Author: RR

Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline

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SUMMARY: Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 13-15% of all lung cancers. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis. Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

The American Society for Radiation Oncology (ASTRO) developed an evidence-based practice guideline addressing the use of RT for patients with both Limited and ES-SCLC. The ASCO Expert Panel critically appraised the ASTRO guideline, and following minor changes, endorsed the recommendations provided in the ASTRO guideline.

Guideline Questions
♦What are the indications, appropriate dose-fractionation schedules, techniques, and timing of thoracic RT for Limited Stage (LS)-SCLC?
♦What is the role of Stereotactic Body Radiotherapy (SBRT) compared with conventional RT in Stage I or II node-negative SCLC?
♦What are the indications, appropriate dose-fractionation schedules, and timing of prophylactic cranial RT for LS-SCLC and Extensive Stage (ES) SCLC?
♦What are the indications, appropriate dose-fractionation schedules, and timing of thoracic consolidation in patients with ES-SCLC?

RECOMMENDATIONS

Thoracic RT for LS-SCLC
Recommendation 1.1. For patients with LS-SCLC who can tolerate definitive therapy, thoracic RT is recommended.
Recommendation 1.2. For patients with LS-SCLC receiving chemotherapy and RT, thoracic RT should begin with cycle 1 or 2 of chemotherapy. It is important to maintain the dosage and timing of chemotherapy with RT based on trial data. Timing is more critical for accelerated dose-intensive RT including twice-daily, hyperfractionated regimens.
Recommendation 1.3. For postoperative patients with LS-SCLC and R1 or R2 resection, postoperative RT is conditionally recommended.
Recommendation 1.4. For postoperative patients with LS-SCLC that is clinically node-negative and pathologically N2-positive, mediastinal RT is conditionally recommended.
Recommendation 1.5. For patients with LS-SCLC, twice-daily RT in 150-cGy fractions to 4,500 cGy is recommended.
Recommendation 1.6. For patients with LS-SCLC, daily RT in 200-cGy fractions to 6,000-7,000 cGy is conditionally recommended as an acceptable alternative to twice-daily RT.
Recommendation 1.7. For patients with LS-SCLC, involved-field RT is recommended as the standard of care. (defined as FDG avid on PET, enlarged on CT, and/or biopsy-positive)
Recommendation 1.8. For tumors that experience shrinkage with chemotherapy in patients with LS-SCLC, treating all involved nodal stations (at time of diagnosis) and postchemotherapy lung parenchymal tumor is recommended.
Recommendation 1.9. For patients with LS-SCLC, highly conformal techniques are recommended to minimize normal tissue dose.

Role of SBRT in Stage I or II Node-Negative SCLC
Recommendation 2.1. For patients with Stage I or II node-negative LS-SCLC who are medically inoperable, either SBRT or conventional fractionation is recommended. Ideally, the node-negative status should be confirmed by invasive nodal staging. Ultracentral tumors, meaning those with the planning target volume touching or overlapping the proximal bronchial tree, esophagus, or trachea, may be more appropriately treated with conventional fractionation schema.
Recommendation 2.2. For patients with Stage I or II node-negative LS-SCLC receiving SBRT, chemotherapy should be delivered to patients in whom it is medically tolerated.

Prophylactic Cranial RT
Recommendation 3.1. For patients with SCLC who respond to initial therapy, restaging with brain MRI to guide decision making regarding PCI is recommended.
Recommendation 3.2. For patients with Stage I SCLC, PCI is conditionally not recommended. In lieu of PCI, surveillance using brain MRI with contrast can serve as an alternative.
Recommendation 3.3. For patients with Stage II-III LS-SCLC who are less than 70 years of age with good performance status (ECOG 0-2) and respond to thoracic chemoradiation, PCI is recommended.
Recommendation 3.4. For patients with LS-SCLC who have limited Performance Status, older age, and/or significant comorbidities, shared decision making on PCI (considering patient- and disease-specific characteristics) is recommended.
Recommendation 3.5. For patients with LS-SCLC receiving PCI, 2,500 cGy in 10 fractions is recommended.
Recommendation 3.6. For patients with ES-SCLC who respond to chemotherapy, consultation with a Radiation Oncologist to enhance shared decision making on PCI versus MRI surveillance (considering patient- and disease-specific characteristics) is recommended.
Recommendation 3.7. For patients with ES-SCLC who elect PCI, 2,500 cGy in 10 fractions or 2,000 cGy in 5 fractions is recommended.

Thoracic Consolidation for ES-SCLC
Recommendation 4.1. For patients with ES-SCLC with a response to chemotherapy alone but residual tumor in the thorax, thoracic RT is recommended.
Recommendation 4.2. For patients with ES-SCLC with a response to chemotherapy alone, thoracic RT to a dose of 3,000 cGy in 10 fractions is conditionally recommended. In patients expected to have a prolonged survival, higher doses may be appropriate.
Recommendation 4.3. For patients with ES-SCLC who will receive thoracic RT, the treatment should be given after completion of chemotherapy alone.
Recommendation 4.4. For patients with ES-SCLC with a response to chemotherapy and immunotherapy and residual disease in the thorax, thoracic RT to 3,000 cGy in 10 fractions within 6-8 weeks of completion of the chemotherapy prior to maintenance immunotherapy, is conditionally recommended.

Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an ASTRO Guideline. Daly ME, NIsmaila N , Decker RH, et al. J Clin Oncol. 2021;39:931-939.

FDA Approves SARCLISA® Combination for Relapsed or Refractory Myeloma

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SUMMARY: The FDA on March 31, 2021, approved SARCLISA® (Isatuximab-irfc) in combination with KYPROLIS® (Carfilzomib) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. 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, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

CD38 is a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with KYPROLIS® and Dexamethasone in 2020, for the treatment of patients with multiple myeloma, who had received 1-3 prior lines of therapy. This was based on the CANDOR open label, Phase III trial, in which the triplet combination of DARZALEX®, KYPROLIS® and Dexamethasone resulted in a 37% reduction in the risk of progression or death, compared with KYPROLIS® and Dexamethasone. 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.

SARCLISA® is a CD38-targeting IgG1monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome.

The present FDA approval was based on IKEMA trial, which is a multicenter, randomized, open label, Phase III study, in which the efficacy and safety of SARCLISA® in combination with KYPROLIS® and Dexamethasone was evaluated among patients with relapsed and/or refractory multiple myeloma, who had received 1-3 prior lines of therapy. In this study, 302 eligible patients were randomized 3:2 to receive SARCLISA® plus KYPROLIS® and Dexamethasone (N=179) or KYPROLIS® and Dexamethasone alone (N=123). SARCLISA® was given at 10 mg/kg IV weekly for 4 weeks and then every 2 weeks. KYPROLIS® was given at 20 mg/m2 IV on days 1 and 2 and then at 56 mg/m2 IV thereafter twice weekly for 3 of 4 weeks and Dexamethasone was given at 20 mg twice weekly. Treatment was continued until disease progression or unacceptable toxicity. The median age was 64 years, 23% had 3 or more prior lines of therapy, 90% of patients had prior treatment with Proteasome Inhibitor, 78% had prior treatment with Immunomodulatory drug (IMiD) and 24% had high-risk cytogenetics. The Primary endpoint was Progression Free Survival as determined by an Independent Review Committee (IRC). Key secondary endpoints included Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity rate (10-5 by NGS), and Overall Survival (OS).

At a prespecified interim analysis, and after a median follow up of 20.7 months, the PFS was Not Reached for SARCLISA® group versus 19.15 months for the KYPROLIS® and Dexamethasone group (HR=0.53; P=0.0007). This represented a 47% reduction in the risk of disease progression or death in patients treated with SARCLISA® plus KYPROLIS® and Dexamethasone, compared to those treated with KYPROLIS® and Dexamethasone. This benefit was seen across all patient subgroups including those with high risk cytogenetics. The Overall Response Rate did not differ significantly between the SARCLISA® combination and control groups (86.6% versus 82.9%), with Complete Response Rates of 39.7% versus 27.6% respectively. MRD negativity rate was 29.6% with SARCLISA® combination versus 13% in the KYPROLIS® and Dexamethasone group (P=0.0004). Overall survival data were not mature at the time of data cutoff.

It was concluded that the addition of SARCLISA® to KYPROLIS® and Dexamethasone, resulted in a superior, statistically significant improvement in PFS, with clinically meaningful improvement in depth of response. The authors added that SARCLISA® combination was well tolerated with manageable safety and a favorable benefit-risk profile, and represents a possible new standard of care treatment for patients with relapsed multiple myeloma.

Isatuximab Plus Carfilzomib and Dexamethasone Vs Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma (IKEMA): Interim Analysis of a Phase 3, Randomized, Open-Label Study. Moreau P, Dimopoulos MA, Mikhael J, et al. 2020 ASH Annual Meeting & Exposition. Abstract# 2316. Presented on December 6, 2020.

FDA Approves Anti-BCMA CAR T-Cell Therapy for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on March 26, 2021, approved ABECMA® (Idecabtagene vicleucel) for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a Proteasome Inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA approved cell-based gene therapy for multiple myeloma. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. 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, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.Chimeric-Antigen-Receptor-T-Cell-Immunotherapy

Anti-BCMA CAR T-Cell Therapy ABECMA® is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

The FDA approval was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. In this study, 128 patients with persistent disease after at least three previous regimens including a Proteasome Inhibitor, an immunomodulatory agent, and an anti-CD38 antibody, received ABECMA® target doses of 150×106 to 450×106 CAR-positive (CAR+) T cells, after receiving lymphodepleting chemotherapy. Lymphodepletion therapy consisted of Fludarabine 30 mg/m2 IV and Cyclophosphamide 300 mg/m2 IV given on 3 consecutive days, followed by 2 days of rest before ABECMA® infusion. The median patient age was 61 years and the median time from diagnosis was 6 years. About 51% of patients had a high tumor burden (50% or more bone marrow plasma cells), 39% had extramedullary disease and 35% had a high-risk cytogenetic abnormalities, defined as del(17p), t(4;14), or t(14;16). Patients had received a median of 6 previous antimyeloma regimens and 94% had received previous Autologous Hematopoietic Stem Cell Transplants. The Primary end point was an Overall Response Rate (ORR) as assessed by an Independent Review Committee (IRC) and key Secondary end point was a Complete Response or better (comprising complete and stringent Complete Responses). Other efficacy endpoints include Time to Response, Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Minimal Residual Disease (MRD) evaluated by Next-Generation Sequencing (NGS) assay, and Safety.

At a median follow up of 13.3 months, the ORR was 73% and 33% had a complete or stringent Complete Response. Of those with a complete or stringent Complete Response, 79% had MRD-negative status at a sensitivity level of 10−5, corresponding to 26% of the treated population. This benefit was consistently observed in most subgroups examined, including older patients, those who received bridging therapy, and those with aggressive disease features, including high-risk cytogenetics, triple or penta-refractory disease, a high tumor burden, and extramedullary disease. The median time to first response was 1.0 month and the median time to a Complete Response or better was 2.8 months. The estimated median Duration of Response was 10.7 months for all patients and 11.3 months among those receiving the highest target dose. The response duration increased with the depth of response. The median PFS was 8.8 months for all patients and 20.2 months in patients having a complete or stringent Complete Response. Data on Overall Survival are immature. Cellular kinetic analysis confirmed CAR+ T cells in 59% at 6 months and 36% at 12 months after infusion. Common toxicities included neutropenia, anemia and thrombocytopenia. Cytokine Release Syndrome was reported in 84% of patients including 5% Grade 3 or higher events. Neurotoxic effects developed in 18% of patients.

It was concluded that ABECMA® induced deep and durable responses in majority of heavily pretreated patients with Refractory and Relapsed myeloma, and fulfills a high unmet need for this patient group.

Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. Munshi NC, Anderson LD, Shah N, et al. N Engl J Med 2021; 384:705-716

FDA Approves First Line KEYTRUDA® in Combination with Chemotherapy for Esophageal or Gastroesophageal Carcinoma

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SUMMARY: The FDA on March 22, 2021, approved KEYTRUDA® (Pembrolizumab) in combination with Platinum and Fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GastroEsophageal Junction (tumors with epicenter 1 to 5 cm above the GastroEsophageal Junction) carcinoma, who are not candidates for surgical resection or definitive chemoradiation. The American Cancer Society estimates that in the US about 19,260 new esophageal cancer cases will be diagnosed in 2021 and about 15,530 people will die of the disease. Esophageal cancer is more common among men than among women. Majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine. The prognosis for advanced esophageal cancer is poor, with median survival of less than 12 months.

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

KEYNOTE-590 is a global, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, in which first line KEYTRUDA® plus chemotherapy was compared with placebo plus chemotherapy, in patients with locally advanced/unresectable or metastatic adenocarcinoma or esophageal Squamous Cell Carcinoma (ESCC) or Siewert type 1 EsophagoGastric Junction adenocarcinoma (EGJ), who were not candidates for surgical resection or definitive chemoradiation. In this study, 749 eligible patients, regardless of PD-L1 expression were randomized 1:1 to KEYTRUDA® 200 mg IV every 3 weeks for up to 35 cycles (2 years) along with chemotherapy consisting of Cisplatin 80mg/m2 IV given on day 1, plus 5FU 800 mg/m2 IV given on days 1-5, every 3 weeks for 6 cycles, or placebo plus chemotherapy. Treatment was continued until disease progression or unacceptable toxicity, and crossover was not permitted. Approximately 50% of all patients had tumors with a PD-L1 Combined Positive Score (CPS) 10 or more, and half the population was Asian. The dual Primary endpoints of the study were Overall Survival (OS) and Progression Free Survival (PFS). The researchers evaluated outcomes in the overall treatment population, in patients with a PD-L1 CPS 10 or more, and according to histology (Esophageal Squamous Cell Carcinoma versus adenocarcinoma). The Secondary end point was Objective Response Rate (ORR) in all patients. The median follow up was 10.8 months.

There was a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA® with chemotherapy. The median OS among all patients was 12.4 versus 9.8 months (HR=0.73; P<0.0001) and the median PFS among all patients was 6.3 versus 5.8 months, respectively (HR=0.65; P<0.0001). The confirmed ORR in all patients was 45% versus 29.3% (P < 0.0001), with a median Duration of Response of 8.3 versus 6.0 months, respectively. In patients with a PD-L1 CPS 10 or higher, the median OS with the KEYTRUDA® plus chemotherapy was 13.5 months versus 9.4 months with chemotherapy alone (HR=0.62; P<0.0001) and the median PFS was 7.5 months versus 5.5 months, respectively (HR=0.51; P<0.0001). The most common adverse reactions reported in 20% or more of patients who received the KEYTRUDA® combination were nausea, vomiting, constipation, diarrhea stomatitis, fatigue/asthenia, decreased appetite, and weight loss.

It was concluded that treatment with KEYTRUDA® plus chemotherapy combination resulted in superior Overall Survival, Progression Free Survival, and Objective Response Rate, with a manageable safety profile, when compared to chemotherapy alone, in patients with advanced untreated esophageal and EsophagoGastric Junction cancer. These data demonstrate that first line KEYTRUDA® plus chemotherapy is a new standard of care in this patient population.

Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Kato K, Sun J, Shah MA, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325.

Advances in Triple Negative Breast Cancer

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Written by: Debra Patt, MD, PhD, MBA
Content Sponsored by: Bristol Myers Squibb
Dr. Patt is a paid consultant for BMS and was compensated for her contribution in drafting this article.

Metastatic triple negative breast cancer (TNBC) is a devastating disease, making up 15% of all cancers, and having a limited outcome with an overall survival average of around a year.1,2 It is a diagnosis of exclusion, as tumor cells do not express the targetable hormone receptors (estrogen or progesterone receptors) or HER2, thus treatment options have historically relied on systemic chemotherapy rather than targeted treatment.3 This aggressive subtype is often associated with an earlier age of onset and an aggressive clinical course. Ethnic disparities have been identified for triple negative disease, with the incidence highest among patients who have a non-Hispanic black ethnic background compared to other ethnic groups.1 Furthermore, African American women are more likely to develop metastases compared to women of other races. Metastatic progression for triple-negative disease is generally characterized by early relapse and predominantly visceral (including liver, pulmonary and central nervous system) metastases.3

Historically, advances in the treatment of triple negative breast cancer have been rare. Multiple immunotherapy options in combination with chemotherapy are now approved in metastatic TNBC for patients with PD-L1 positive, first-line disease, and today there is much excitement about further evidence supporting its use in the metastatic and early stage settings.4 However, no head-to-head data exists to identify the optimal chemotherapy partner for checkpoint inhibition and not all chemotherapy agents appear to provide similar efficacy based on current data, hence more investigations are needed.5,6 Furthermore, while the incidence of immune-related adverse events such as endocrinopathies are low, the permanence of these side effects, particularly in the early stage setting, is concerning to some and should be closely monitored.

Germline BRCA mutations occur in approximately 10–30% of TNBC cases.7 In previously treated metastatic disease, the use of poly (ADP-ribose) polymerase (PARP) inhibitors in germline BRCA mutation positive patients has also shown improvements in survival, with the main reported side effects being hematologic, fatigue and diarrhea.3,8 In heavily pretreated metastatic TNBC patients, the use of antibody-drug conjugates has also resulted in anti-cancer effects.9

While advances in the aggressive and difficult-to-treat triple negative breast cancer subset are promising, all of these recent advances leave us with new treatment options but also unanswered questions. Our knowledge is limited and certainly will improve over time as we understand better predictors of outcome like PD-L1 expression, tumor infiltrating lymphocytes, and other factors as well as the importance of chemotherapy backbone choice. Other agents are now available for previously treated metastatic TNBC patients and further studies will be needed to assess the efficacy of these agents in earlier lines of therapy. Additionally, long-term follow up of studies will also be important to truly understand the impact of these new targeted approaches and the impact of drug tolerability on efficacy and patient quality of life.

References
1. DeSantis CE, Fedewa SA, Sauer AG, Kramer JL, Smith RA, Jemal A. CA Cancer J Clin. 2016;66:31-42.
2. Marra A, Viale G, Curigliano G. BMC Medicine. 2019;17:90-99.
3. Bergin ART, and Loi S. F1000Research. 2019;8: F1000 Faculty Rev-1342. Published online 2019 Aug 2.
4. Simmons CE, Brezden-Masley C, McCarthy J, McLeod D, Joy AA. Ther Adv Med Oncol. 2020;12:1-15.
5. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, et al. DOI: 10.1200/JCO.2020.38.15_suppl.1000 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 1000-1000.
6. Miles D, Gligorov J, Andre F, Cameron D, Schneeweiss A, et al. Annals of Oncology. 2020;31 (suppl 4):S1142-S1215. 10.1016/annonc/annonc325.
7. Vagia E, Mahalingam D, Cristofanilli M. Cancers (Basel). 2020 Apr;12:916-941.
8. Madariaga A, Bowering V, Ahrari S, Oza AM, and Lheureux S. Int J Gynecol Cancer. 2020; 30:903-915.
9. Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, et al. N Engl J Med. 2019;380:741-751.

Therapy for Stage IV Non–Small-Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Joint Guideline Update

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, MET, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

The ASCO and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated the 2017 ASCO guideline on systemic therapy for patients with Stage IV NSCLC with driver alterations and provided evidence-based recommendations, based on a systematic review of Randomized Controlled Trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020.

This clinical practice guideline addresses three comprehensive clinical questions for patients with Stage IV NSCLC with driver alterations
1) What is the most effective first-line therapy?
2) What is the most effective second-line therapy?
3) Is there a role for a third-line therapy or beyond?

The guideline addresses patients with NSCLC in the following histologic or subgroups: EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK. This update does not apply to patients with Stage IV NSCLC without known driver alterations and those with rarer histologies such as large cell, neuroendocrine, etc.

Summary of Key Recommendations

Recommendation 1.1: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with T790M, L858R, or exon 19 deletion mutations, Osimertinib should be offered.

Recommendations 1.2, 1.3, 1.4, and 1.5: For patients with Stage IV NSCLC and driver alterations in EGFR-if Osimertinib is not available
֍In the first-line setting, if Osimertinib is not available, Gefitinib with chemotherapy may be offered or Dacomitinib may be offered.
֍Other options that may be offered include Afatinib or Erlotinib/Bevacizumab or Erlotinib/Ramucirumab or Gefitinib, Erlotinib, or Icotinib.

Recommendation 1.6: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with a Performance Status (PS) of 3, an EGFR Tyrosine Kinase Inhibitor (TKI) may be offered.

Recommendation 1.7: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with EGFR mutations other than exon 20 insertion mutations, T790M, L858R, or exon 19 deletion alterations, Afatinib may be offered or Osimertinib may be offered or treatments outlined in the ASCO/OH nondriver mutation guideline may be offered.

Recommendation 1.8: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the first-line setting, for patients with any activating EGFR mutation (including exon 20 insertion mutations), regardless of Programmed Death Ligand-1 (PD-L1) expression levels, single-agent immunotherapy should not be used.

Recommendation 1.9: For patients with Stage IV NSCLC and driver alterations in EGFR causing resistance to first- and second-generation EGFR TKIs
֍In the first-line setting, for patients with EGFR exon 20 insertion mutation causing resistance to first- and second-generation EGFR TKIs, doublet chemotherapy with or without Bevacizumab or standard treatment outlined in the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 2.1 and 2.2: For patients with Stage IV NSCLC and driver alterations in EGFR
֍In the second-line setting, for patients who did not receive Osimertinib and have a T790M mutation at the time of progressive disease, Osimertinib should be offered.
֍In the second-line setting, for patients with any EGFR mutation who have progressed on EGFR TKIs with no T790M mutation OR whose disease has progressed on Osimertinib, treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendation 3.1: For patients with Stage IV NSCLC and driver alterations in ALK
֍In the first-line setting, Alectinib or Brigatinib should be offered.
֍In the first-line setting, if Alectinib and Brigatinib are not available, Ceritinib or Crizotinib should be offered.

Recommendations 4.1, 4.2, and 4.3: For patients with stage IV NSCLC and driver alterations in ALK
֍In the second-line setting, if Alectinib or Brigatinib was given in the first-line setting, Lorlatinib may be offered.
֍In the second-line setting, if Crizotinib was given in the first-line setting, then Alectinib, Brigatinib, or Ceritinib should be offered.
֍In the third-line setting, if Crizotinib was given in the first-line setting and Alectinib, Brigatinib, or Ceritinib in the second-line setting, then Lorlatinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 5.1, 5.2, and 5.3: For patients with Stage IV NSCLC and driver alterations in ROS1
֍In the first-line setting, Crizotinib or Entrectinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered or Ceritinib or Lorlatinib may be offered.

Recommendations 6.1 and 6.2: For patients with Stage IV NSCLC and driver alterations in ROS1
֍In the second-line setting, if ROS1-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, if nontargeted therapy was given in the first-line setting, Crizotinib, Ceritinib, or Entrectinib may be offered.

Recommendations 7.1 and 7.2: For patients with Stage IV NSCLC and driver alterations with BRAF V600E mutation
֍In the first-line setting, Dabrafenib/Trametinib may be offered or standard first-line treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 8.1, 8.2 and 8.3: For patients with Stage IV NSCLC and driver alterations with BRAF V600E mutation
֍In the second-line setting, if previous BRAF/MEK-targeted therapy (Dabrafenib/Trametinib) was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, if BRAF-targeted therapy was not given in the first-line setting, Dabrafenib/Trametinib may be offered or Dabrafenib or Vemurafenib alone may be offered.
֍If previous chemotherapy, immunotherapy, and/or BRAF-targeted therapy were given in the first- or subsequent-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.

Recommendation 8.4: For patients with Stage IV NSCLC and driver alterations with BRAF mutations other than V600E
֍In the second-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.

Recommendations 9.1 and 9.2: For patients with Stage IV NSCLC and MET exon 14 skipping mutation
֍In the first-line setting, for patients with an MET exon 14 skipping mutation, MET-targeted therapy with Capmatinib or Tepotinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 10.1 and 10.2: For patients with Stage IV NSCLC and MET exon 14 skipping mutation
֍In the second-line setting, for MET abnormalities other than exon 14 skipping mutations or if MET-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline should be offered.
֍In the second-line setting, patients with an MET exon 14 skipping mutation who previously received or were ineligible for first-line chemotherapy with or without immunotherapy (ie. if MET-targeted therapy was not given in the first-line setting), Capmatinib or Tepotinib may be offered.

Recommendations 11.1, 11.2, and 11.3: For patients with Stage IV NSCLC and driver alterations in RET
֍In the first-line setting, Selpercatinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered or Pralsetinib may be offered.

Recommendations 12.1, 12.2, and 12.3: For patients with Stage IV NSCLC and driver alterations in RET
֍In the second-line setting, if RET-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.
֍In the second-line setting, if RET-targeted therapy was not given in the first-line setting, Selpercatinib may be offered or Pralsetinib may be offered.

Recommendations 13.1 and 13.2: For patients with Stage IV NSCLC and driver alterations in NTRK
֍In the first-line setting, Entrectinib or Larotrectinib may be offered or standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.

Recommendations 14.1 and 14.2: For patients with Stage IV NSCLC and driver alterations in NTRK
֍In the second-line setting, if NTRK-targeted therapy was given in the first-line setting, standard treatment based on the ASCO/OH nondriver mutation guideline may be offered.
֍In the second-line setting, if NTRK-targeted therapy was not given in the first-line setting, Entrectinib or Larotrectinib may be offered.

Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Hanna NH, Robinson AG, Temin S, et al. J Clin Oncol. 2021;39: 1040-1091

FDA Approves TheraSphere Y-90 Glass Microspheres for Hepatocellular Carcinoma

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SUMMARY: The FDA on March 18, 2021 approved TheraSphere Y-90 Glass Microspheres, developed for the treatment of patients with HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2021, about 42,230 new cases of primary liver cancer and and intrahepatic bile duct cancer will be diagnosed in the US and 30,230 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis.

Patients with HCC, with disease confined to one lobe of the liver often undergo liver resection if feasible, and liver transplantation when HCC is associated with chronic liver disease and cirrhotic livers. Other liver-directed therapies include ablative modalities such as SBRT (Stereotactic Body Radiation Therapy), Cryoablation, RFA (RadioFrequency Ablation), as well as Trans Arterial ChemoEmbolization (TACE) and Selective Internal Radiation Therapy (SIRT), also referred to as radioembolization. HepatoCellular Carcinoma’s derive their blood supply almost exclusively from the hepatic arteries, whereas the liver has a dual blood supply from the portal vein (75-80%) and hepatic arteries (20-25%). By taking advantage of the differential blood supply of hepatic tumors, chemo and radioembolization can be targeted to the tumor tissue, minimizing damage to the surrounding normal liver parenchyma.

TheraSphere treatment is a type of SIRT with low toxicity, and is comprised of millions of microscopic glass beads containing radioactive yttrium (Y-90), which is delivered to liver tumors via a hepatic arterial catheter, and results in minimal radiation exposure to surrounding normal liver parenchyma.

LEGACY trial is a single-arm, multicenter, retrospective study designed to evaluate the safety and efficacy of Yttrium-90 (Y90) glass microspheres in patients with unresectable solitary hepatocellular carcinoma (HCC). The objective of this study was to assess the Objective Response Rate (ORR) and Duration of Response (DoR) following treatment with Yttrium-90 (Y90), and the objective of the analyses presented was to evaluate ORR, DoR, and Overall Survival (OS) by transplant/resection status (neoadjuvant therapy with the intent to bridge patients to transplant or resection), and to compare these outcomes with patients who did not go on to transplantation/resection after receiving treatment with Y90. This study included 162 patients with Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) A or C disease, with unresectable solitary liver lesion that was 2-8 cm. The median patient age was 66 yrs and patients with portal vein thrombosis or extrahepatic disease were excluded. No prior liver transplantation, resection, locoregional treatment or systemic therapy was allowed. Primary efficacy endpoints included Objective Response Rate (ORR) and Duration of Response (DoR). ORR included patients who achieved either a Complete response or Partial Response, and response was determined by Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS) and number and type of subsequent treatments, including transplantation and resection.

This study met both Primary endpoints and the ORR was 72.2% at 4 weeks and DoR (more than 6 months) was 76.1%. The median follow up for all 162 patients enrolled was 29.9 months and 3-year OS was 86.6%. Among the 45 of the total 162 patients who received neoadjuvant Y90 treatment, 21% went on to transplantation and 7% went on to have resection. In the neoadjuvant treatment group, ORR was 100%, DoR (more than 6 months) was 30.6% and 3-year OS was 93%. Liver function as determined by levels of albumin and bilirubin were maintained in over 85% of patients.

It was concluded that treatment of solitary unresectable HCC with Y90 glass microspheres, performed as an outpatient procedure, resulted in significant ORR, DoR, and OS, both as neoadjuvant therapy prior to transplantation/resection and as treatment in non-surgical candidates.

Use of yttrium-90 (Y90) glass microspheres (TheraSphere) as neoadjuvant to transplantation/resection in hepatocellular carcinoma: Analyses from the LEGACY study. Lewandowski R, Johnson GE, Kim E, et al. DOI: 10.1200/JCO.2021.39.3_suppl.300 Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021) 300-300.

Sugar-Sweetened Beverages May Increase Breast Cancer Mortality

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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 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. It is estimated that more than 3.5 million breast cancer survivors are alive in the US. Understanding risk factors and modifying lifestyle behaviors can impact outcomes in this patient group.

Consumption of sugar-sweetened beverages has significantly increased over the past 3 decades worldwide, increasing the risk of obesity, hypertension and Type 2 diabetes, and in turn impacting cardiometabolic health. It is estimated that among all worldwide yearly deaths from diabetes and cardiovascular diseases, over 178,000 were attributable to sugar-sweetened beverages consumption.

More recently published large prospective French study (BMJ 2019;366:l2408) concluded that consumption of sugary drinks was positively associated with the risk of overall cancer and breast cancer. It has been hypothesized that sugar-sweetened beverages contain large quantities of sucrose and fructose which promote visceral adiposity, which can boost tumorigenesis through alterations in adipokine secretion and cell signaling pathways, independent of body weight. Further, long term consumption of sugary drinks result in high glycemic index or glycemic load, with chronically high blood glucose, and therefore chronically elevated insulin concentration. Insulin increases bioactive IGF-1, as well as proinflammatory markers, such as C reactive protein, and systemic inflammation is thought to promote cancer development by inhibiting apoptosis and stimulating cell proliferation, thereby increasing the risk of several cancers, including breast, liver, pancreas, endometrium, colorectal and bladder. Even though there is growing evidence of an association between sugar-sweetened beverages and increased risk of mortality in various populations, the effect of sugary drinks on mortality among breast cancer patients is unknown.

The researchers in this Western New York Exposures and Breast Cancer (WEB) Study assessed the relationship between sugar-sweetened soda and both all-cause and breast cancer mortality among 927 women between ages 35 to 79, who had been diagnosed with breast cancer. In this study, a food frequency questionnaire was used to assess frequency of sugar-sweetened soda consumption in the 12 to 24 months prior to diagnosis of breast cancer. Breast cancer cases were followed for a median of 18.7 years, with ascertainment of vital status via the National Death Index (NDI). This study focused on sugar-sweetened soda, as they are sugar loaded and add extra calories to the diet with no nutritional benefit.

Consumption of sugar-sweetened soda five times or more per week was noted to result in a 62% higher likelihood of dying from any cause and 85% more likely to die from breast cancer specifically, compared to women who never or rarely consumed sugar-sweetened soda. The risk of mortality was similarly increased among ER-positive, but not ER-negative patients, among women with BMI above the median, but not below the median. The risk of total mortality was higher in premenopausal women but not post-menopausal women.

It was concluded from this study that a higher frequency of sugar-sweetened soda consumption was associated with increased risk of total and breast cancer mortality among breast cancer patients, supporting existing guidelines on reducing consumption of sugar-sweetened beverages, including for women with a diagnosis of breast cancer. The authors added that this study provides evidence that diet may impact longevity of women after breast cancer.

Study Finds Regularly Drinking Sugar-Sweetened Soda May Increase Total and Breast Cancer Mortality. Koyratty N, McCann SE, Millen AE, et al. Cancer Epidemiol Biomarkers Prev March 2 2021 DOI: https://doi.org/10.1158/1055-9965.EPI-20-1242.

FDA Approves PEPAXTO® for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on February 26, 2021, granted accelerated approval to PEPAXTO® (Melphalan flufenamide) in combination with Dexamethasone for adult patients with Relapsed or Refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refractory to at least one Proteasome Inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.

Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. 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, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

PEPAXTO® is a novel, first-in-class peptide-drug conjugate that links a peptide carrier to a cytotoxic agent, resulting in a highly lipophilic compound. The lipophilicity allows PEPAXTO® to readily diffuse across cell membranes and get distributed into cells. Through its passive uptake into cells, the conjugated agent circumvents the development of transporter-associated resistance. The drug compound then leverages aminopeptidases, which are overexpressed in multiple myeloma cells, resulting in the release of the cytotoxic alkylating payload, which irreversibly damages tumor DNA and induces apoptosis.

The HORIZON trial is a pivotal, single-arm, multicenter, Phase II study of PEPAXTO® plus Dexamethasone in heavily pretreated patients with Relapsed or Refractory multiple myeloma. This study included 157 patients with relapsed or refractory disease, of whom 97 patients were triple-class refractory to at least one Immunomodulatory agent, one Proteasome Inhibitor, and a CD38-directed monoclonal antibody, and had received at least four prior lines of therapy. Patients received PEPAXTO® 40 mg IV on day 1 and Dexamethasone 40 mg orally (20 mg for patients 75 years of age or older) on day 1, 8, 15 and 22 of each 28-day cycle, until disease progression or unacceptable toxicity. The Primary end point was Overall Response Rate (Partial Response or better) assessed by the investigator, and Secondary end points included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), and Safety.

The FDA approval was based on the efficacy in a subgroup of patients (N=97), who were triple-class refractory and had received at least four prior lines of treatment. The Overall Response Rate for the patients within this group of patients was 23.7 % and the Median Duration of Response was 4.2 months. Among these 97 patients, 41% had extramedullary disease (N=40), an aggressive and resistant characteristic associated with poor prognosis. The most common adverse reactions in 20% or more were fatigue, fever, nausea, diarrhea and respiratory tract infection. Most common laboratory abnormalities in 50% or more were cytopenias and increased creatinine.

It was concluded that PEPAXTO® is a novel and innovative therapeutic option for patients with refractory myeloma, and is an important addition to the myeloma treatment armamentarium, in an area of unmet medical need.

Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. Richardson PG , Oriol A, Larocca A, et al. J Clin Oncol. 2021; 39:757-767