The Evolution of Therapeutics for Patients with aRCC

Written by Dr. Thomas Hutson, Texas Oncology

Renal cell carcinoma (RCC) is one of the most frequently diagnosed cancers with an incidence of around 400,000 cases worldwide.1 In the United States alone, RCC accounted for 73,820 new cases and 14,770 deaths in 2019.2 In patients with RCC, about 30% present with metastatic disease at the time of initial diagnosis typically requiring systemic therapy, and of those treated for localized RCC, almost 30% develop recurrent disease during the follow-up.3 To address this patient population, multiple targeted therapies focused predominantly on two major molecular pathways, namely angiogenesis and intracellular signal transduction pathways, have gained increasing attention in recent years as prospective therapies for advanced RCC (aRCC).4

The Advent of New Therapeutics for RCC

After the approval of high-dose IL2, there was remarkable progress in the treatment of RCC with approval of VEGF inhibitors, as well as mammalian target of rapamycin (mTOR) pathway inhibitors. These agents have gained regulatory approval and have drastically improved the outcome of patients with advanced RCC.5 More recently, key insights obtained in regard to the Von Hippel-Lindau (VHL) pathway provided the basis for the development of the VHL-hypoxia pathway-based therapeutic landscape in renal cancers.6 For instance, the newer generation tyrosine kinase inhibitors (TKIs) block not only vascular endothelial growth factor receptor (VEGFR) but also fibroblast growth factor receptor (FGFR), and hepatocyte growth factor receptor (C-Met) and Axl, respectively.6 These additional targets have been implicated to help escape angiogenesis blockade which may explain their incremental improvement in efficacy demonstrated in pivotal clinical trials.6 While significant progress has occurred, there is still room for improvement for targeted therapies as current drug interventions for metastatic RCC (mRCC) have yet to demonstrate the ability to circumvent recurrence and several therapies are accompanied by severe adverse events.5

Given that RCC is considered immune-responsive in nature with high numbers of immune cells present in the tumor microenvironment (TME), targeted immunotherapy (IO) was more recently approved as another potential therapy in RCC.7 One strategy involves the use of immune checkpoint inhibitors (ICI). In particular, the use of sophisticated ICIs – anti-programmed death receptor-1 (PD-1), anti-programmed death receptor ligand-1 (PD-L1), and anti-cytotoxic T lymphocytes antigen-4 (CTLA-4) – have been studied in large international phase 3 trials demonstrating significant and clinically relevant improvements in efficacy.4,8 As such, these new therapies have quickly been integrated into the RCC landscape with PD-1 and PD-L1 antibody-based novel ICIs now approved by the FDA as the standard second-line treatment for mRCC as well as in the first-line for moderate to high risk mRCC.9,10

Recently reported and FDA-approved combinations of ICI or ICI with TKI therapy have been rapidly integrated into the first-line treatment setting based upon recent international phase 3 trials.4 It has been proposed that anti-VEGF therapies used in combination with targeted immunotherapies may overcome resistance by modulating the TME. Moreover, inhibition of the VEGF pathway was shown to facilitate access of T-cell population into the TME and decrease the activity of T-regulatory cells and myeloid-derived suppressor cells, thereby enhancing responsiveness to immunotherapy.9,11,12

Strategizing Therapeutic Approach

When patients with mRCC progress through first-line therapies (TKI-ICI, TKI, ICI-ICI), there are many second-line choices to choose from, including ICI, mTOR pathway inhibitors and TKI-mTOR inhibitor combinations.

Before starting therapy, it is necessary to educate the patient about the possibility of adverse reactions that may ensue in the weeks and months after therapy begins. Setting expectations of therapy will serve to maximize patient compliance through early intervention as adverse reactions emerge. This will require close communication between the clinical treatment team, the patient, and their caregivers. Withholding therapy and dose adjustments may be required in some cases to enable patients to remain on therapy.13,14

References
1. Bray F, Ferlay J, Soerjomataram I, et al. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2018;68:394-424
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
3. Abara E, Chivulescu I, Clerk N, et al. Recurrent renal cell cancer: 10 years or more after nephrectomy. Canadian Urological Association. 2010;4(2):E45-E49.
4. Wang J, Li X, Wu X, et al. Role of immune checkpoint inhibitor-based therapies for metastatic renal cell carcinoma in the first-line setting: A Bayesian network analysis. EBioMedicine. 2019;47:78-88.
5. Barata P, Ornstein M, Garcia J. The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patinents Progressing after VEGF Inhibition. J Kidney Cancer VHL 2017;4(2):10-18.
6. Jonasch E. Implications of VHL-HIF pathway dysregulation in renal cell carcinoma: current therapeutic strategies and challenges. Kidney Cancer Journal. 2020;18(1):6-10.
7. Leite KR, Reis ST, Junior JP, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol. 2015;10:189.
8. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813.
9. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115.
10. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.
11. Rini B.I, Plimack E.R, Stus V, et al. Pembrolizumab plus Axitinib versus
Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116-27
12. Suk Lee W, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Experimental and Molecular Medicine. 2020; 52:1475-1485
13. Philip L. Management of Targeted Therapy Adverse Effects. Pharmacytimes. 2020. https://www.pharmacytimes.com/publications/Directions-in-Pharmacy/2019/December2019/featured-article-management-of-targeted-therapy-adverse-effects. Accessed 10/27/2020.
14. Barber FD. Adverse Events of Oncologic Immunotherapy and Their Management. Asia Pac J Oncol Nurs. 2019;6:212-26

This article is sponsored by Eisai Inc.

LENV-US4722

Considerations in the Treatment of Metastatic Pancreas Cancer

Written by: Carlos Becerra, MD
Content Sponsored by: Bristol Myers Squibb
Dr. Becerra is a paid consultant for BMS and was compensated for his contribution in drafting this article.

Pancreas adenocarcinoma is a highly aggressive and fatal disease that is projected to become the second leading cause of cancer related death in the US by the year 2030.1 Upon diagnosis, over 50% of the patients present with metastatic disease and we do not have an effective screening tool to detect pancreas cancer at an earlier and potentially curable stage.2-3 Some improvement has been made in median survival for patients with metastatic disease due to better supportive measures and more effective chemotherapy options.3-4 However, the COVID 19 pandemic threatens to disrupt the gains obtained in recent years due to delay in diagnosis and management of this disease.5 In the next paragraphs I will review some key features for the management of patients with metastatic pancreas cancer so that patients can continue to benefit from the current available treatment options in spite of the COVID-19 pandemic.

Key elements to consider at diagnosis and during management of patients with metastatic pancreas cancer include pain control with adequate narcotic analgesics titrated to the patient’s pain and consideration for local treatment modalities, such as palliative radiation therapy and celiac block to help control the pain. Patients should also be closely monitored with early intervention in case of bowel obstruction (consider even surgical intervention with a bypass procedure if the patient has an adequate performance status) and obstructive jaundice (with metal stent preferred over plastic stent; Figure 1). Additional elements include adequate control of nausea and vomiting either due to chemotherapy or to bowel dysfunction, optimal management of the hyperglycemia, and replacement therapy with pancreatic enzymes. Consultation of nutritional services and starting medications to stimulate the appetite should also be considered.3,4,6 Genetic counseling for new patients and testing for germline mutations along with testing the tumor for presence of actionable mutations should also be strongly considered, based on recent advances.7 Patients should also be screened for depression.3,4

Figure 1: Key Elements to Consider at Diagnosis and Follow-Up


The overall goal of systemic chemotherapy should be to improve overall survival of patients while maintaining the best possible quality of life.4 To that end we have several treatment options based on evidence from randomized phase III clinical trials. Keep in mind that at present we do not have a marker that will help select one regimen up front for clinical efficacy and or toxicity but the general consensus is to use a multi-drug regimen for patients with a good to marginal performance status or even a single agent in very frail patients.8,9

In 2011, the results of a phase III clinical trial demonstrated efficacy of 5-FU based combination therapy compared to single agent chemotherapy, at the expense of some increased toxicity.10 Since then, a multi-drug regimen approach has been shown to be effective.11 Today, the gemcitabine-based or 5-FU based treatments are recommended for patients with metastatic disease.12 Choice of treatment is based on overall assessment of the patient with regards to performance status, comorbidities, symptom burden, prior treatments, patient preference, goals of therapy and the patient’s home support system along with consideration of the potential side effects of the therapy.4,12

Once a patient begins treatment, close monitoring of the patient for evidence of disease progression is very important in order to offer patients second line chemotherapy. Thus, evaluation of the patient’s clinical status, restaging scans, and CA19-9 in a timely fashion will help guide the clinician on starting second line therapy.7,3 For patients with tumors that have a mutation in BRCA 1 or 2 gene (~7% of patients) maintenance with a PARP inhibitor, after receiving chemotherapy is recommended. Additional targeted agents are a possible treatment option if the tumors have presence of specific mutations.3,7

Despite advances, metastatic pancreatic cancer can be difficult to treat. The aggressive nature of the disease along with a high symptom burden make diligent patient management of the utmost importance, particularly during today’s challenging times. Recognizing and addressing symptoms proactively along with choosing the optimal treatment to allow for anti-tumor efficacy combined with a side effect profile that best fits the patient’s tolerance remains important.3,8,13

References
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Cancer Res. 2014;74:2913-2921.
2. National Cancer Institute: Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed November 2, 2020.
3. Mizrahi JD, Surana R, Valle JW, Shroff RT. Lancet. 2020;395:2008-2020.
4. Moffat GT, Epstein AS, O’Reilly EM. Cancer. 2019;125:3927-3935.
5. Benyon B. Oncology Nursing News. Published online March 31, 2020. https://www.oncnursingnews.com/web-exclusives/to-treat-or-not-to-treat-cancer-during-the-covid-19-pandemic. Accessed November 3, 2020.
6. Gilliland TMVillafane-Ferriol N, Shah KP, Shah RM, Tran Cao HS, Massarweh NN et al. Nutrients. 2017;9:243.
7. Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH et al. J Clin Oncol. 2020;38:3217-3230.
8. Sohal DPS, Mangu PB, Khorana AA, Shah MA, Philip PA, O’Reilly EM, et al. J Clin Oncol. 2016;34:2784-2796.
9. Zhang L, Sanagapalli S, Stoita A. World J Gastroenterol. 2018;24:2047-2060.
10. Conroy T, Desseigne FD, Ychou M, Bouche O, Guimbaud R, Becouarn Y et al. N Engl J Med. 2011;364:1817-1825.
11. Von Hoff DD, Ervin T, Areana FP, Chiorean EG, Infante J, Moore M et al. N Engl J Med. 2013;369:1691-1703.
12. Sohal DPS, Kennedy EB, Khorana A, Copur MS, Crane CH, Garrido-LagunaI et al. J Clin Oncol. 2018;36:2545-2556.
13. Catanese S, Pentheroudakis G, Douillard J-Y, Lordick F. ESMO Open. 2020;5:e000804.

Challenges and Unmet Needs in Squamous Non-Small Cell Lung Cancer

Written by Dr. Irfan A. Mirza
This article is sponsored and developed by Boehringer Ingelheim Pharmaceuticals

Significant strides have been made in the last decade for systemic treatment options for stage IV non-small cell lung cancer (NSCLC), including those tailored for squamous and non-squamous histology.1,2 While non-squamous NSCLC has benefited from advances such as the introduction of personalized, genotyped-directed therapies, and immunotherapy drugs, the treatment options for squamous cell NSCLC remain limited.1,2

Historically, the NCCN guidelines recommended the use of platinum-based chemotherapy in the first line setting, followed by immunotherapy in the second-line.3 However, following the results of the KEYNOTE-407 study, immunotherapy together with platinum doublet chemotherapy is now recommended in the first-line setting.4,5 This leaves an unmet need for patients with metastatic squamous NSCLC who have progressed, where most treatments consist of chemotherapy.2,6

Afatinib is an oral, non-chemotherapy option for patients with metastatic squamous NSCLC who have progressed on platinum-based chemotherapy.7 Afatinib is an irreversible second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor that selectively inhibits homo- and hetero-dimers of the ErbB receptor family (EGFR, ErbB2, and ErbB4).7

LUX-Lung 8 was a multicenter, open label, phase 3, randomized, controlled trial across 23 countries that enrolled 795 patients with advanced (stage III B and stage IV) squamous NSCLC, progressing after at least 4 cycles of platinum-based chemotherapy.8 Patients were randomized (1:1) to either afatinib 40 mg daily or erlotinib 150 mg daily until disease progression.8 The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC), using RECIST v1.1 and secondary endpoints included overall survival (OS) and objective response rates as assessed by an IRC.8

In LUX-Lung 8, significant improvement in PFS and overall survival was observed for afatinib compared with erlotinib.8 The median PFS was reported as 2.4 months with afatinib and 1.9 months with erlotinib [HR, 0.82 (95% CI 0.68-0.99)] (Figure 1).8
LUX-Lung-8-Median-Progression-Free-Survival
After a median follow up of 18.4 months, median OS was 7.9 months in the afatinib group and 6.8 months in the erlotinib group [HR 0.81 (95% CI 0.69-0.95), p = 0.0077].8 Estimates of OS among patients treated with afatinib were 64% at 6 months, 36% at 1 year, and 22% at 18 months (Figure 2).8

LUX-Lung-8-K-M-Estimates-of-Survival
More than half (51%) of patients treated with afatinib were able to achieve disease control (defined as complete response, partial response, stable disease, or non-complete response and non-progressive disease) compared with 40% with erlotinib.8 Excluding patients with non-complete response and non-progressive disease, disease control with afatinib was 37%, vs 29% with erlotinib, in a post hoc analysis.8 The median duration of objective response was 7.3 months with afatinib and 3.7 months with erlotinib.8

The most common adverse effects associated with afatinib were diarrhea, rash/acneiform dermatitis, stomatitis, decreased appetite, nausea, vomiting, paronychia, and pruritus.8,9 Twenty percent of patients discontinued afatinib treatment due to adverse reactions, with the most frequent adverse reactions leading to discontinuation being diarrhea in 4.1% of patients and rash/acne in 2.6%.9 Serious adverse reactions occurred in 44% of patients, with pneumonia (6.6%), diarrhea (4.6%), dehydration, and dyspnea (3.1% each) being the most frequent.9 Fatal adverse reactions in afatinib-treated patients included interstitial lung disease, pneumonia, respiratory failure, acute renal failure, and general physical health deterioration, all occurring in less than 1% of patients.9

Adverse Reactions (ARs) Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 89*:
GILOTRIF (n=392), erlotinib (n=395) – All Grades & Grades 3-4 ARs
Gastrointestinal Disorders
Diarrhea – GILOTRIF all grades: 75%; grades 3-4: 11%; erlotinib all grades: 41%, grades 3-4: 3%
Stomatitis – GILOTRIF all grades: 30%; grades 3-4: 4%; erlotinib all grades: 11%, grades 3-4: 1%
Nausea – GILOTRIF all grades: 21%; grades 3-4: 2%; erlotinib all grades: 16%, grades 3-4: 1%
Vomiting – GILOTRIF all grades: 13%; grades 3-4: 1%; erlotinib all grades: 10%, grades 3-4: 1%
Skin and Subcutaneous tissue disorders
Rash/acneform dermatitis – GILOTRIF all grades: 70%; grades 3-4: 7%; erlotinib all grades: 70%, grades 3-4: 11%
Pruritus – GILOTRIF all grades: 10%; grades 3-4: 0%; erlotinib all grades: 13%, grades 3-4: 0%
Metabolism and nutrition disorders
Decreased appetite – GILOTRIF all grades: 25%; grades 3-4: 3%; erlotinib all grades: 13%, grades 3-4: 0%
Infections
Paronychia§ – GILOTRIF all grades: 11%; grades 3-4: 1%; erlotinib all grades: 5%, grades 3-4: 0%
*NCI CTCAE v 3.0
Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular,

rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
§ Includes paronychia, nail infection, nail bed infection

In summary, LUX-Lung 8 met its primary and secondary endpoints and remains the largest prospective head-to-head trial that compares two TKIs for second-line treatment of patients with squamous NSCLC.8 Future studies should focus on understanding the clinical profile of afatinib within the context of other commonly-used treatment modalities, such as chemotherapy. In a disease setting with few treatment options, and a pandemic which can make delivery of infusions challenging, afatinib offers patients with metastatic squamous NSCLC an opportunity to receive a chemotherapy-free, oral option once they have progressed following treatment with standard, platinum based, first line treatment.8,9

INDICATIONS AND USAGE

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (afatinib) TABLETS
WARNINGS AND PRECAUTIONS

Diarrhea
• GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
• For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
• Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.

Bullous and Exfoliative Skin Disorders
• GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
• Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
• Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.

Interstitial Lung Disease
• Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.

Hepatic Toxicity
• Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.

Gastrointestinal Perforation
• Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
• Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
• Permanently discontinue GILOTRIF in patients who develop GI perforation.

Keratitis
• Keratitis has been reported in patients taking GILOTRIF.
• Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Embryo-Fetal Toxicity
• GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.

ADVERSE REACTIONS

Adverse Reactions observed in clinical trials were as follows:

Previously Treated, Metastatic Squamous NSCLC
• In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
• Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).

DRUG INTERACTIONS

Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
• Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.

USE IN SPECIFIC POPULATIONS

Lactation
• Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.

Females and Males of Reproductive Potential
• GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.

Renal Impairment
• Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.

Hepatic Impairment
• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

REFERENCES
1. Baxevanos P, Mountzios G. Novel chemotherapy regimens for advanced lung cancer: have we reached a plateau? Ann Transl Med. 2018;6(8):139.
2. Santos ES, Hart L. Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib. Onco Targets Ther. 2020 Sep 22;13:9305-9321.
3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.1.2016. ©National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
4. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous NSCLC. N Engl J Med. 2018;379: 2040-2051; DOI:10.1056/NEJMoa1810865
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.8.2020. ©National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
6. Paik PK, et al. New treatment options in advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book. 2019;39:e198-e206.
7. Hirsh V. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib. BioDrugs. 2015;29(3):167 183.
8. Soria JC, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897 907.
9. GILOTRIF [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.

Please review the Full Prescribing Information and Patient Information at www.gilotrifhcp.com

Minimal Residual Disease Testing in Multiple Myeloma: The Time has Arrived.

Special Written by Dr. Robert Rifkin, Rocky Mountain Cancer Center | Sponsored by Adaptive Biotechnologies

Rising Importance of MRD Testing in Multiple Myeloma

In the early 2000s, the average overall survival rate for patients with multiple myeloma (MM) was only 3 years.1 With the advent of new therapies over the last 5 years, many patients with MM can now expect to achieve clinical complete response (CR). However, while this trend is expected to continue, the majority of these patients who achieve CR will eventually relapse, suggesting that existing therapies are insufficient and more sensitive testing is necessary to identify potentially undetected malignant cells.2

Minimal residual disease (MRD) refers to the small number of cancer cells that can remain in a patient’s body during and after treatment and may eventually cause recurrence of the disease. MRD is commonly assessed in lymphoid malignancies such as B-cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). In the event of the persistence of malignant B cells, the possibility of recurrence is more likely.3 To address this, MRD testing is now being used to monitor the effectiveness of therapies as well as subsequent treatment decisions by identifying the presence of MRD over time.

The Application of Next-Generation Sequencing

MRD testing in lymphoid malignancies has become increasingly valuable in predicting patient outcomes. While next-generation flow cytometry has been used for MRD testing in B-ALL, and has been standardized for highly sensitive MRD measurements (e.g. 10-6), as reported by Theunissen and Colleagues, standard flow cytometry is limited to a level of detection of 1 malignant cell in 10,000 cells assessed (e.g. 10-4)4. In contrast, next-generation sequencing (NGS) has a level of sensitivity of up to 1 malignant cell in 1,000,000 cells assessed (e.g. 10-6). 5,6

In the era of NGS, it is now possible to assess MRD beyond the standard response criteria for assessment of treatment efficacy. In a review that evaluated the prognostic value of MRD, patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of initial treatment.7

The clonoSEQ® Assay, an in vitro diagnostic (IVD) test that uses multiplex PCR and NGS to identify and quantify disease-associated DNA sequence rearrangements (or clonotypes) of the IgH, IgK and IgL receptor genes, has been FDA-cleared to monitor MRD in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). The assay can accurately and precisely quantify MRD at the DNA-sequence level. According to a recent analysis, clonoSEQ maintains accurate reporting of disease burden down to one malignant cell in 1 million healthy cells provided sufficient sample input.5,6

Patient-specific clonal sequences are identified at the time of diagnosis or high disease burden and can be used as a marker for MRD. Oftentimes, at the conclusion of therapy, MRD measurements can also be used to firmly establish a diagnosis of a molecular complete remission. In order to do this with an NGS assay, it is important to remember to obtain a baseline fresh bone marrow sample at the time of diagnosis. This will facilitate the identification of a dominant clone. In the event such a sample is not available, it is possible to identify the clone utilizing archived or fixed tissue.

Incorporating MRD Testing in Clinical Practice Guidelines

The future of MRD testing in MM, as reviewed by Oliva and colleagues, is clear: MRD testing in MM will be increasingly important as we strive for a cure.8 The course of MM is highly variable, and the clinical behavior is equally diverse. For this reason, MRD testing has been incorporated into clinical practice guidelines as a Standard of Care, as evidenced by the NCCN’s recommendation to assess MRD after each stage of treatment: post-induction, post-high-dose therapy/ASCT, post-consolidation, post-maintenance. NCCN updated their guidelines recently to note that during upfront diagnosis you could consider “baseline clone identification and storage of aspirate samples for future MRD testing by NGS”.9

In short, MRD testing in lymphoid malignancies should be leveraged to track a patient’s disease over time. This approach may aid in key clinical decision-making throughout the course of treatment. For example, if MRD is present in a B-ALL patient, therapy with blinatumomab is suggested over other agents and is now part of guidelines. If MRD is negative, alternative maintenance with the POMP regimen is often employed. Similar guidelines for MM and CLL are on the therapeutic horizon, and I suspect will soon be incorporated into evidence-based guidelines.

As we enter the new area of targeted therapy and the development of novel agents for all the diseases, testing for MRD will become increasingly important. In order to maintain a state-of-the-art clinical practice, and to foster best clinical practice in patient care, it essential that every clinician and stakeholder in the patient’s journey become familiar with these new MRD technologies, and how to integrate them into his or her overall care plan in order to improve clinical outcomes.

Important information

clonoSEQ is available as an FDA-cleared in vitro diagnostic (IVD) test service provided by Adaptive Biotechnologies to detect measurable residual disease (MRD) in bone marrow from patients with multiple myeloma or B-cell acute lymphoblastic leukemia (B-ALL) and blood or bone marrow from patients with chronic lymphocytic leukemia (CLL). clonoSEQ is also available for use in other lymphoid cancers as a CLIA-validated laboratory developed test (LDT) service. For important information about the FDA-cleared uses of clonoSEQ including test limitations, please visit https://www.clonoseq.com/technical-summary/.

References
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