INTRODUCTION

The year 2020 was unprecedented year in many ways, including the number and importance of advances in oncology. Even as the world focused on a coronavirus pandemic, more than 20 new drugs with oncology indications were approved by the U.S Food and Drug Administration (FDA) (Table 1).¹ In addition, 30 new indications were approved for existing oncology drugs, most of them for immunotherapy drugs, specifically checkpoint inhibitors. Additionally, advancements in most types of hematologic cancers and solid tumors have occurred as well as cancer prevention, screening, and supportive care.

In this continuing education program for generalist pharmacists, key oncologic advancements of 2020 are detailed.

Immunotherapy Update

Normally, the immune system’s role is to recognize and destroy foreign cells, including cancer cells.² However, cancer cells have created maneuvers to trick the immune system and avoid being destroyed, commonly known as mechanisms of resistance. Some examples of resistance mechanisms include: 1) genetic changes that allow cancer cells to hide from the immune system 2) the addition of surface proteins, allowing for downregulating the activity of immune cells, and 3) change in the healthy cells surrounding the tumor, which alters the immune system’s activity against the cancer cells. To better combat these setbacks, immunotherapy can be used to aid the immune system in killing cancer cells.

The era of cancer immunotherapy is not new. In fact, it began nearly 125 years ago when William Coley discovered the induction of inflammation by direct tumor inoculation of bacterial products.³ It was not until the 1980s, however, that the first immunotherapy, interleukin-2, was approved by FDA. Although interleukin-2 was highly effective in some patients with cancer, its widespread use was limited by its severe toxicity. Other immunotherapies such as interferons also had limited use due to efficacy and safety.

The second immunotherapy breakthrough occurred nearly 2 decades later, when checkpoint blockade immunotherapy was discovered. The initial finding was that cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blocking antibodies enhanced antitumor immunity.³ Another important checkpoint of the immune system is the programmed cell death receptor 1 (PD-1) molecule, which negatively regulates T cell effector function following binding to its ligand, PD-L1. PD-L1 is expressed on the surface of tumor cells or other immune cells.

Both PD-1 and PD-L1 antibodies are on the market and widely used to treat many cancers. Ipilimumab (Yervoy) is the sole drug currently in the CTLA-4 inhibitor drug class. PD-1 inhibitor drugs currently include nivolumab (Opdivo), pembrolizumab (Keytruda) and cemiplimab-rwlc (Libtayo). PD-L1 inhibitors include atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi).

As of 2020, these medications are no longer considered “last ditch” agents, as they have been in the past. These therapies are now often used as first- or second-line therapy in some advanced forms of cancer and can also be considered as adjuvant therapy in some early-stage cancers. Additionally, checkpoint inhibitors are now indicated in many different types of solid tumors and hematologic malignancies as monotherapy or as combination therapy (see Tables 2, 3, and 4).^4-10

Initially, checkpoint inhibitors were evaluated and approved as monotherapy. However, as the understanding of the complex immunosuppressive nature of cancer unfolds, novel combination strategies targeting the various elements have been found to be successful in many solid tumors (see Table 4).

Similarly, immunotherapy is being used as maintenance therapy in some cancers after a response has been achieved with chemotherapy. Examples are avelumab for locally advanced or metastatic urothelial carcinoma following first-line platinum-based therapy and durvalumab for stage III non-small cell lung cancer patients following adjuvant concurrent platinum-based chemotherapy and radiation therapy.^9,10 Interest is growing in the use of immune checkpoint inhibitor maintenance therapy as a strategy for prolonging the benefits of first-line therapy while minimizing toxicity.

Another advancement in checkpoint inhibitor therapy is the extended-dosing interval (see Table 5). Initially, checkpoint inhibitors were approved in dosing intervals of every 2 or 3 weeks. As of 2020, atezolizumab, nivolumab, pembrolizumab, ipilimumab, and durvalumab have been approved for extended dosing intervals.^4-7,9 Evidence supporting extended-interval dosing regimens is still preliminary, but this could minimize the risk of hospital-acquired transmission of infections, minimize work burden for oncology nursing/staff, and improve patient quality of life.¹¹ These extended-dosing intervals were approved under accelerated approval based on tumor response rate, durability of response, pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety.¹¹ Continued approval for this extended-dosing interval may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Continued March Toward Personalized Anticancer Therapy

In many but not all cancers, the tumors are associated with specific genetic mutations. Personalized anticancer therapy is based upon the premise that each patient’s tumor has a unique genetic profile, and therefore the concept that a single therapeutic option should be used for all patients and every tumor should be replaced with personalized anticancer treatments.¹²

Such personalized therapy allows for specific anticancer regimens to be used in patients with specific mutations. A good example of this is with advanced or metastatic non-small cell lung cancer (NSCLC). The treatment of NSCLC is dependent on the histologic subtype (i.e., the microscopic anatomy of the tumor) and molecular testing. The most common histologic NSCLC subtype is adenocarcinoma. Many of these tumors have genetic mutations, such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) gene rearrangements (also known as fusions), ROS1 rearrangements (also known as fusions), neurotrophic tyrosine receptor kinase (NTRK) gene fusions, BRAF mutations, c-mesenchymal-epithelial transition factor (c-MET) exon 14 skipping mutations, and rearranged during transfection (RET) fusions.¹³

Another concept that has begun to be incorporated into personalized anticancer therapy is the use of precision immunotherapy. This entails the optimal use of immunotherapy based upon the presence of predictive biomarkers for clinical response and new drug development that targets neo-antigens and mutational signatures of tumors.

Advanced NSCLC is also a good example of a condition in which precision immunotherapy is commonly used. Some tumors express PD-L1, indicating a more likely chance of responding to checkpoint inhibitors.¹² Thus, the selection of therapy for a patient with advanced NSCLC of adenocarcinoma subtype is based upon the presence or absence of a mutation or PDL1 expression. The use of personalized therapy expands far beyond NSCLC, but is not as integral to all cancers as it is with advanced NSCLC.

Nonetheless, during 2020, many novel therapies were approved for personalized therapy indications as well as some that were already approved for previous indications but now have new indications (see Table 6).¹

Pembrolizumab was the only anticancer agent to have a tumor-agnostic indication approved in 2020.¹ Tumor-agnostic therapies are drugs used to treat cancer based on the cancer’s genetic and molecular features without regard to the cancer type. That is, tumor-agnostic drugs can be used for any cancer that has that particular genetic and molecular feature.¹⁴ To date, only 3 therapies have this designation: pembrolizumab, larotrectinib, and entrectinib. It is expected that many more of these tumor-agnostic indications will be approved in the future.

In 2017, the PD-1 inhibitor pembrolizumab became the first drug to receive this approval for the treatment for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H), or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no suitable alternative treatment options. In 2020, it received its second tumor-agnostic indication: adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB H) [≥10 mutations/megabase (mut/Mb)] solid tumors.^1,6

Larotrectinib (Vitrakvi) is an oral tyrosine kinase inhibitor that specifically inhibits tropomyosin receptor (TRK) kinase.^14,15 It was approved in November 2018 for treatment of adult and pediatric patients with solid tumors that have a neurotrophic TRK gene fusion in the metastatic setting or for whom surgical resection is not an option.

Entrectinib (Rozlytrek) is another TRK inhibitor that received approval in August 2019 for the same population as larotrectinib.¹⁶ In addition to these tumor-agnostic indications, entrectinib also has tumor-specific indications.¹⁶

Disease Updates: Bladder and Small-Cell Lung Cancer

Bladder Cancer

Big advancements in both bladder and small-cell lung cancer occurred in 2020. Historically, systemic therapy has not been used for treatment of early bladder or upper urinary tract cancers.^1,17 In fact, until 2020, all of the anticancer treatments approved had been for advanced or metastatic disease.¹

In January 2020, pembrolizumab (Keytruda) became the first systemic therapy approved for early-stage bladder cancer.¹ Bladder cancer is the sixth most common cancer diagnosed in the United States.^17,18 It typically is a disease of older patients, with the median age of diagnosis of 73 years. The most common form of bladder cancer is nonmuscle invasive bladder cancer (NMIBC), accounting for 70% of bladder cancers.¹⁹ It has 5-year survival rate of more than 88%, but these tumors typically recur after initial treatment, and 10% to 20% can progress to the more advanced form, muscle-invasive bladder cancer (MIBC). The management of NMIBC, therefore, is aimed at reducing recurrences and preventing progression to MIBC.¹⁷ In fact, these high rates of progression and recurrent with current therapy require life-long surveillance.

The typical treatment of NMIBC is a transurethral resection of the bladder tumor (TURBT) with or without intravesical therapy with Bacillus Calmette-Guerin (BCG) or chemotherapy (e.g., mitomycin, gemcitabine). In patients who are unresponsive to BCG and have high-risk disease with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy, pembrolizumab is a new treatment option. Efficacy and safety data come from the KEYNOTE-057 study, which was a multicenter, single-arm study evaluating 148 patients with high-risk NMIBC. They received pembrolizumab 200 mg intravenously every 3 weeks for 24 months; 41% of the 96 patients with BCG-unresponsive CIS with or without papillary tumors had a complete response lasting for a median of 16.2 months. Overall, this therapy was very well tolerated, with fatigue occurring in about 30% of patients. Immune-mediated adverse events requiring discontinuation occurred in only 11% of patients.⁶

In April 2020, mitomycin for pyelocalyceal solution (Jelmyto) was approved for the treatment of adult patients with low-grade upper tract urothelial cancer.¹ Mitomycin, a cytotoxic drug that inhibits the synthesis of DNA, RNA, and proteins, was first approved in 1974 for the treatment of advanced cancer of the stomach or pancreas but has been used off-label for several other cancers, such as anal, bladder, cervical, esophageal, hepatocellular, or vulvar cancers.^20,21 With newer, more effective drugs for each of these cancers, mitomycin is not used often. This new formulation of mitomycin is a ureteral gel (not an intravenously administered drug) and is the first therapy approved by FDA for upper tract urothelial cancer. Based on recent findings, it is now considered the standard of care following complete or near complete resection of upper tract urothelial tumors (e.g., tumors that originate in the renal pelvis or ureter).^17,22

These upper tract urothelial tumors are quite rare and up until 2020, the primary treatment was surgery alone.¹⁷ For patients with low-grade tumors, the primary treatment is an endoscopic resection or nephroureterectomy (removal of kidney, entire ureter, and a small piece of bladder with the ureter and bladder connect). For high-grade tumors, neoadjuvant chemotherapy followed by nephroureterectomy is preferred. Because low-grade tumors often recur, adding mitomycin gel following complete resection or ablation of the tumor improves disease outcomes.¹⁷

The OLYMPUS study, a single-arm, multicenter, phase 3 study showed that 6 weekly instillations (via pyelocaliceal application and can be administered via ureteral catheter or a nephrostomy tube) of mitomycin ureteral gel into the renal pelvis and calyces produced a durable response in 84% of patients at 12 months.²³ Overall, this drug is well tolerated; however, ureteric stenosis, urinary tract infections, hematuria, flank pain, and nausea did occur in more than 20% of patients.

This gel formulation of mitomycin has some unique administration considerations. Several steps are involved in its preparation, including using a chilling block and determining the volume to be administered based on the patient’s kidney volume.²² Having the patient take 1.3 grams of sodium bicarbonate orally the evening before, morning of, and 30 minutes before improves efficacy.

In May 2020, the interim results of the JAVELIN Bladder 100 study were presented at the annual American Society of Clinical Oncology meeting; these led to significant changes in the way clinicians manage metastatic MIBC.^17,24 Metastatic MIBC is not curable; therefore, the goal of therapy is to prolong life while maintaining quality of life.¹⁷

The JAVELIN Bladder 100 study included 700 patients with complete or partial response or stable disease after first-line platinum-based chemotherapy for metastatic MIBC; they were randomized to the PD-L1 inhibitor avelumab 10 mg/kg intravenously every 2 weeks plus best supportive care or best supportive care alone.^24,25 Until now, maintenance therapy was not part of the management of metastatic MIBC. The results of this study, however, showed that maintenance therapy with avelumab improved overall survival regardless of PD-L1 status (21.4 mo vs 14.3 mo; hazard ratio [HR], 0.69; 95% confidence interval [CI] 0.56–0.86; P <0.001). Avelumab was well tolerated with only 11% of patients experiencing treatment-related events. Avelumab is now part of the standard of care as maintenance therapy following platinum-based chemotherapy. It is continued until disease progression or treatment-related adverse effects require discontinuation.¹⁷

Small-Cell Lung Cancer

In the United States, lung cancer remains the leading cause of cancer-related deaths in both men and women.¹⁸ Lung cancers can be categorized as non-small cell lung cancer, small cell lung cancer (SCLC), and primary neuroendocrine tumors. Approximately 10% to 15% of all lung cancers are in the SCLC category; these are aggressive tumors often characterized by rapid growth, leading to early metastatic spread but also initially very sensitive to chemotherapy and radiation therapy.²⁶ Almost all SCLC cases are attributable to smoking.

Most patients are diagnosed with advanced SCLC, often referred to as extensive-stage SCLC. The goal of treatment in these patients is to improve survival while maintaining quality of life. Until 2018, the standard treatment for extensive-stage SCLC had remained the same for 20 years: 4 to 6 cycles of a platinum (either carboplatin or cisplatin) + etoposide chemotherapy.²⁶ Treatment for relapsed extensive-stage SCLC depended on timing of the relapse, and outcomes with single-agent chemotherapy were dismal. Nivolumab and pembrolizumab were found to be effective in relapsed disease in 2018 and 2019, respectively.^5,6 Since those approvals, checkpoint inhibitor therapy is being used in combination with 4 cycles of platinum/etoposide chemotherapy and is then continued as maintenance therapy.²⁶

In 2020, further advancements in the treatment of SCLC occurred, continuing to change the way this disease is treated. In March 2020, durvalumab was approved as first-line therapy in combination with platinum/etoposide for 4 cycles followed by durvalumab maintenance therapy. ¹ This was based on the results of the CASPIAN trial, a randomized, phase 3 trial comparing this regimen to platinum/etoposide alone.²⁷ The overall survival time with durvalumab plus chemotherapy was 13.0 months compared to 10.3 months with platinum plus etoposide alone, for a HR of 0.73 (95% CI, 0.59–0.91; P = 0.0047). These data provide a choice for providers in terms of the first-line combinations and maintenance therapies.

In March 2019, the FDA approved atezolizumab as first-line therapy of SCLC in combination with 4 cycles of carboplatin and etoposide and continued as maintenance based on the results of the IMpower133 study.²⁸ Therefore, providers can choose either this regimen or the durvalumab + cisplatin or carboplatin plus etoposide followed by durvalumab maintenance therapy. No head-to-head comparisons have been done so far.

A new cytotoxic agent lurbinectedin (Zepzelca) was approved in June 2020 for the treatment of extensive-stage SCLC that has progressed on or after platinum-based chemotherapy.¹ Lurbinectedin is a cytotoxic agent, an alkylating drug that binds to guanines in DNA.29-³¹ This results in the formation of adducts, bending the DNA helix, thereby interrupting the cell cycle and producing apoptosis.

Results of a single-arm, open-label, phase 2 basket trial showed that lurbinectedin 3.2 mg/m² intravenously every 3 weeks was effective as a second-line therapy in extensive-stage SCLC patients.²⁹ In this study, a 35.2% of patients had an overall response, with most partial responses and stable disease, with a median duration of response of 5.3 months (95% CI, 4.1-6.4). Although this response rate may not seem very optimistic, it is indeed noteworthy in the second-line treatment setting for extensive-stage SCLC, particularly in patients who are resistant to platinum-based therapy. To date, the only evidence-based second-line therapy is topotecan, with overall response rates of 16%.²⁶

Lurbinectedin is overall safe with an acceptable toxicity profile. Reversible myelosuppression is the most common adverse event. No treatment-related deaths were observed. As a result of this trial, the NCCN guidelines for treatment of extensive-stage SCLC recommend either topotecan, lurbinectedin, or enrollment in a clinical trial for patients who relapse within 6 months of first-line therapy.²⁶

Monoclonal Antibodies – Moving Toward Subcutaneous Administration

Monoclonal antibodies are widely used in the treatment of both solid tumors and hematologic malignancies and are mainly given intravenously.³² This route of administration often requires several hours because of the risk of infusion-related reactions. Therefore, the appeal of subcutaneous administration is not only shorter visits for the patient, but also a less invasive administration method that creates the possibility of self-administration. Challenges include reducing pain when with larger fluids volumes sometimes necessary to deliver the appropriate dose, ensuring good absorption and bioavailability, and appropriate technique to ensure exact doses are administered.

Subcutaneous administration of biologics has been well established in noncancer disease states, such as multiple sclerosis and rheumatoid arthritis for many years.³² In 2017, the first oncology monoclonal antibody for subcutaneous administration was approved, rituximab and hyaluronidase human (Rituxan Hycela).¹ A similar trastuzumab product was approved in 2019, trastuzumab and hyaluronidase-oysk injection (Herceptin Hylecta). In 2020, 2 more subcutaneous monoclonal antibodies were approved: daratumumab + hyaluronidase-fihj (Darzalex Faspro) for adult patients with newly diagnosed or relapsed/refractory multiple myeloma and a fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase–zzxf (Phesgo). The hyaluronidase component of these products improves absorption within the skin.³³ It is important to note that these drugs are not completely interchangeable with similar intravenous products, and they are not intended for home self-administration because of the risk of reactions and in some cases complicated doses/administration (see Table 7).^33-36

COVID-19 and Cancer

During the pandemic of coronavirus disease 2019 (COVID-19), older adults and those with severe underlying medical conditions (e.g., heart disease, chronic obstructive pulmonary disease, type 2 diabetes) or cancer have had a higher likelihood of morbidity and mortality after developing symptoms from the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).³⁷ In fact, several retrospective studies have been undertaken to learn more about those with cancer who had COVID-19.^38-40 Some of the factors that been linked include a higher incidence in males than females and similar to the normal population, it occurs more commonly in older adults and those with comorbidities.³⁸

No one type of cancer seems to cause an increased risk of developing COVID-19. However, those with recent exposure to the health care system were more likely to have an increased risk of COVID-19 infection and subsequently severe outcomes (e.g., intubation, death). In patients with COVID-19 treated in the United States, Canada, and Spain, COVID-19 resulted in hospitalization in 40% of patients with cancer, intubation in 12%, and death in 13%. The 30-day mortality rate was higher in older adults (odds ratio [OR], 1.84), those that were male (OR, 1.63), had 2 or more comorbidities (OR, 4.5) and a poorer performance status (Eastern Cooperative Oncology Group performance status: 2 or higher; OR, 3.89).³⁹

The third and largest study was conducted by Memorial Sloan Kettering Cancer Center, evaluating 2,035 patients with cancer tested between March 10 and April 7, 2020.⁴⁰ Of these patients, 423 (21%) were diagnosed with symptomatic COVID-19, 40% of whom were hospitalized and 20% had severe respiratory illness. Nine percent of patients were ventilated and 12% died within 30 days of diagnosis. Risks associated with hospitalization included nonwhite race, hematologic malignancy, chronic lymphopenia and/or corticosteroid use, and immune checkpoint inhibitor therapy. Risks associated with severe respiratory illness included age >65 years and immune checkpoint inhibitor therapy. Interestingly, chemotherapy within the 30 days prior to COVID-19, surgery, and metastatic disease were not associated with a higher risk of poor outcomes. The rationale for risk associated with immune checkpoint inhibitor therapy is unclear. Some theories include treatment-related lung injury, corticosteroid use for immune-related adverse events; or an immune checkpoint inhibitor–triggered immune dysregulation by T-cell hyperactivation, leading to acute respiratory distress syndrome.

As a result of this information about patients with cancer and the need to reduce the rates of COVID-19, best practices have quickly emerged in caring for patients with cancer. The American Society of Clinical Oncology (ASCO) has provided some guidance for management of cancer patients during the pandemic (see Table 8).⁴¹ As the COVID-19 pandemic continues and clinicians learn more about how to best manage patients, new information is likely to become available.

Some other great COVID-19 resources for patients with cancer can be found on the Hematology/Oncology Pharmacy Association’s COVID-19 website: https://www.asco.org/asco-coronavirus-resources/care-individuals-cancer-during-covid-19/cancer-treatment-supportive-care, which has links to multiple organizations that are keeping up to date with the latest best practices.

Conclusion

Many advancements were made in oncology during 2020. It can be difficult to stay abreast of the evolving treatment options for each type of cancer. However, because pharmacists are instrumental in the management of patients undergoing treatment for cancer, it is important to stay up to date.

More than 20 new tyrosine kinase inhibitors and cytotoxic agents were approved in 2020 as well as 30 additional indications for existing treatments. Extended-dosing intervals for immune checkpoint inhibitors have allowed patients to receive immunotherapy less frequently in some cases, potentially minimizing their risk of exposure to COVID-19. Differences exist in monoclonal antibodies that are available both in intravenous and subcutaneous formulations, and it is important for the pharmacist to be aware of these differences. Advancements in both bladder cancer and SCLC will allow more patients to receive systemic treatment and have better outcomes. Finally, as researchers and clinicians learn more about COVID-19 and cancer, it will be important for pharmacists to remain familiar with the latest guidance on how to manage patients with cancer while SARS-CoV-2 is circulating.

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