. Cancer J. 2016;22(3):232-235. doi:10.1097/PPO.0000000000000194; Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large b-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980; Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970; Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229; Zhong L, Altan M, Shannon VR, et al. Immune-related adverse events: pneumonitis. Adv Exp Med Biol. 2020;1244:255-269. doi:10.1007/978-3-030-41008-7_13.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Wrzesinski’s lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Wrzesinski was recorded at the 26th Anniversary of the Asthma, Allergy, and Immunology Update, held on July 13, 2023, in Saratoga Springs, NY, and presented by Albany Medical College. For information about upcoming CME activities from this presenter, please visit https://albanymed.cloud-cme.com/. Audio Digest thanks the speakers and sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.50 CE contact hours.

Lecture ID:

OT570401

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.