Category: Hem/Onc Updates

FDA Approves MARGENZA® for HER2 Positive Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2 oncoprotein is also expressed by tumor cells in gastroesophageal and other solid tumors.

HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (Ado-Trastuzumab Emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.MOA-of-MARGENZA

MARGENZA® (Margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that binds to the HER2 oncoprotein with high specificity and affinity and inhibits tumor cell proliferation, and survival by mediating Antibody-Dependent Cellular Cytotoxicity (ADCC). It is postulated that the Fab portion of MARGENZA® has the same specificity and affinity to HER2 oncoprotein as Trastuzumab, with similar ability to disrupt signaling. However, the modified Fc region of MARGENZA® which binds Fc receptor expressing cells such as immune cells, has increased affinity for activating Fc receptor FCGR3A (CD16A) and decreases affinity for inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater ADCC and Natural Killer cell activation.

The SOPHIA study is a randomized, multicenter, open-label Phase III clinical trial, in which MARGENZA® plus chemotherapy was compared to Trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. This study enrolled 536 patients who were randomized 1:1 to receive either MARGENZA® 15 mg/kg IV every three weeks (N=266) or Trastuzumab 6 mg/kg (or 8 mg/kg for loading dose) IV every three weeks (N=270), in combination with either Capecitabine, Eribulin, Gemcitabine or Vinorelbine, given at the standard doses. All study patients had previously received Trastuzumab, all but one patient had previously received PERJETA® (Pertuzumab), and 91% of patients had previously received KADCYLA®. Patients were stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting and number of metastatic sites. The dual Primary endpoints of the study were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Additional efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR) assessed by BICR.

This study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with MARGENZA® plus chemotherapy compared with Trastuzumab plus chemotherapy (HR= 0.76; P=0.033), with a median PFS of 5.8 months versus 4.9 months respectively. Treatment benefit was more pronounced in patients with CD16A genotypes containing a 158F allele (median PFS 6.9 versus 5.1 months, HR=0.68; P=0.005). The ORR for MARGENZA® plus chemotherapy was 22%, with a median Duration of Response of 6.1 months, compared to an ORR of 16% and median Duration of Response of 6.0 months for Trastuzumab plus chemotherapy. The final Overall Survival (OS) analysis is expected in the second half of 2021. The most common adverse drug reactions occurring in more than 10% of patients receiving MARGENZA® plus chemotherapy included fatigue/asthenia, nausea, diarrhea, vomiting, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

It was concluded that MARGENZA® in combination with chemotherapy significantly improved PFS, compared to Trastuzumab plus chemotherapy, in pretreated patients with HER2 positive metastatic breast cancer. MARGENZA® along with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.

SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy (C) versus trastuzumab + C in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. Rugo HS, Im SA, Shaw Wright GL, et al. J Clin Oncol 37, 2019 (suppl; abstr 1000)

FDA Approves ORGOVYX® for Advanced Prostate Cancer

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SUMMARY: The FDA on December 18, 2020 approved the first oral Gonadotropin-Releasing Hormone (GnRH) receptor antagonist, ORGOVYX® (Relugolix), for adult patients with advanced prostate cancer. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide).

Androgen Deprivation Therapies such as GnRH analogs/Luteinizing Hormone Releasing Hormone (LHRH) agonists are standard treatment for patients with advanced prostate cancer. These agents when first administered trigger an initial surge in Luteinizing Hormone, Follicle Stimulating Hormone (FSH), and testosterone levels. With continuous administration, LHRH agonists desensitize the pituitary receptor and suppress the production of Luteinizing Hormone and testosterone, thus blocking the pulsatile secretion of GnRH by the hypothalamus. LHRH agonists however do not fully suppress FSH which is a potential mitogenic growth factor for prostate cancer cells. The initial testosterone surge may result in flaring up of symptoms such as bone pain, obstructive urinary symptoms, and rarely spinal cord compression. For this reason, anti-androgen agents are recommended for the first few weeks after initiation of an LHRH agonist. LHRH agonists have been shown to increase the near-term risk of major adverse cardiovascular events, by promoting plaque destabilization and rupture.

Degarelix (FIRMAGON®) is a GnRH antagonist, and the depot injection was approved by the FDA in December 2018. Degarelix suppresses both Luteinizing Hormone and FSH, resulting in rapid testosterone suppression, without an initial testosterone surge. This agent however has to be administered monthly and approximately 40% of patients experience reactions at the injection site.

ORGOVYX® is a highly selective, GnRH antagonist that can be given orally once daily, and has a half-life of 25 hours. In multiple Phase I and Phase II studies, ORGOVYX® has been shown to lower testosterone levels by rapidly inhibiting the pituitary release of Luteinizing Hormone and FSH. The HERO trial is a multinational, randomized, open-label, Phase III study, which evaluated the efficacy and safety of ORGOVYX®, an oral GnRH antagonist, as compared with those of Leuprolide (LUPRON®) (GnRH agonist), in men with advanced prostate cancer. In this study, a total of 930 patients were randomly assigned in a 2:1 ratio to receive either ORGOVYX® 120 mg orally once daily, after a single oral loading dose of 360 mg (N=622) or Leuprolide acetate 22.5 mg IM every 3 months (N=308), for 48 weeks.MOA-of-GnRH-Agonists-and-Antagonists

Eligible patients had one of three clinical disease presentations: 1) Evidence of biochemical (PSA) or clinical relapse after local primary intervention with curative intent. 2) Newly diagnosed hormone-sensitive metastatic disease. 3) Advanced localized disease unlikely to be cured by local primary intervention with curative intent. Patients with major adverse cardiovascular events within 6 months before trial initiation were excluded. Patients were stratified according to the presence or absence of metastatic disease, as well as age (75 yrs or less, and over 75 years). Approximately 32% of patients had metastatic disease and 50% had biochemical recurrence after definitive treatment. The Primary endpoint was sustained testosterone suppression to castrate levels (less than 50 ng/dL) through 48 weeks. Secondary end points included noninferiority of ORGOVYX® to Leuprolide with respect to sustained castration rate, castrate levels of testosterone on day 4, and profound castrate levels (less than 20 ng/dL) on day 15. Testosterone recovery after discontinuation of the trial drug was to be evaluated in a subgroup of patients. The median follow up time in both groups, including the 30-day safety follow-up period for adverse events, was 52 weeks.

ORGOVYX® was associated with a significantly higher rate of maintained castrate levels of testosterone, when compared to Leuprolide. Castrate levels of testosterone were maintained through 48 weeks in 96.7% of patients in the ORGOVYX® group compared to 88.8% of patients in the Leuprolide group. The difference of 7.9 percentage points showed noninferiority as well as superiority of ORGOVYX® (P<0.001 for superiority) over Leuprolide. All other key Secondary end points showed superiority of ORGOVYX® over Leuprolide (P<0.001). These endpoints included the percentage of patients with castrate levels of testosterone on day 4 (56% versus 0%) and on day 15 (98.7% versus 12%), testosterone suppression to less than 20ng/dL on day 15 (78.4% versus 1%) and confirmed PSA response of more than 50% decrease at day 15 (79.4% versus 19.8%; P<0.001). In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone level 90 days after treatment discontinuation was 288.4 ng/dL in the ORGOVYX® group and 58.6 ng/dL in the Leuprolide group. The incidence of major adverse cardiovascular events among all the patients was 2.9% in the ORGOVYX® group and 6.2% in the Leuprolide group (HR=0.46).

The authors concluded that in this trial involving men with advanced prostate cancer, ORGOVYX® achieved rapid and sustained suppression of testosterone levels that was superior to that with Leuprolide, with a 54% lower risk of major adverse cardiovascular events.

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer. Shore ND, Saad F, Cookson MS, et al. for the HERO Study Investigators. N Engl J Med 2020; 382:2187-2196.

SABCS 2020: Ongoing Benefit with VERZENIO® in High Risk Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women 12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-ABEMACICLIB-A-CDK4-and-CDK6-Inhibitor

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

VERZENIO® is presently approved by the FDA as monotherapy as well as in combination with endocrine therapy for patients with HR-positive, HER2- negative advanced breast cancer. The addition of VERZENIO® to FASLODEX® resulted in a statistically significant improvement in Overall Survival among patients with HR-positive, HER2-negative advanced breast cancer, who had progressed on prior endocrine therapy. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk early breast cancer.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5 to 10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included distant Relapse Free Survival, Overall Survival, and safety. At a preplanned interim analysis, the addition of VERZENIO® to endocrine therapy resulted in a 25% reduction in the risk of developing a Invasive Disease Free Survival (IDFS) event, relative to endocrine therapy alone. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and Overall Survival. The current study describes outcomes following an extended follow up of this trial, with a median follow up time of 19 months.

At the time of this primary outcome analysis, 1,437 patients (25.5%) had completed the two-year treatment period and 3,281 patients (58.2%) were in the two-year treatment period. The combination of VERZENIO® plus endocrine therapy continued to demonstrate superior Invasive Disease Free Survival (IDFS) compared to endocrine therapy alone, with a 28.7% reduction in the risk of developing invasive disease (P=0.0009; HR=0.713). The 2-year IDFS in the combination group was 92.3% and 89.3% in the endocrine therapy alone treatment group. This IDFS benefit with VERZENIO® was consistently noted in all prespecified subgroups. Further, there was an improvement in the 2-year distant Relapse Free Survival rate among patients who received the combination treatment compared with those who received endocrine therapy alone (93.8% versus 90.8%, respectively). Overall Survival data was immature at the time of analysis.

The researchers also evaluated outcomes among 2,498 patients with centrally assessed high tumor Ki-67 status. Among patients in this cohort, those who received the combination treatment had a 30.9% decreased risk of invasive disease compared with those who received endocrine therapy alone (P=0.01; HR=0.691) and the 2-year IDFS rates in the combination group and the endocrine therapy alone group were 91.6% and 87.1%, respectively. There were no new safety signals observed with VERZENIO®.

It was concluded that at the time of this primary outcome analysis, VERZENIO® combined with endocrine therapy continued to demonstrate a clinically meaningful improvement in Invasive Disease Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer.

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Presented at the 2020 San Antonio Breast Cancer Symposium, December 8-11. Abstract. GS1-01.

ASH 2020: Subcutaneous DARZALEX® Plus Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.Mechanism-of-Action-of-Daratumumab

DARZALEX® is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. DARZALEX® has activity as both a single agent and when combined with other standard regimens. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID®, and has been shown to be active in REVLIMID® and VELCADE® refractory patients. In the EQUULEUS Phase Ib study, intravenous DARZALEX® in combination with POMALYST® and Dexamethasone in relapsed or refractory Multiple Myeloma resulted in an Overall Response Rate (ORR) of 59% with Very Good Partial Response (VGPR) noted in 28% of patients, and Complete Response (CR) achieved in 6% of patients.

Recently published studies have concluded that the subcutaneous formulation of DARZALEX® resulted in non-inferior pharmacokinetics and efficacy compared to the current IV formulation, and also importantly offers the potential for a fixed-dose administration, shorter administration times and a lower rate of infusion-related reactions with improved safety profile.

APOLLO study is an open-label, randomized, multicenter, Phase III trial, conducted by the European Myeloma Network investigators, to evaluate SubCutaneous (SC) formulation of DARZALEX® in combination with POMALYST® (Pomalidomide) and Dexamethasone (D-Pd; N=151) versus POMALYST® (Pomalidomide) and Dexamethasone (Pd; N=153) alone in relapsed/refractory Multiple Myeloma patients who have received one or more prior lines of therapy including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. This study enrolled 304 patients with relapsed or refractory Multiple Myeloma, and prior treatment with anti-CD38 antibody or Pomalidomide was not permitted. Treatment for all patients consisted of POMALYST® 4 mg orally daily plus Dexamethasone 40 mg orally on days 1, 8, 15, and 22 (20 mg for patients aged 75 years or older), given every 28 days. Patients in the D-Pd group additionally received DARZALEX® 1800 mg SC co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.), given weekly for cycles 1 to 2, every 2 weeks for cycles 3 to 6, and every 4 weeks thereafter. The median age was 67 years, and 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). The median prior lines of therapy were 2, approximately 80% of patients were refractory to REVLIMID®, 48% of patients were refractory to a Proteosome Inhibitor, and 42% of patients were refractory to both agents. Treatment was continued until disease progression or unacceptable toxicity. The median duration of treatment was 11.5 months with D-Pd, compared with 6.6 months with Pd. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Very Good Partial Response (VGPR), Complete Response (CR), MRD negativity rate, Overall Survival (OS), and Safety.

The study met its Primary endpoint of improved PFS in the primary analysis. The median PFS for the D-Pd group was 12.4 months versus 6.9 months for Pd group (HR=0.63; P=0.0018). This represented a 37% reduction in the risk of progression or death in patients treated with D-Pd. Among patients who were refractory to REVLIMID®, median PFS was 9.9 months in the D-Pd group versus 6.5 months in the Pd group. This benefit was seen across all subgroups of patients, regardless of age, stage, prior line of therapy, REVLIMID® refractoriness and cytogenetic risk. D-Pd regimen was also superior to Pd regimen in terms of other endpoints, including ORR (69% versus 46%), VGPR or better (51% versus 20%), CR (25% versus 4%), and MRD negativity (9% versus 2%). Survival data are immature and follow up is ongoing. Infusion-related events were rare, and seen in 6% of patients treated with D-Pd, and local injection-site reactions which were all Grade 1 were seen in 2% of patients in the D-Pd group. Treatment discontinuation due to treatment-related adverse events, were similar for the D-Pd and Pd groups (2% versus 3%).

It was concluded that Subcutaneous DARZALEX® given along with POMALYST® and Dexamethasone significantly reduced the risk of progression or death by 37% in patients with relapsed/refractory Multiple Myeloma, compared to POMALYST® and Dexamethasone alone. The infusion-related reaction rate was very low and median duration of injection administration was short at 5 minutes. Subcutaneous DARZALEX® thus has a high likelihood of changing clinical practice, increasing convenience for patients and decreasing treatment burden.

Apollo: Phase 3 Randomized Study of Subcutaneous Daratumumab Plus Pomalidomide and Dexamethasone (D-Pd) Versus Pomalidomide and Dexamethasone (Pd) Alone in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM). Dimopoulos MA, Terpos E, Boccadoro M, et al. Presented at the 62nd ASH Annual Meeting and Exposition, 2020. Abstract 412.

Considerations in the Treatment of Metastatic Pancreas Cancer

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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.

ASH 2020: CRISPR-Cas9 Gene-Editing Technique May Cure Sickle Cell Disease and Beta Thalassemia

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SUMMARY: Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the United States is approximately 40-60 years. Beta thalassemia affects at least 1000 Americans and according to the WHO, more than 300,000 babies are born worldwide each year with hemoglobin disorders such as Transfusion-Dependent beta-Thalassemia (TDT) and Sickle Cell Disease (SCD). Both diseases are caused by mutations in the hemoglobin beta-globin gene.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation. Mutations in the hemoglobin beta-globin gene result in reduced (B+) or absent (B0) beta-globin synthesis creating an imbalance between the alpha and beta globin chains of hemoglobin, resulting in ineffective erythropoiesis. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea, whereas management of beta Thalassemia include transfusion support and iron chelation therapy. None of the presently available therapies addresses the underlying cause of these diseases nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure both these genetic disorders, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for beta-Thalassemia and Sickle Cell Disease.

Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin which consists of two alpha and two beta chains increases. It has been noted that elevated levels of fetal hemoglobin are associated with decreased morbidity and mortality in patients with Sickle Cell Disease and Thalassemia. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.CRISPR-Cas9-Nuclease-Gene-Editing-Technique

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique cuts the DNA at the targeted location. The authors in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin.

The authors reported the interim safety and efficacy data from 10 patients who received the investigational CRISPR-Cas9 nuclease gene-editing based therapy, following enrollment in CLIMB THAL-111 and CLIMB SCD-121 studies. These patients were infused with CTX001 (autologous CRISPR-Cas9-edited CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) that were genetically edited to reactivate the production of fetal hemoglobin. In the CLIMB THAL-111 and CLIMB SCD-121 open-label, PhaseI/II trials, patients with Transfusion-Dependent beta-Thalassemia and sickle cell disease , respectively, received a single intravenous infusion of CTX001. The production of CTX001 involved collection of CD34+ Hematopoietic Stem and Progenitor Cells (HSPCs) from patients by apheresis, following stem cell mobilization with either NEUPOGEN filgrastim and/or MOZOBIL® (plerixafor), after a minimum of 8 weeks of transfusions of packed red cells, to achieve a level of sickle hemoglobin of less than 30% in the patient with SCD. CTX001 was then manufactured from these CD34+ cells by editing with CRISPR-Cas9 with the use of a single-guide RNA molecule, following preclinical studies of BCL11A editing. Patients received myeloablation with pharmacokinetically adjusted, single-agent Busulfan, before the infusion of CTX001.

Eligible patients were between ages 18 and 35 years. In the CLIMB THAL-111 trial, eligible patients had a diagnosis of beta-Thalassemia (including the hemoglobin E genotype) with either homozygous or compound heterozygous mutations and had received transfusions of PRBC consisting of at least 100 ml/kg of body weight (or 10 units) per year during the previous 2 years. In the open-label CLIMB SCD-121 trial, eligible patients had a documented BS/BS or BS/B0 genotype and had a history of two or more severe vaso-occlusive episodes per year during the previous 2 years. Patients were monitored for engraftment, adverse events, total hemoglobin, hemoglobin fractions on high-performance liquid chromatography, F-cell expression (defined as the percentage of circulating erythrocytes with detectable levels of fetal hemoglobin), laboratory signs of hemolysis, requirements for transfusion support with PRBC, and occurrence of vaso-occlusive episodes in the patient with SCD. Bone marrow aspirates were obtained at 6 and 12 months after infusion, and DNA sequencing was used to measure the fraction of total DNA that was edited at the on-target site in CD34+ bone marrow cells and in nucleated peripheral-blood cells.

The Primary endpoint of the CLIMB THAL-111 trial was the proportion of patients with a transfusion reduction of 50% for at least six months, starting three months after CTX001 infusion. The Primary endpoint of CLIMB SCD-121 Sickle Cell Disease trial was the proportion of patients with fetal hemoglobin of 20% or more, sustained for at least three months, starting six months after CTX001 infusion.

CLIMB THAL-111 trial: Data was reported on 7 patients enrolled in the CLIMB THAL-111 trial, as they had reached at least three months of follow up after CTX001 infusion and therefore could be assessed for initial safety and efficacy. All seven showed a similar pattern of response, with rapid and sustained increases in total hemoglobin, fetal hemoglobin, and transfusion independence at last analysis. All 7 patients were transfusion independent with follow up ranging from 3-18 months after CTX001 infusion, with normal to near normal total hemoglobin levels at last visit. Their total hemoglobin levels ranged from 9.7 to 14.1 g/dL, and fetal hemoglobin ranged from 40.9% to 97.7%. Bone marrow allelic editing data collected from 4 patients with 6 months of follow up, and from one patient with 12 months of follow-up after CTX001 infusion showed the treatment resulted in a durable response. The safety data from all seven patients were generally consistent with an Autologous Stem Cell Transplant (ASCT) and myeloablative conditioning. There were four Serious Adverse Events (SAEs) considered related or possibly related to CTX001 reported in one patient and included headache, Hemophagocytic LymphoHistiocytosis (HLH), Acute Respiratory Distress Syndrome, and Idiopathic Pneumonia Syndrome. All four SAEs occurred in the context of HLH and resolved. Most of the non-SAEs were considered mild to moderate. CLIMB-111 is an ongoing trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.

CLIMB SCD-121: Data was reported on 3 patients enrolled in the CLIMB SCD-121 sickle cell disease trial as they had reached at least three months of follow up after CTX001 infusion, and therefore could be assessed for initial safety and efficacy. Again, all 3 patients showed a similar pattern of response, with rapid and sustained increases in total hemoglobin and fetal hemoglobin, as well as elimination of Vaso-Occlusive Crises through last analysis. All 3 patients remained Vaso Occlusive Crises-free with follow up ranging from 3-15 months after CTX001 infusion and had hemoglobin levels in the normal to near normal range, including total hemoglobin from 11.5 to 13.2 g/dL and Fetal hemoglobin levels from 31.3% to 48.0%. Bone marrow allelic editing data collected from one patient with six months of follow-up and from one patient with 12 months of follow-up after CTX001 infusion demonstrated a durable response. Again the safety data were consistent with an ASCT and myeloablative conditioning. There were no Serious Adverse Events noted, thought to be related to CTX001, and the majority of non-SAEs were considered mild to moderate. CLIMB-121 is an ongoing open-label trial and will enroll up to 45 patients and follow patients for approximately two years after infusion.

It was concluded from this initial follow up that, CTX001 manufactured from Hematopoietic Stem Cells, edited of BCL11A with CRISPR-Cas9, has shown durable engraftment, with high levels of fetal hemoglobin expression, and the elimination of vaso-occlusive episodes or need for transfusion. The authors added that these preliminary results support further testing of CRISPR-Cas9 gene-editing approaches to treat other genetic diseases.

Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β- Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells. Frangoul H, Bobruff Y, Cappellini MD, et al. Presented at the 62nd ASH Annual Meeting and Exposition, 2020. Abstract#4

Salvage YERVOY® and OPDIVO® Combination after Prior Immune Checkpoint Inhibitor Therapy in Advanced RCC

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SUMMARY: The American Cancer Society estimates that 73,750 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2020 and about 14,830 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease.

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The FDA in 2018, approved combination immunotherapy, OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC), based on significantly higher Overall Survival (OS) and Objective Response Rates (ORR), compared with Sunitinib, a multikinase inhibitor (CheckMate 214). Subsequently, two studies, a combination of BAVENCIO® (Avelumab), a PD-L1 targeted monoclonal antibody and INLYTA® (Axitinib), a Receptor Tyrosine Kinase inhibitor (JAVELIN Renal-101), and KEYTRUDA® (Pembrolizumab), a PD-1 targeted monoclonal antibody and INLYTA® (KEYNOTE-426), demonstrated superior OS, compared to Sunitinib, and for the first time set the stage for the use of a combination of Immune Checkpoint Inhibitor (ICI) and targeted therapy as first line treatment in this patient population.

The safety and activity of the combination of YERVOY® and OPDIVO® in patients with prior exposure to anti-PD-1 pathway targeted therapy, but no prior exposure to anti-CTLA-4 pathway targeted therapy, remains unknown. The rationale behind combining YERVOY® and OPDIVO® is that these two agents act in different phases of the immune response. Blocking the PD-1/PD-L1 pathway does not induce antitumor immunity if antigen-specific CD8-positive T cells are not present in cancer tissues. However, blocking the CTLA-4 pathway leads to increased activation of CD8-positive cells in the lymph nodes as well as increased infiltration of activated CD8-positive T cells into the tumor. This mechanistic difference between an anti-PD-1 antibody and an anti-CTLA-4 targeted therapy may allow activity of anti-CTLA-4 antibody in combination with anti-PD-1 antibody, upon treatment failure on prior anti-PD-1 targeted therapy.

The authors in this publication evaluated YERVOY® and OPDIVO® combination in patients with metastatic RCC, after prior treatment with anti-PD-1 pathway targeted therapy. This study included 45 patients with metastatic Renal Cell Carcinoma from 5 medical centers in the US and all patients had received prior therapy with Immune Checkpoint Inhibitors (ICIs) targeting the PD-1 pathway. The Primary objective of this study was to estimate the Objective Response Rate (ORR) to salvage YERVOY® and OPDIVO® combination, in patients with metastatic RCC, who received ICI as prior treatment.

The median number of prior lines of therapy was 3 and all patients had received at least one prior therapy targeting the PD-1 pathway. About 76% of patients received an anti-PD-1 antibody, and 24% received an anti-PDL-1 antibody before receiving YERVOY® and OPDIVO® combination. Of the 45 patients included in this study, 60% received monotherapy with prior anti-PD-1 or anti-PDL-1 antibody, 18% received PD-1 pathway targeted Immune Checkpoint Inhibitor (ICI) in combination with a VEGF receptor inhibitor (Axitinib,Sunitinib, or Cabozantinib), 9% received an ICI in combination with Bevacizumab, and 13% received an ICI in combination with another agent . Approximately 71% of the study patients received one line of prior ICI therapy and 29% of the study patients had received more than one prior ICI regimen. The best Objective Response Rate to prior ICI therapy was a Partial Response Rate of 53%, Stable disease in 27%, and Progressive disease in 20%. The median time on prior ICIs was 13 months. The median age at the time of initiation of YERVOY® and OPDIVO® combination was 62 years and all patients had more than one metastatic site, and 38% had brain metastasis. Twenty percent of the patients were favorable risk on the basis of IMDC criteria, 64% were intermediate risk, 7% were poor risk, and 9% were unknown risk.

At a median follow up of 12 months, the Objective Response Rate with the YERVOY® and OPDIVO® combination was 20% and the median Duration of Response was 7 months. An additional 16% of patients had stable disease. The median Progression Free Survival while on YERVOY® and OPDIVO® combination was 4 months. Immune-related Adverse Events of any grade with YERVOY® and OPDIVO® combination were noted in 64% of patients, and Grade 3 Immune-related Adverse Events were noted in 13% of the study patients.

It was concluded from this study that YERVOY® and OPDIVO® combination demonstrated antitumor activity with acceptable toxicity in patients with metastatic Renal Cell Carcinoma, who had prior treatment with Immune Checkpoint Inhibitors, suggesting that responses are possible in a subset of patients with metastatic Renal Cell Carcinoma who are naïve to therapy with anti-CTLA-4 antibody, and had prior exposure to therapy targeting the PD-1 pathway. Salvage YERVOY® and OPDIVO® therapy after single-agent OPDIVO® is currently being evaluated in multiple clinical trials.

Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors. Gul A, Stewart TF, Mantia CM, et al. J Clin Oncol 2020;38:3088-3094

Adjuvant Trastuzumab Monotherapy for Older Patients with HER-2 Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Trastuzumab is a humanized monoclonal antibody targeting HER2. Adjuvant and neoadjuvant chemotherapy given along with Trastuzumab reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of Trastuzumab, several other HER2-targeted therapies have become available. The duration of adjuvant Trastuzumab therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

Elderly patients with HER-2 positive breast cancer may not be candidates for adjuvant chemotherapy. Single agent Trastuzumab used as adjuvant treatment without chemotherapy could be of potential benefit, avoiding chemotherapy-induced toxicities. However, the benefit of single agent Trastuzumab has not been investigated in patients older than 70 years. The present study was designed to investigate the efficacy of Trastuzumab monotherapy, compared with Trastuzumab in combination with chemotherapy, incidence of Adverse Events, as well as Quality of Life, in terms of the noninferiority criterion.

RESPECT Study is a multicenter, open-label, randomized controlled, prospective, adjuvant, noninferiority trial, in which Trastuzumab monotherapy was compared with Trastuzumab plus chemotherapy, among patients older than 70 years, with HER-2 positive breast cancer. A total of 275 patients, aged 70-80 years with surgically treated HER-2 positive invasive breast cancer, were randomly assigned in a 1:1 ratio to receive either Trastuzumab monotherapy (N=137) or Trastuzumab plus chemotherapy (N=138). Trastuzumab plus chemotherapy treatment consisted of a loading dose of Trastuzumab at 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks for 1 year. Chemotherapy regimens consisted of either Paclitaxel 80 mg/m2 IV weekly for 12 weeks, Docetaxel 75 mg/m2 IV every 3 weeks for 4 cycles, Doxorubicin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (AC) every 3 weeks for 4 cycles, Epirubicin 90 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (EC) every 3 weeks for 4 cycles, Cyclophosphamide 75-100 mg orally, Methotrexate 40 mg/m2, and 5-fluorouracil 500-600 mg/m2 IV (CMF) for 6 cycles, Docetaxel 75 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (TC) every 3 weeks for 4 cycles or Docetaxel 60-75 mg/m2 IV, Carboplatin AUC 5-6 mg/ml/min IV along with Trastuzumab IV (TCH) every 3 weeks for 6 cycles. Patients treated with Trastuzumab monotherapy received similar doses of loading and maintenance Trastuzumab. Patients were stratified based on Performance Status, Hormone Receptor status and pathologic nodal status. Approximately 44% of patients had Stage I disease, 42% had Stage IIA, 13% had IIB, and 1% had IIIA disease. Approximately 14% of patients received Selective Estrogen Receptor Modulators such as Tamoxifen, and about 69% of patients received Aromatase Inhibitors. The Primary endpoint was Disease Free Survival (DFS) with assessment of prespecified Hazard Ratio (HR) and Restricted Mean Survival Time (RMST) for each treatment group. (RMST has been advocated as an alternative or a supplement to the Hazard Ratio for reporting the effect of an intervention in a randomized clinical trial, and is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the KM curve up to that point. RMST measure is especially informative for older patient populations in which Quality of Life issues are more important). Secondary endpoints included Overall Survival (OS), Relapse-Free Survival (RFS), Adverse Events (AEs) and Health-Related Quality of Life (HRQoL). The median follow up time was 4.1 years.

The 3-year DFS was 89.5% with Trastuzumab monotherapy versus 93.8% with Trastuzumab plus chemotherapy (HR=1.36; P=0.51) and this study failed to meet the prespecified criterion for noninferiority. However, a preplanned analysis of DFS according to RMST was -0.39 months, suggesting that only 0.39 months of DFS were lost within 3 years, by avoiding chemotherapy. The 3-year RFS was 92.4% with Trastuzumab monotherapy versus 95.3% with Trastuzumab plus chemotherapy (HR=1.33) and the difference in RMST for RFS between treatment groups at 3 years was −0.41 months (P=0.53). There were significant differences noted in clinically meaningful HRQoL deterioration rate at 2 months (31% for Trastuzumab monotherapy versus 48% for Trastuzumab plus chemotherapy; P=.016) and at 1 year (19% versus 38%; P=0.009). Breast cancer-specific survival at 3 years was 99.2% with Trastuzumab monotherapy versus 99.2% with Trastuzumab plus chemotherapy (HR=0.20; P=0.14).

The authors concluded that even though the Primary endpoint of noninferiority for Trastuzumab monotherapy was not met, the Restricted Mean Survival Time revealed that the observed loss of survival without chemotherapy was less than 1 month at 3 years, and Health-Related Quality of Life was better, with lower toxicities. Therefore, Trastuzumab monotherapy can be considered as a reasonable adjuvant therapy option for a select group of elderly patients with favorable outcomes.

Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. Sawaki M, Taira N, Uemura Y, et al. J Clin Oncol. 2020;38:3743-3752.

High Tumor Mutational Burden Predicts Response to KEYTRUDA®

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SUMMARY: Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High and less than 10 mutations/Megabase as Low. (A megabase is 1,000,000 DNA basepairs). KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1 monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the tumor-specific effector T cells.

The authors in this publication prospectively explored the association of high tissue TMB with outcomes, following treatment with KEYTRUDA®, in patients with selected, previously treated, advanced solid tumors. KEYNOTE-158 is a multicenter, multicohort, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. Eligible patients had advanced unresectable or metastatic solid tumors (Anal, Biliary, Cervical, Endometrial, Mesothelioma, Neuroendocrine, Salivary, Small-cell lung, Thyroid, and Vulvar), who had progressed on, or were intolerant to one or more lines of standard therapy, had measurable disease, as well as tumor sample available for biomarker analysis.

This study enrolled 1073 patients of whom 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients, with sufficient tissue for testing. Of these 790 patients, 102 patients (13%) had tumors identified as TMB-High, defined 10 or more mutations /Megabase. TMB status was assessed in Formalin-Fixed Paraffin-Embedded tumor samples using the FoundationOne® CDx assay. Patients received KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety. The median study follow up was 37.1 months.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. The ORR in the non-TMB-High group was 6%. The median duration of response was not reached in the TMB-H group and was 33.1 months in those without high TMB, at the time of data cutoff. There was low correlation between TMB and PD-L1 expression. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

The authors concluded that high Tumor Mutational Burden status identifies a subgroup of patients who could have a robust tumor response to KEYTRUDA® monotherapy . They added that tissue TMB therefore could be a novel and useful predictive biomarker for response to KEYTRUDA® monotherapy in patients with previously treated recurrent or metastatic advanced solid tumors.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Marabelle A, Fakih MG, Lopez J, et al. Lancet Oncol. 2020;21:1353-1365.

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

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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.

Full Prescribing Information URL: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Gilotrif/Gilotrif.pdf?DMW_FORMAT=pdf

Patient Information URL: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Gilotrif/Patient%20Info/gilotrif_patient%20information.pdf?DMW_FORMAT=pdf