Bryan Fitzgerald, PharmD, BCOP

Myelosuppression is one of the most common and dangerous doselimiting toxicities of traditional chemotherapy.

Chemotherapy-induced myelosuppression (CIM) can cause clinically significant sequelae, including bleeding, fatigue, and potentially fatal infections. Historically, CIM has been managed with transfusions, chemotherapy dose delays, dose reductions, and drugs.

Pharmacologic management of CIM has consisted of administering growth factors, including erythropoietin-stimulating agents (ESAs) and granulocyte colony-stimulating factors (G-CSFs). By stimulating the production of erythrocytes and neutrophils, respectively, these agents promote bone marrow recovery after chemotherapy administration. Despite their proven clinical benefit, risks and toxicities exist, ranging from bone pain with G-CSFs to an increase in thrombotic events with ESAs. The risks of these agents must be weighed against their clinical benefits.

In 2021, the FDA approved trilaciclib (Cosela, G1 Therapeutics) to prevent CIM in patients with extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib reversibly inhibits cyclin-dependent kinase (CDK) 4/6 and arrests hematopoietic stem cells (HSCs) in the G1 phase of the cell cycle.

 Contrary to growth factors that promote HSC production after chemotherapy, trilaciclib protects HSCs from the cytotoxic effects of chemotherapy during chemotherapy exposure. This mechanism has been used by other CDK 4/6 inhibitors, including abemaciclib (Verzenio), palbociclib (Ibrance), ribociclib (Kisqali) in the management of breast cancer. However, trilaciclib is the first CDK 4/6 inhibitor approved for a supportive-care indication.

Trilaciclib was approved to prevent CIM specifically in patients with ES-SCLC receiving chemotherapy regimens containing a platinum/etoposide or topotecan. These indications are based on results of 3 randomized phase 2 trials enrolling patients with ES-SCLC receiving treatment with 1 of 3 regimens: first-line carboplatin plus etoposide; first-line carboplatin plus etoposide plus atezolizumab; or second-line or third-line topotecan.

 In each trial, patients were randomly assigned to receive trilaciclib 240 mg/m2 intravenously daily or a placebo, given prior to chemotherapy infusions. The primary end points in each trial were duration of severe neutropenia during cycle 1 of chemotherapy and percentage of patients with severe neutropenia during treatment. Severe neutropenia was defined as an absolute neutrophil count of less than 0.5 Å~ 109 cells/L, which is classified as a grade 4 toxicity by Common Terminology Criteria for Adverse Events version 4.03.

Across the 3 trials, 242 patients were randomly assigned to receive either trilaciclib (n = 123) or placebo (n = 119) prior to chemotherapy. Patients receiving trilaciclib had significant improvements in both primary outcomes, with a lower percentage of patients experiencing severe neutropenia (11.4% vs 52.9%, P < .0001) and a shorter mean duration of severe neutropenia during cycle 1 (0 days vs 4 days, P < .0001).

The trilaciclib group also had improved secondary outcomes, including improvements in the rates of grade 3 to 4 anemia, grade 3 to 4 thrombocytopenia, G-CSF administration, and ESA administration.

The pooled safety analysis from the 3 trials showed that the majority of patients in both groups had at least 1 adverse event (AE): 94.3% with trilaciclib vs 96.6% with the placebo.

 The most common AEs reported with trilaciclib were aspartate aminotransferase elevation, fatigue, headache, hypocalcemia, hypokalemia, hypophosphatemia, and pneumonia.

 Less common but still-notable reactions in the trilaciclib group were injection site reactions (13.9% vs 2.5% in the placebo group), phlebitis or thrombophlebitis (9.0% vs 0.8%), and hypersensitivity reactions (4.1% vs 3.4%).

 Compared with 3 patients in the placebo group, 6 patients in the trilaciclib group had fatal AEs, including cerebrovascular accident, hemoptysis, pneumonia, and respiratory failure.

 The FDA approved trilaciclib with a warning for pulmonary toxicity, a warning that other CDK 4/6 inhibitors also carry in their labeling.

Because of its mechanism in arresting cell cycle progression, it is important to investigate any effects of trilaciclib on tumor response rates and concerns for tumor progression. Fortunately, the pooled analysis of the 3 trials suggested that tumor response rates were similar between trilaciclib and the placebo, with objective responses achieved in 49.1% of patients taking trilaciclib vs 51.8% of those taking the placebo.

Median durations of response, overall survival, and progression-free survival also were considered to be similar between the 2 groups.

The choice of investigating the use of trilaciclib in patients with ES-SCLC was deliberate. Because of their loss of the retinoblastoma protein, SCLC tumor cells do not depend on CDK 4/6 for replication.

 Therefore, inhibition of the CDK 4/6 enzyme with trilaciclib would selectively arrest the replication of healthy cells and not affect SCLC tumor cells. Future studies investigating the use of trilaciclib to prevent CIM will require careful consideration in select tumor types that replicate outside of the CDK 4/6 pathway.

Trilaciclib was approved at the same dose investigated in the trials of 240 mg/m2 as a 30-minute intravenous infusion prior to chemotherapy administration. Trilaciclib should be administered on each day that chemotherapy is given and must be completed within 4 hours prior to the start of chemotherapy infusion.

 An inline 0.2- or 0.22-μm filter is required during trilaciclib administration.

The approval of trilaciclib to prevent CIM marks an exciting new development for patients with ES-SCLC. However, data are limited to phase 2 trials. Therefore, larger, more robust phase 3 trials are needed to confirm these results and determine any clinical implications. Additionally, the benefit of trilaciclib is limited to patients with ES-SCLC because of the cells’ independence from the CDK4/6 pathway. Time will tell if any additional tumor types would be candidates for this novel therapy in preventing CIM.

 is a clinical specialist in oncology at the University of Rochester Specialty Pharmacy in New York.

1. Weiss J, Goldschmidt J, Andric Z, et al. Effects of trilaciclib on chemotherapy-induced myelosuppression and patient-reported outcomes in patients with extensive-stage small cell lung cancer: pooled results from three phase II randomized, double-blind, placebo-controlled studies. Clin Lung Cancer. 2021;22(5):449-460. doi:10.1016/j.cllc.2021.03.010

2. Daniel D, Kuchava V, Bondarenko I, et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: a multicentre, randomised, double-blind, placebo-controlled phase II trial. Int J Cancer. 2020;148(10):2557-2770. doi:10.1002/ijc.33453

3. Weiss JM, Csoszi T, Maglakelidze M, et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving fi rst-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol. 2019;30(10):1613-1621. doi:10.1093/annonc/mdz278

4. Hart LL, Ferrarotto R, Andric ZG, et al. Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase II study. Adv Ther. 2021;38(1):350-365. doi:10.1007/s12325-020-01538-0

5. Cosela (trilaciclib). Prescribing information. G1 Therapeutics Inc; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214200s000lbl.pdf

6. Ibrance (palbociclib). Prescribing information. Pfizer Inc; 2019. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207103s008lbl.pdf

7. Kisqali (ribociclib). Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209092s004lbl.pdf

8. Verzenio (abemaciclib). Prescribing information. Lilly USA, LLC; 2021. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf

Articles

Treatment's approval marks exciting new development for patients with ES-SCLC to prevent CIM.

Trilaciclib Protects Against Chemotherapy-Induced Myelosuppression

Cutaneous melanoma, a type of skin cancer arising from malignant melanocytes, is the fifth most prevalent cancer in the United States, with 99,780 new cases estimated in 2022.

Depending on disease stage, the treatment landscape of melanoma includes immunotherapy, local therapies, surgical resection, and targeted agents. For patients with metastatic melanoma, systemic therapy with targeted agents or immunotherapy is the standard of care.

Approximately half of melanoma cases possess an activating mutation in the BRAF gene, which encodes the BRAF kinase of the mitogen-activated protein kinase (MAPK) pathway.

 Specifically, BRAF V600 mutations have been shown to respond to and benefit from targeted therapy with a BRAF inhibitor. Trial results have supported the addition of a MEK inhibitor to BRAF inhibitor therapy, leading to this combination being established as a standard-of-care option for patients with BRAF V600 mutations.

The FDA has approved 3 pairs of BRAF and MEK inhibitors to treat melanoma with BRAF V600 mutations: dabrafenib and trametinib (Tafinlar, Mekinist; Novartis), encorafenib and binimetinib (Braftovi, Mektovi; Pfizer), and vemurafenib and cobimetinib (Zelboraf, Cotellic; Genentech). All 6 agents are orally administered and are available through specialty pharmacies.

BRAF and MEK inhibitors are associated with various unique toxicities that may require close monitoring and management. Common toxicities include alopecia, arthralgia, diarrhea, fatigue, nausea, pyrexia, rash, and vomiting. Rarer ones that may require nuanced monitoring plans include cardiac, dermatologic, and ocular toxicities.

Pyrexia is defined as a temperature of 38.0oC or greater (≥ 100.4oF), and its incidence ranges with the 3 combinations of BRAF and MEK inhibitors.

 The dabrafenib-trametinib combination is associated with a higher incidence (57%) than vemurafenib and cobimetinib (22%) and encorafenib and binimetinib (19%).

 Pyrexia may be complicated by chills, hypotension, renal injury, or rigors. At the onset of pyrexia, holding BRAF/MEK inhibitors until its resolution is generally recommended.

 Additional management may be warranted, including antipyretics, fluids, rest, and, potentially, low-dose steroids.

 Antipyretics may be used as primary or secondary prophylaxis with dabrafenib and trametinib therapy. Pharmacists should counsel patients about the incidence and signs and symptoms of pyrexia, the importance of hydration, and having a thermometer on hand to monitor temperature.

Several dermatologic toxicities are common with BRAF and MEK inhibitor therapy, including hyperkeratosis, palmar-plantar erythrodysesthesia, photosensitivity, and rash. Photosensitivity is most common with vemurafenib, with a reported incidence of up to 49%.

 Pharmacists should advise patients to avoid intense sun exposure, use broad spectrum sunscreen with a sun protection factor of 30 or higher, and wear protective clothing when outside.

Cutaneous malignancies, including cutaneous squamous cell carcinoma (cSCC) and keratoacanthomas, have been reported with BRAF and MEK inhibitors. This risk of an additional cutaneous malignancy may be particularly alarming for patients with melanoma. The incidence of cSCC is higher with BRAF inhibitor monotherapy because of a paradoxical activation of the MAPK pathway to overcome BRAF inhibition. With the addition of a MEK inhibitor, the risk of cSCC is reduced. For example, there is an 11% incidence with vemurafenib vs 3% with vemurafenib and cobimetinib.

 To screen for suspicious skin changes, routine dermatologic evaluation every 2 months is recommended for patients on BRAF/MEK inhibitor therapy.

Rarely, cases of drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome have been reported with BRAF and MEK inhibitors. These reactions may be life-threatening or fatal, and treatment should be discontinued if either condition occurs.

 Based on the myriad potential dermatologic changes with BRAF and MEK inhibitors, pharmacists should encourage patients to self-monitor for any new skin changes or growths and to report any changes.

Prolongation of the QT interval is a risk with BRAF inhibitors, particularly with vemurafenib and encorafenib, although it has rarely been reported with dabrafenib.

 Baseline and routine electrocardiogram monitoring may be warranted, especially if patients are taking other QT-prolonging medications. The prescribing information for vemurafenib has explicit electrocardiogram monitoring recommendations, with QTc measurement at day 15, monthly during the first 3 months, then every 3 months thereafter.

 Cardiomyopathy with decreased left ventricular ejection fraction is associated with the use of MEK inhibitors and when MEK inhibitors are used in combination with BRAF inhibitors. Assessment of left ventricular ejection fraction, typically with an echocardiogram, is recommended prior to starting therapy with a MEK inhibitor, 1 month after starting treatment, and every 2 to 3 months thereafter.

 Counsel patients about signs and symptoms of decreased left ventricular ejection fraction and the recommended monitoring schedule for these agents.

Both BRAF and MEK inhibitors are associated with unique ocular toxicities. With BRAF inhibitors, conjunctivitis, dry eye, and uveitis have been reported, whereas retinal vein occlusions and retinopathies are more frequently associated with MEK inhibitors. Uveitis from BRAF inhibitors may be managed with topical ophthalmic agents and treatment interruption.

 Only in the prescribing information for encorafenib is routine ophthalmologic monitoring recommended at “regular intervals.” However, patients may benefit from more routine monitoring. When starting these agents, patients should be monitored and counseled to report any ocular pain, photophobia, vision changes, and vision loss.

is a clinical specialist in oncology at the University of Rochester Specialty Pharmacy in New York.

1. Cancer stat facts: melanoma of the skin. National Cancer Instit ute. Accessed March 14, 2022. https://seer.cancer.gov/statfacts/html/melan.html

2. Key statistics for melanoma skin cancer. American Cancer Society. Updated January 12, 2022. Accessed March 14, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html

3. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 3.2022. Accessed March 14, 2022. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf

4. Common terminology criteria for adverse events (CTCAE). National Cancer Institute. November 27, 2017. Accessed March 14, 2022. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

5. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868

6. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888. doi:10.1056/NEJMoa1406037

7. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690

8. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6

9. Tafinlar. Prescribing information. Novartis Pharmaceuticals Corp; 2022. Accessed April 11, 2022. https://www.novartis.us/sites/www.novartis.us/files/tafinlar.pdf

10. Zelboraf. Prescribing information. Genentech USA, Inc; 2016. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf

11. Braftovi. Prescribing information. Array BioPharma Inc; 2018. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf

12. Mekinist. Prescribing information. Novartis Pharmaceuticals Corp; 2021. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204114s018lbl.pdf

13. Cotellic. Prescribing information. Genentech USA, Inc; 2015. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf

14. Mektovi. Prescribing information. Array BioPharma Inc; 2018. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf

Watch for alopecia, arthralgia, diarrhea, fatigue, nausea, pyrexia, rash, and vomiting, among others.

Help Manage Toxicities With BRAF and MEK Inhibitors

a rare type of cancer that originates from the cellular lining of the cervix, representing approximately 0.8% of all new cancer cases and 0.7% of all cancer deaths each year in the United States.

In 2021, there were 14,440 new cases of cervical cancer and approximately 4290 deaths from cervical cancer in the United States, according to data from the National Cancer Institute.

 The 5-year relative survival rate for patients with cervical cancer is 66.3%, with a lower 5-year survival rate of 17.6% for patients with distant metastatic disease.

Along with lower survival rates, recurrence rates for metastatic cervical cancer remain high, despite the implementation of newer therapies. Platinum-doublet chemotherapy alone was initially seen as a preferred first-line treatment option for patients with metastatic cervical cancer. Over time, however, the addition of newer agents such as the VEGF inhibitor bevacizumab (Avastin, Genentech) to first-line cervical cancer regimens has improved overall survival for patients who have metastatic disease.

 Regardless, patients with metastatic disease will ultimately fail treatment in the first-line setting because of chemotherapy intolerance or disease progression. National Comprehensive Cancer Network guidelines recommend numerous second- and subsequent-line therapies for metastatic cervical cancer.

 Therefore, there has been a general push for the development of newer, more effective, and safer treatments in this setting.

Antibody-drug conjugates (ADCs) are targeted agents that have shown promise in the treatment of certain cancers, including acute leukemias, breast cancer, and Hodgkin lymphoma. An ADC comprises a cytotoxic drug (“payload”) that has been artificially combined with a monoclonal antibody designed to carry, selectively target, and bind to tumor antigens. It then delivers the cytotoxic payload to the tumor sites, which results in cell death. Once the payload is internalized by a tumor cell, a phenomenon known as “bystander killing” can occur, where the cytotoxic payload is diffused to adjacent cells. By itself, the cytotoxic payload is incredibly potent. ADCs have been theorized to be more efficacious and safer than standard chemotherapy because of the lower incidence of systemic chemotherapy exposure through localized delivery.

 Even though ADCs are more selective than other chemotherapy agents, risks for off-target toxicities exist, oftentimes involving major organs.

Tissue factor (TF), also known as platelet coagulation factor III, is normally found within the body and is involved with the initiation of the coagulation cascade.

 Unfortunately, in cervical and many other cancers, malignant cells have developed mechanisms to manipulate TF. Some cancer cells can increase overall TF levels in the bloodstream, resulting in surges of tumor cell angiogenesis, metastasis, growth, and risks for thrombosis.

 Specifically in cervical cancer, higher levels of TF expression have been associated with higher-stage disease and an increased rate of invasion and metastasis.

The FDA approved tisotumab vedotin-tftv (Tivdak, Seagen/Genmab) in September 2021 for patients with metastatic or recurrent cervical cancer with disease progression during or after prior treatment with chemotherapy. As the first ADC approved to target TF on tumor cells, tisotumab vedotin comprises a TF-directed antibody attached to a cytotoxic microtubule inhibitor, monomethyl auristatin E (MMAE). After selectively binding to extracellular TF, the ADC complex becomes internalized and MMAE is released intracellularly, leading to cell death.

The innovaTV 204 clinical trial (NCT03438396) was a multicentered, open-label, single-arm, phase 2 trial where 101 patients with either metastatic or recurrent cervical cancer were treated with tisotumab vedotin.

 Eligible patients had to have disease progression either during or after treatment involving doublet chemotherapy (paclitaxel, plus either platinum or topotecan) plus bevacizumab. Patients received tisotumab vedotin at a dose of 2 mg/kg (maximum 200 mg/dose) intravenously every 3 weeks until either disease progression or unacceptable toxicities.

After a median follow-up of 10 months at the time of data cutoff, 24% of patients had a confirmed disease response.

 The data were supported by a 6-month survival rate of 79% and a median overall survival rate of 12.1 months. With approximately 79% of patients having reductions in target lesion size and a median time to response of 1.4 months, the rapid antitumor effects of tisotumab vedotin may be clinically attractive as a subsequent-line treatment option.

Numerous toxicities were seen in the innovaTV 204 trial, including alopecia, bleeding events, fatigue, nausea, and peripheral neuropathy.

 Ocular toxicities have been seen with tisotumab vedotin, as well, reported in 53% of patients in the trial. These ocular toxicities include conjunctivitis, dry eye, keratitis, and vision changes, with rare cases of corneal ulceration and severe vision loss. The FDA label for tisotumab vedotin includes a boxed warning for ocular toxicities, and it is recommended that patients undergo ophthalmic exams at baseline and prior to each cycle.

 In addition, it is recommended that patients premedicate each infusion of tisotumab vedotin with corticosteroid and vasoconstrictor eye drops and ocular lubricants and use cooling eye pads during the infusion.

Tisotumab vedotin is one of the newest subsequent-line treatment options for patients with recurrent metastatic cervical cancer, who have generally poorer prognoses. As an ADC, tisotumab vedotin is among a growing class of antitumor therapies with more than 100 others under investigation.

 is a PharmD candidate at St. John Fisher College of Wegmans School of Pharmacy in Rochester, New York.

, is an oncology clinical pharmacy specialist at UR Medicine/Wilmot Cancer Institute at the University of Rochester Specialty Pharmacy in New York.

Cancer stat facts: cervical cancer. National Cancer Institute. Accessed December 3, 2021. https://seer.cancer.gov/statfacts/html/cervix.html

NCCN. Clinical Practice Guidelines in Oncology. Cervical cancer, version 1.2022. Accessed December 3, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf

Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. 

2019;394(10200)793-804. doi:10.1016/S0140-6736(19)31774-X

Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. 

2009;27(29):4834-4838. doi:10.1200/JCO.2009.22.6324

Zhao X, Cheng C, Gou J, et al. Expression of tissue factor in human cervical carcinoma tissue. 

2018;16(5):4075-4081. doi:10.3892/etm.2018.6723

Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety o f tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. 

2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5

Tivdak (tisotumab vedotin-tftv). Prescribing information. Seagen Inc; 2021. https://www. seagen.com/medicines/tivdak

Tisotumab vedotin-tftv is used as antitumor therapy for patients with disease progression during or after chemotherapy.

FDA Approves Newest Antibody-Drug Conjugate for Cervical Cancer

Oropharyngeal cancer (OPC) is a type of head and neck cancer that affects structures in the back of the throat, including the base of the tongue, the posterior pharynx, the soft palate, and the tonsils.

 In the United States, rates of OPC are increasing each year, with an estimated 54,010 new cases in 2021.

 Well-established risk factors include alcohol abuse; exposure to tobacco, including chewing tobacco, cigarettes, and pipes; and infection with human papillomavirus (HPV). 

With an estimated 43 million infections in 2018, HPV is the most common sexually transmitted infection in the United States.

 HPV infection is causally linked with cancers of the anogenital region, including anal, cervical, penile, vaginal, and vulvar cancers. When HPV is spread orally, infections can also lead to the development of OPC. In the United States, more than 70% of OPC cases are caused by HPV.

HPV is a group of more than 100 viruses, including certain high-risk strains associated with the development of cancer. The HPV-16 strain is responsible for causing the majority of HPV-positive (HPV+) OPC cases, with HPV-18, HPV-33, and HPV-35 also contributing, albeit significantly less than HPV-16.

 In these high-risk HPV strains, the viral genome encodes several oncogenic proteins that inhibit tumor suppressor proteins, leading to chromosomal instability and malignancy in infected cells.

HPV+ OPC is considered a genetically distinct form of OPC. Compared with HPV-negative (HPC–) OPC cases, HPV+ OPC is associated with a favorable prognosis with improved rates of response prognosis with improved rates of response to treatment and overall survival. Because of the difference in tumor biology, the National Comprehensive Cancer Network (NCCN) has adopted different staging criteria for HPV+ and HPV– disease and recommends that HPV status be used to stratify patients with OPC.

The treatment landscape for localized OPC typically involves a multidisciplinary approach consisting of chemotherapy, radiation, and/or surgery. For fit patients with locally advanced OPC who are able to tolerate intensive therapy, concurrent radiation with systemic high-dose cisplatin chemotherapy is the preferred treatment regimen.

 Unfortunately, treatment of OPC is associated with a high risk of treatment-related morbidity, which may leave patients cured of their malignancy but with lifelong complications, such as dysgeusia, dysphagia, and xerostomia, but also systemic complications from cisplatin chemotherapy, including hearing loss and neurotoxicity.

Because patients with HPV+ OPC are generally younger with more favorable prognoses, clinicians have hypothesized that less intensive treatment could result in fewer long-term complications from treatment but with continued favorable cancer-related outcomes.

 This concept, called deintensification, has become popular in recent years. Several strategies for treatment deintensification have been proposed, including reducing the dose of radiation; substituting cisplatin for an alternative agent with less toxicity, such as cetuximab; and surgical resection. Several phase 3 comparison trials have been conducted, and other trials are ongoing.

Aptly named De-ESCALaTE (NCT01874171), this phase 3 trial randomized patients with 334 HPV+ OPC to receive radiation plus cetuximab or cisplatin.

Unfortunately, the trial results did not favor substitution of cisplatin with cetuximab. At 2 years, the incidence of severe toxicities did not significantly differ between cetuximab and cisplatin (

 = .98), nor did rates of overall toxicities (

= .49). Significant differences in 2-year overall survival rates and recurrence rates were seen. However, these results favored cisplatin (HR, 5.0; 

RTOG-1016 (NCT01302834) was a second phase 3 trial published comparing cetuximab with cisplatin in HPV+ OPC patients.

 This trial analyzed 805 patients who were randomized to receive radiation plus cetuximab or cisplatin. Similar to the De-ESCALaTE trial, the RTOG-1016 trial results favored cisplatin over cetuximab, with 5-year overall survival rates of 84.6% versus 77.9%.

Because of the De-ESCALaTE and RTOG-1016 results, experts advise against the substitution of cisplatin for chemoradiation regimens for patients with localized HPV+ OPC, and cisplatin plus radiation continues to be the preferred systemic treatment option per the NCCN guidelines.

 Because cisplatin continues to be standard of care for the treatment of localized OPC, the role of deintensification for patients with HPV+ OPC may lie in adjustments to surgical strategies or radiation therapy. Treatment deintensification should be pursued only through clinical trials, and experts encourage clinicians to conduct and analyze phase 2 trials before moving on to phase 3 studies.

The treatment landscape of cancer is ever-changing. Specifically in localized HPV+ OPC, the difference in tumor biology presents a unique clinical area where reducing the intensity of treatment may be warranted, particularly with long- and short-term toxicities associated with cisplatin. Interestingly, phase 3 data have shown evidence of harm in removing cisplatin from chemoradiation regimens for HPV+ OPC; therefore, cisplatin-based chemoradiation remains the standard of care for these patients. Future trials may support treatment deintensification in ways other than removing cisplatin.

1. NCCN. Clinical Practice Guidelines in Oncology. Head and neck cancers, version 3.2021. Accessed June 16, 2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf

2. Cancer stat facts: oral cavity and pharynx cancer. National Cancer Institute. Accessed June 16, 2021. https://seer.cancer.gov/statfacts/html/oralcav.html

3. Genital HPV infection – fact sheet. CDC. Updated January 19, 2021. Accessed June 17, 2021. https://www.cdc.gov/std/hpv/stdfact-hpv.htm

4. HPV and oropharyngeal cancer. CDC. Updated September 3, 2020. Accessed June 17, 2021. https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm

5. Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a head and neck cancer intergroup framework for future de-escalation studies. J Clin Oncol. 2020;38(22):2552-2557. doi:10.1200/JCO.20.00056

6. Mehanna H, Robinson M, Hartley A, et al; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393(10166):51-60. doi:10.1016/S0140-6736(18)32752-1

7. Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393(10166):40-50. doi:10.1016/S0140-6736(18)32779-X

8. Gardasil 9. Prescribing information. Pfi zer; 2017. Accessed June 23, 2021. https://www.fda.gov/fi les/vaccines,%20blood%20&%20biologics/published/Package-Insert---Gardasil.pdf

Clinicians cite long-term complications and younger patients with better prognoses as reasons to pull back on oropharyngeal cancer therapy.

Calls Grow for Treatment Deintensification of HPV-Positive OPC

Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases, with almost all cases attributed to tobacco smoke exposure.

SCLC is generally characterized by an aggressive, rapidly growing disease course with a high rate of metastasis. Although this rapid growth and proliferation translate into higher response rates to chemotherapy and radiation, patients relapse quickly with increased rates of disease progression.

Clinical staging for SCLC has historically been classified using the Veterans Administration Lung Study Group's 2-stage system to categorize patients to having either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC) disease.

 This system differs from most solid tumor staging, which uses the American Joint Committee on Cancer TNM staging system. The National Comprehensive Cancer Network (NCCN) uses a combined approach for staging SCLC using the TNM staging criteria but ultimately classifies patients with SCLC as having LS-SCLC or ES-SCLC.

 Patients with ES-SCLC have a more advanced disease course. Therefore, the goal of treatment for these patients shifts from curative intent to an intent geared toward disease control and palliation.

For several decades, first-line treatment for ES-SCLC has consisted of systemic chemotherapy with a platinum agent (carboplatin or cisplatin) plus etoposide. Because of the favorable toxicity profile of carboplatin over cisplatin and comparable efficacy rates between the 2 platinum agents, carboplatin was preferred over cisplatin in ES-SCLC treatment regimens. Although response rates were reported as high as 80%, median overall survival rates for patients treated with carboplatin and etoposide were approximately 10 months.

In recent years, immune checkpoint inhibitors have revolutionized oncology treatment with 7 checkpoint inhibitors approved by the FDA to treat various types of cancer, including melanoma, non–small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and many others. By manipulating physiologic immune checkpoint pathways in place to reduce autoimmunity, cancer cells can evade recognition and targeting by cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors target these pathways, either by inhibiting CTL antigen-4 (CTLA-4) or the interaction between PD-1 receptors and its ligands, PD-L1/L2.

Two immune checkpoint inhibitors, atezolizumab (Tecentriq; Genentech) and durvalumab (Imfinzi; AstraZeneca), were recently studied in the first-line setting for patients with ES-SCLC in combination with a platinum agent and etoposide. This addition of immunotherapy to chemotherapy represents the first change in ES-SCLC treatment since the 1990s. Both atezolizumab and durvalumab are humanized, IgG monoclonal antibodies targeting PD-L1 on the surface of tumor cells.

Atezolizumab was studied in combination with carboplatin and etoposide for first-line treatment in ES-SCLC in the phase 1/3 IMpower133 trial.

 In a 1:1 fashion, 403 patients with untreated ES-SCLC were randomized to receive treatment with carboplatin, etoposide, and atezolizumab or a matching placebo every 21 days for 4 cycles. After the initial 4-cycle induction phase of treatment, patients received maintenance therapy with atezolizumab or a placebo every 21 days until loss of clinical benefit, disease progression, or unacceptable toxicity.

After a median follow-up of 13.9 months, patients in the atezolizumab arm had a longer median overall survival (12.3 months) compared with the placebo arm (10.3 months).

=.007), suggesting a 30% lower risk of death with the addition of atezolizumab to standard carboplatin-etoposide therapy. In February 2021, an updated analysis was published after a median follow-up of 22.9 months, supporting the original results of the IMpower133 trial.

 The update reported a median overall survival of 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm (HR, 0.76; 95% CI, 0.60-0.95; 

Durvalumab was the second PD-L1 inhibitor approved by the FDA based on the results of the CASPIAN trial.

 In this trial, 805 patients with untreated ES-SCLC were randomized 1:1:1 to receive treatment with a platinum agent (carboplatin or cisplatin) and etoposide; platinum-etoposide plus durvalumab; or platinum-etoposide plus durvalumab and tremelimumab, a CTLA-4 inhibitor. Initial treatment was given for 4 cycles (up to 6 cycles in the platinum-etoposide arm), followed by maintenance durvalumab every 4 weeks until disease progression or unacceptable toxicity. 

The published results of the CASPIAN trial included analysis of the platinum-etoposide and platinum-etoposide-durvalumab arms.

 After a median follow-up of 25.1 months, updated results were published showing that the median overall survival was longer in the platinum-etoposide-durvalumab arm (12.9 months) compared with the platinum-etoposide arm (10.5 months).

=.0032), similar to the results from the IMpower133 trial. 

As with other checkpoint inhibitors, treatment with both atezolizumab and durvalumab is associated with a unique immune-mediated toxicity profile, ranging from mild toxicities to potentially life-threatening toxicities. With a heterogeneous clinical presentation, immune-mediated toxicities can affect any organ system, most commonly the gastrointestinal tract, liver, skin, and thyroid gland. Immune-mediated toxicities should be identified as early as possible for close monitoring, prompt initiation or high-dose corticosteroids, and supportive care.

Based on the results of both the CASPIAN and IMpower133 trials, the addition of atezolizumab or durvalumab to platinum-etoposide therapy is considered the standard of care for patients with untreated ES-SCLC, as recommended by the NCCN guidelines. Pharmacists should recognize the role of adding atezolizumab and durvalumab to first-line treatment for ES-SCLC, along with the unique toxicities with which these patients may present.

1. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. doi:10.1038/s41572-020-00235-0

2. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219. doi:10.1002/ijc.27339

3. Jett JR, Schild SE, Kesler KA, Kalemkerian GP. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl5):e400S-e419S. doi:10.1378/chest.12-2363

4. Recently updated guidelines. National Comprehensive Cancer Network. Accessed April 28, 2021. https://www.nccn.org/guidelines/recently-published-guidelines

5. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27(28):4787-4792. doi:10.1200/JCO.2009.23.1548

6. Horn L, Mansfield NS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

7. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

8. Paz-Ares L, Dvorkin ML, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

9. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

 is an oncology clinical pharmacy specialist at University of Rochester Medical Center in New York.

Addition of atezolizumab and durvalumab to chemotherapy is a win for patients with extensive-stage small cell lung cancer