Category: Precision Oncology

Universal Genetic Testing Detects More Inherited Mutations Than Guideline Based Approach

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics. Very few studies have compared the prevalence of germline findings in patients with cancer, not selected by practice guidelines, and the impact of universal testing strategy for inherited germline variants in patients with cancer has remained unclear. The purpose of this present study was to determine if universal genetic testing in patients with cancer identifies more inherited cancer predisposition variants than a guideline-based approach, and also find out if there is an association between universal genetic testing and clinical management.

The authors in this prospective, multicenter cohort study, assessed germline genetic alterations among patients with solid tumors, receiving care at Mayo Clinic Cancer Centers and Mayo Clinic Health System community oncology practice in the US, between April 2018, and March 2020, as a part of 2 year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) program. Patients were NOT selected based on cancer type, stage of disease, family history of cancer, race/ethnicity, age at diagnosis, multifocal tumors, or personal history of multiple malignant neoplasms. Clinical, demographic, and family history data and pathologic information were collected on all patients from medical records or self-administered questionnaires.Single-Gene-versus-MultiGene-Testing

Germline sequencing using a Next-Generation Sequencing panel of 84 genes was offered at no cost, utilizing the Invitae Multi-Cancer Panel. Whole Genome Sequencing, deletion and duplication analysis, and variant interpretation were performed and Pathogenic Germline Variants (PGV) were classified as High (relative risk more than 4), Intermediate (relative risk, 2-4), or Low (relative risk less than 2) penetrance, or recessive medically actionable variants. Test results were disclosed to the patient, and those with Pathogenic Germline Variants (PGVs) were invited for genetic counseling.

The authors compared multi-gene panel testing with guideline-based testing, using guidelines from the National Comprehensive Cancer Network (NCCN) and the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG), to determine whether genetic testing was indicated for a particular patient. For patients who met the guidelines, the only genes tested were those recommended by the tumor-specific guideline. This study included patients with a broad mix of cancer types at various stages. The final analytic cohort consisted of 2984 patients, out of the 3095 patients enrolled in the study. The mean patient age was 61 years, 53% were male and 44% of patients had Stage IV disease at the time of genomic analysis. A family history of cancer in a first-degree relative was reported in 34% of the participants. The goals of this study were to examine the proportion of Pathogenic Germline Variants (PGVs) detected with a universal testing strategy compared with a targeted testing strategy based on clinical guidelines, as well as uptake of cascade genetic testing in families, when offered at no cost.

It was noted that Pathogenic Germline Variants (inherited mutation in a gene) associated with the development of their cancer was found in 13.3% of patients, including moderate and high-penetrance cancer susceptibility genes. In this study, 1 in 8 patients had a PGV, half of which would not have been detected using a guideline-based testing approach. Of those with a high-penetrance PGVs, 28.2% had modifications in their treatment, based on the finding. About 6.4% had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. However, only 17.6% of participants with PGVs had family members undergoing no-cost cascade genetic testing when offered.

It was concluded that in this large, prospective, multicenter cohort study with a broad mixture of cancer types and stages, universal multigene panel testing was associated with increased detection of clinically actionable heritable variants, compared with a targeted testing strategy based on clinical guidelines. Approximately 30% of patients with high-penetrance variants had modifications in their treatment, suggesting that wider clinical implementation of universal genetic testing and acceptance in oncology practice, may be beneficial.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. Samadder NJ, Riegert-Johnson D, Boardman L, et al. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252

LYNPARZA® Superior to Chemotherapy in BRCA Mutated Platinum Sensitive Advanced Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13, and they regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).MOA-of-LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. LYNPARZA® is a PARP inhibitor that traps PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, leading to cumulative DNA damage and tumor cell death.

Previously published studies demonstrated a durable response to LYNPARZA® administered as treatment (rather than maintenance), in women with heavily pretreated relapsed ovarian cancer and a germline BRCA mutation, with an Objective Response Rate (ORR) of 42% in the subgroup of patients with platinum-sensitive disease, who had received at least 3 prior chemotherapy regimens. Single-agent nonplatinum chemotherapy is often used in heavily pretreated women with relapsed ovarian cancer. The authors conducted this study to evaluate whether LYNPARZA® monotherapy improves outcomes, compared with physician’s choice single-agent nonplatinum chemotherapy, in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA mutation, who have received at least 2 prior lines of platinum-based chemotherapy.

SOLO3 is an International, randomized, controlled, open label Phase III trial, that compared LYNPARZA® with non-platinum chemotherapy, in patients with platinum sensitive, relapsed ovarian cancer, and a germline BRCA1/2 mutation. This study included 266 patients who were randomly assigned 2:1 to LYNPARZA® 300 mg orally given twice a day (N=178) or physician’s choice of single-agent chemotherapy (N=88), which could be either Pegylated Liposomal Doxorubicin (PLD) 50 mg/m2 IV on day 1 every 4 weeks, Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks, Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks or Topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. Eligible patients had relapsed high-grade serous or high-grade endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer, with at least 1 measurable and/or nonmeasurable lesion, that could be accurately assessed at baseline, by CT or MRI, and was suitable for repeated evaluation. Patients had received at least 2 prior lines of platinum-based chemotherapy for ovarian cancer and were platinum sensitive (progression more than 6 months after the end of the last platinum-based regimen). Treatment groups were well balanced and the median patient age was 59 years. The Primary end point was Objective Response Rate (ORR) in those with measurable disease, as assessed by Blinded Independent Central Review (BICR). The key Secondary end point was Progression Free Survival (PFS) assessed by BICR in the intent-to-treat population.

It was noted that ORR was significantly higher in the LYNPARZA® group than in the chemotherapy group (72.2% versus 51.4%; Odds Ratio=2.53; P=0.002), suggesting a 2.53 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. In the subgroup who had received 2 prior lines of treatment, the ORR with LYNPARZA® was 84.6% and 61.5% with chemotherapy (Odds Ratio= 3.44), suggesting a 3.44 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. The median time to onset of response was 2 months with LYNPARZA®, versus 3.5 months with chemotherapy, and the median Duration of Response was 9.4 months and 10.2 months respectively. The PFS also significantly favored LYNPARZA® versus chemotherapy (13.4 versus 9.2 months; HR=0.62; P=0.013). Adverse events were consistent with the established safety profiles of LYNPARZA® and chemotherapy. The most common Grade 3 or more adverse events were anemia in the LYNPARZA® group and PPE (Palmar-Plantar Erythrodysesthesia) and neutropenia in the chemotherapy group.

It was concluded that treatment with LYNPARZA® resulted in statistically significant and clinically relevant improvements in Objective Response Rate and Progression Free Survival, compared with nonplatinum chemotherapy, in patients with germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer, who had received at least 2 prior lines of platinum-based chemotherapy. This chemotherapy-free treatment option will be welcome news for patients with germline BRCA-mutated advanced ovarian cancer.

Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. Penson RT, Valencia RV, Cibula D, et al. J Clin Oncol. 2020;38:1164-1174.

Adjuvant TAGRISSO® in Resected EGFR-Mutated Non-Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian).
Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy. The authors reported the results from the unplanned interim analysis.

It was noted that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo.

In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo.

The benefit favoring TAGRISSO® with respect to DFS was observed consistently across all predefined subgroups including disease Stages IB, II, and IIIA and use or nonuse of adjuvant chemotherapy. The benefit with TAGRISSO® was greater at more advanced stages of disease (among patients with Stage IIIA disease, the overall HR was 0.12, among those with Stage II disease, the HR was 0.17, and among those with Stage IB disease, the HR was 0.39). At 2 years, 98% of the patients in the TAGRISSO® group and 85% of the patients in the placebo group were alive without CNS-related disease (HR for CNS disease recurrence or death=0.18). This indicated an 82% reduction in the risk of CNS disease recurrence or death with TAGRISSO®. The Overall Survival data were immature at the time of this interim analysis. Adverse Events were consistent with the known safety profile of TAGRISSO®.

The authors concluded that adjuvant TAGRISSO® is the first targeted agent in a global randomized trial, to show a statistically significant and clinically meaningful improvement in Disease Free Survival, among patients with Stage IB/II/IIIA EGFR mutation-positive NSCLC, and provides an effective new treatment strategy for this patient group.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. Wu Y-L, Tsuboi M, He J, et al. for the ADAURA Investigators. N Engl J Med 2020; 383:1711-1723.

GILOTRIF® in EGFR Positive Non Small Cell Lung Cancer Harboring Uncommon Mutations

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients, and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations. The majority of patients have classical EGFR mutations which are either Exon 19 deletions or L858R substitution mutation in Exon 21, and for those patients with EGFR mutation-positive NSCLC, EGFR-TKIs are the first choice of treatment. However, around 5-20% of tumors harbor Major uncommon mutations, such as G719X, L861Q and S768I, as well as other more rare mutations, and these uncommon EGFR mutations show heterogeneity in their response to EGFR-TKIs. Compared with other EGFR mutations, G719X, L861Q and S768I substitution mutations are associated with a poorer prognosis and have limited treatment options.

GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® demonstrated clinical activity against Major uncommon EGFR mutations such as G719X, L861Q and S768I which is more often seen in Asian patients, and is FDA approved in this setting. There are however, few clinical data regarding the efficacy of the available EGFR-TKIs against other uncommon EGFR mutations, and there is no knowledge of ethnic differences in prevalence and outcomes.

This study investigated the efficacy of GILOTRIF® in EGFR mutation positive NSCLC among Asian and non-Asian patients with uncommon mutations. Uncommon mutations were classed into five categories– Major uncommon (G719X, L861Q and S768I), Compound, Exon 20 insertions, T790M Mutation, and Other. Patients may have more than uncommon mutation.

The researchers conducted a pooled analysis from randomized clinical trials and Real-World Studies and examined the activity of GILOTRIF® in Asian and non-Asian patients with NSCLC and uncommon EGFR mutations, who had not received prior treatment with EGFR TKIs. All identified patients included in this study had outcome data such as Time to Treatment failure (TTF) or Objective Response Rate (ORR) available. The total number of evaluable patients were 298 (N=298), of whom 60% were Asian (N=178) and 40% were Non-Asian (N=120). The median patient age ranged from 60-66 years across the different mutation groups. Approximately 40% of patients had Major uncommon mutations such as G719X, L861Q and S768I, 24% had Exon 20 insertions, 12% had T790M mutations and 24% had Compound and Other mutations. When broken by ethnicity, among Asian patients, approximately 62% had Major uncommon mutations, 14% had Compound mutations and 16% had Exon 20 insertions. Among non-Asian patients, 35% had Major uncommon mutations, approximately 7% had Compound mutations and 39% had Exon 20 insertions. The Endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Treatment Failure (TTF), and outcomes were compared in Asian and non-Asian EGFR-TKI-naïve patients.

This analysis showed that the efficacy of GILOTRIF® was unaffected by ethnicity, and the Overall Response Rate (ORR) among tumors with Major uncommon mutations was 66% in Asian patients versus 59% in non-Asian patients, and the median Duration of Response (DoR) was 14.7 months compared with 15.9 months respectively. Among those with Major uncommon mutations, the ORR in tumors harboring G719X mutation was 62% in Asian patients and 65% in non-Asian patients. Among those tumors with a L861Q mutation, the ORRs were 60% versus 50%, respectively and among those with a S768I mutation, the ORRs were 80% versus 25%, respectively. The Overall Response Rate (ORR) among tumors with Compound mutations was 81% in Asian patients versus 100% in non-Asian patients and the median Duration of Response (DoR) was 11.5 months compared with 18.6 months respectively. Among patients who harbored Exon 20 insertions, the ORR with GILOTRIF® in Asian patients was 21% versus 23% in non-Asian patients, with a Duration of Response of 11 months and 10.7 months, respectively.

It was concluded that GILOTRIF® shows clinical activity against uncommon EGFR mutations in both Asian and non-Asian patients, with durable clinical responses, and should be considered as a first-line treatment option in Asian and non-Asian patients with Major uncommon (G719X, L861Q and S768I) and Compound EGFR mutations.

Afatinib in Asian and non-Asian patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC harboring major uncommon mutations. Yang JC-H, Schuler M, Popat S, et al. Presented at: 2020 IASLC North America Conference on Lung Cancer; October 16-17, 2020; Virtual. Abstract MO01.36.

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

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SUMMARY: The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.
KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of Colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that Sotorasib inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The authors conducted a multicenter, open label Phase I trial of Sotorasib, in patients with advanced solid tumors harboring the KRAS-G12C mutation. This trial consisted of dose escalation and expansion cohorts and included a total of 129 patients, of whom 59 patients had NSCLC, 42 had Colorectal cancer, and 28 patients had other tumor types (Appendiceal, Endometrial, Pancreatic cancers and Melanoma). Sotorasib was administered orally once daily and each treatment cycle was 21 days. The planned dose levels for the escalation cohorts were 180, 360, 720, and 960 mg. Treatment was continued until disease progression or unacceptable toxicity. The median patient age was 62 years and most of the enrolled patients were heavily pretreated and had received a median of 3 previous lines of anticancer therapy for metastatic disease. Among the NSCLC patient cohort, approximately 90% of patients were current or former smokers and had received anti- Programmed cell Death protein-1 (PD-1) or PD-Ligand 1 (PD-L1) therapies. All patients had received previous platinum-based chemotherapy. The Primary endpoint was safety, including the incidence of dose-limiting toxicities and key Secondary end points were pharmacokinetics and Objective Response Rates. The Sotorasib dose of 960 mg daily was identified as the dose for the expansion cohort. The median follow up was 11.7 months and the median duration of treatment was 3.9 months, with 57% of patients having received treatment for 3 months or more, and 29% of patients, for 6 months or more.

Among those patients with NSCLC, 32.2% of the patients had a confirmed Objective Response (Complete or Partial Response at all dose levels, and 88% had disease control (Objective Response or Stable disease), with a median Progression Free Survival of 6.3 months. Responses were rapid and were seen at week 6, and these responses were durable and ongoing at a median follow up of nearly a year.

Among the colorectal cancer subgroup, at a median follow up of 12.8 months, 7% had a confirmed response, and 74% had disease control, with a median duration of stable disease of 5.4 months and median PFS of 4 months. Responses were also observed in patients with Pancreatic, Endometrial, and Appendiceal cancers and Melanoma. It has been postulated that the inconsistent tumor responses noted between NSCLC and Colorectal cancer suggests either that KRAS-G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways such as Wnt or EGFR pathways may mediate oncogenic signaling beyond KRAS. The authors suggest that a viable option would be to combine Sotorasib with therapies that block additional pathways, as was shown by studies in BRAF V600E-mutant Colorectal cancer. Approximately 57% of patients had treatment-related Adverse Events, of whom, about 12% had Grade 3 or 4 events. These toxicities included abnormal liver function studies, anemia, lymphopenia and diarrhea.

It was concluded Sotorasib showed promising anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS-G12C mutation. Studies evaluating Sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are under way

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. Hong DS, Fakih MG, Strickler JH, et al. N Engl J Med 2020; 383:1207-1217.

Five Year Analysis of Adjuvant TAFINLAR® plus MEKINIST® in Stage III Melanoma

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SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas and result in constitutive activation of the MAPK pathway.

TAFINLAR® (Dabrafenib) is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected, Stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had Stage IIIA disease, 41% had Stage IIIB disease, and 40% had Stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

The authors had previously reported that at a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not been reached in the combination therapy group, and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001).

The authors in this publication reported the results for RFS and Distant metastasis-free survival at 5 years. Overall survival was not analyzed as the data was not mature. The minimum duration of follow up was 59 months. The RFS at 5 years 52% with TAFINLAR® plus MEKINIST® and 36% with placebo (HR for relapse or death=0.51). The Distant metastasis-free survival at 5 years was 65% with TAFINLAR® plus MEKINIST® and 54% with placebo (HR for distant metastasis or death=0.55). As has been reported in previous studies, majority of relapses occurred, within the first 3 years after surgery. There were no clinically meaningful differences noted in the incidence or severity of serious Adverse Events during the follow up period.

It was concluded that in this 5-year analysis of extended follow up from the COMBI-AD trial, 12 months of adjuvant therapy with a combination of TAFINLAR® and MEKINIST® resulted in longer Relapse Free and Distant metastasis-free Survival, compared to placebo, in patients with resected Stage III melanoma with BRAF V600 mutations.

Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Dummer R, Hauschild A, Santinami M, et al. N Engl J Med 2020; 383:1139-1148

FDA Approves GAVRETO® for Metastatic RET Fusion-Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on September 4, 2020, granted accelerated approval to GAVRETO® (Pralsetinib) for adult patients with metastatic RET fusion-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA approved test. The FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for GAVRETO®. Lung cancer is the second most common cancer in both men and women MOA-of-GAVRETOand accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

GAVRETO® is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of GAVRETO® was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). The main efficacy outcome measures were Overall Response Rate (ORR) and response duration, as determined by a blinded Independent Review Committee, using RECIST criteria.

The efficacy for RET fusion-positive NSCLC was evaluated in 87 patients previously treated with platinum-based chemotherapy. Patients received GAVRETO® 400 mg orally once daily. The ORR was 57%, with a Complete Response (CR) rate of 5.7% and 80% of responding patients had responses lasting 6 months or longer. The median Duration of Response was not reached. Efficacy was also evaluated in 27 patients who never received systemic treatment and the ORR in this patient group was 70% with 11% CR rate and 58% of responding patients had responses lasting 6 months or longer. The most common adverse reactions (25% or more) were fatigue, constipation, musculoskeletal pain and hypertension.

It was concluded that patients treated with GAVRETO® had a rapid, potent, and durable clinical response, in patients with advanced RET fusion positive NSCLC, regardless of RET fusion partner, presence of brain metastases, or prior therapies.

Gainor JF, Curigliano G, Kim D-W, et al. DOI: 10.1200/JCO.2020.38.15_suppl.9515 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 9515-9515.

Precision Medicine in Pancreatic Cancer May Improve Overall Survival

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SUMMARY: The American Cancer Society estimates that for 2020, about 57,600 people will be diagnosed with pancreatic cancer and about 47,050 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 9%.

Patients with metastatic Pancreatic Ductal AdenoCarcinoma (PDAC) are often treated with chemotherapy and treatment regimens include FOLFIRINOX and Gemcitabine with nab-Paclitaxel (ABRAXANE®). However, resistance to current treatment modalities is common, and the median Overall Survival (OS) remains less than 1 year, suggesting that treatment with chemotherapy alone probably may not increase response rates and Overall Survival.

In an attempt to improve outcomes in patients with metastatic PDAC, molecular profiling using Next Generation Sequencing (NGS) and protein IHC panel-based examination of patients’ tumors, has enabled grouping patients into molecular subgroups with therapeutically actionable molecular alterations. It is estimated that approximately 25% of pancreatic cancers harbor actionable molecular alterations, defined as molecular alterations for which there is clinical or strong preclinical evidence of a predictive benefit from a specific therapy. However, less than 5% of patients with pancreatic cancer having actionable molecular alterations receive targeted therapies. This may be because of the aggressive nature of the disease or economic and logistical barriers. The commonly altered pathways include DNA repair (15%), cell cycle (11%), and AKT/mTOR (19%). Molecular targets have included Homologous Recombination Repair genes (14-17%), HER2 amplification genes (2%) and MisMatch Repair gene deficiency (MicroSatellite Instability 2-3%). Mutations in DNA repair genes are the most common “highly actionable” alterations (15%). The most frequently mutated DNA repair genes are ATM (4.5%) and BRCA2 (2.9%). Some examples of available targeted agents for patients with metastatic PDAC include PARP inhibitors for BRCA1 and BRCA2 mutations, TRK inhibitors for NTRK1, NTRK2, or NTRK3 fusions, and Immune Checkpoint Inhibitors for MMR-deficient or MSI-H tumors. Patients with these genetic alterations constitute about 8% of patients, with pancreatic cancer.

Know Your Tumor (KYT) is a precision medicine program, which is a collaboration between Perthera Inc. and the Pancreatic Cancer Action Network (PanCAN), and utilizes Perthera’s precision medicine system for multiomic molecular profiling of a nonselected patient population. Multiomics is data analysis at multiple levels such as genome, epigenome, transcriptome, proteome, and metabolome, to comprehensively understand human health and diseases, by interpreting molecular intricacy and variations. The intent of the KYT program is to match patients with appropriate clinical trials and therapies, based on actionable molecular alterations, treatment history, and geographical locations. The purpose of this study was to determine whether patients with pancreatic cancer whose tumors harbored actionable molecular alterations and who received molecularly matched therapy, had a longer median Overall Survival, than similar patients who did not receive molecularly matched therapy.

In this program, of the 1082 patients who received reports on their tumor genomic profile, outcomes were available for 677 patients, of whom 189 patients had actionable molecular alterations. At a median follow up of 383 days, patients with actionable molecular alterations who received a matched therapy (N=46) had a significantly longer median Overall Survival, compared to those patients who only received unmatched therapies (N=143), and this was statistically significant (2.58 years versus 1.51 years; HR=0.42: P=0.0004). The 46 patients who received a matched therapy also had significantly longer Overall Survival than the 488 patients who did not have an actionable molecular alteration (2.58 years versus 1.32 years; HR=0.34; P<0.0001). The median Overall Survival was not different between the patients who received unmatched therapy and those without an actionable molecular alteration (HR=0.82; P=0.10).

It was concluded from these Real-World outcomes that a matched therapy for patients with actionable molecular alterations can have a substantial effect on survival, in patients with pancreatic cancer. The authors acknowledged that only 2% of patients who were referred to undergo molecular profiling ultimately received a matched therapy and 143 patients with actionable molecular alterations received only unmatched therapies due to a variety of reasons including logistical issues and economic barriers.

Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Pishvaian MJ, Blais EM, Brody JR, et al. Lancet Oncol. 2020 Apr;21(4):508-518.doi: 10.1016/S1470-2045(20)30074-7. Epub 2020 Mar 2.

Next-Generation Sequencing Superior to Single Gene Testing in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, MET, HER2 are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors. Patients with nonsquamous NSCLC should therefore be tested for Actionable Driver Oncogenes, as highly effective treatments may be available for these patients. Nonetheless, Single Gene Testing for EGFR and ALK is more common in the US rather than broad multigene panel testing with Next-Generation Sequencing.Overview-of-Next-Generation-Sequencing

Next-Generation Sequencing (NGS) platforms or second-generation sequencing, unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. There are a number of different NGS platforms using different sequencing technologies and NGS can be used to sequence and systematically study the cancer genomes in their entirety or specific areas of interest in the genome or small numbers of individual genes. Recently reported genomic profiling studies, performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.

The authors in this study used a decision analytic model they had developed, and compared the value of broad NGS-based testing, to Single Gene Testing (SGT), in patients with nonsquamous NSCLC, and discussed their implications for the US population. The authors noted that Single Gene Testing for EGFR and ALK is relatively common (>80%) in the US, whereas testing for less common Actionable Driver Oncogenes is rare. The broader NGS Actionable Driver Oncogene panel includes EGFR, ALK, ROS1, BRAF, RET, MET, NTRK. The authors took into consideration reimbursement by CMS for broad NGS-based testing ($627.50), reimbursement for Single Gene testing (EGFR+ALK $732.30), and the cost of treatment for 2 years at $10K/year ($20,000). The expected prevalence of Actionable Driver Oncogenes among non squamous NSCLC patients, as well as survival outcomes of patients, in the presence versus absence of an Actionable Driver Oncogenes treatment strategy, was calculated based on current literature. The number of eligible patients with nonsquamous NSCLC, for testing in the US, were 89,000 (N=89,000). The estimated number of patients with Actionable Driver Oncogenes (EGFR, ALK, ROS1, BRAF, RET, MET, NTRK) was 26,300 (N=26,300). The goal of this study was to measure the cost and value differences when one chose to run a Single Gene Testing (narrow genomics panel), which included interrogation for either EGFR or ALK, versus a broader NGS panel. The potential value of each testing approach was measured based on Life Years Gained (LYG) and the cost per LYG. (Life Years gained is a modified mortality measure where remaining life expectancy is taken into account).

It was noted that a broad NGS approach to test for genetic alterations resulted in additional Life Year Gains with cost savings, compared to Single Gene Testing for EGFR or ALK. This analytical model suggested that at the current 80% testing rate, replacing Single Gene Testing with NGS would result in an additional 21,019 Life Year Gained, with reduced cost per LYG of $599. Increasing testing from 80% to 100% of eligible patients would further increase the Life Year Gained by 15,017. If 100% of eligible patients were tested with NGS and every identified patient received treatment, the cost per Life Year Gained with this strategy would be $16,641.57.

According to this decision model, the estimated median survival and 5-year survival for a patient who was tested with NGS, followed by a highly effective therapy selected on the basis of that alteration, would be 39 months and 25%, respectively. For a patient who had an Actionable Driver Oncogene that was not identified by Single Gene Testing, the estimated median survival would be 14 months and 5-year survival would be 5%. This analysis suggested that not running broad multigene NGS panel routinely for eligible patients, and only using Single Gene Testing could be a missed opportunity, as actionable mutations would be missed and patients may not get the most effective therapy for their disease.

The authors concluded that based on their decision analytic model, when highly effective therapy is available to all identified patients with Actionable Driver Oncogenes, broad NGS testing, compared to Single Gene Testing for EGFR or ALK, leads to large gains in Life Years, at reduced cost per Life Year Gained, compared to Single Gene Testing. This model supports universal NGS testing of all patients with advanced nonsquamous NSCLC.

A model comparing the value of broad next-gen sequencing (NGS)-based testing to single gene testing (SGT) in patients with nonsquamous non-small cell lung cancer (NSCLC) in the United States. Pennell NA, Zhou J, Hobbs B. J Clin Oncol 38: 2020 (suppl; abstr 9529)

FDA Approves IO in Combination with Targeted Therapies for BRAF Positive Advanced Melanoma

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SUMMARY: The FDA on July 30, 2020, approved TECENTRIQ® (Atezolizumab), in combination with COTELLIC® (Cobimetinib) and ZELBORAF® (Vemurafenib), for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes.BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF, demonstrated significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), compared to Dacarbazine. Squamous cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF® has addressed some of these limitations, in previously published studies, with improvement in Objective Response Rates (ORR) and decrease in the incidence of cutaneous secondary cancers. coBRIM is a multicenter, randomized, Phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. The final analysis of this trial evaluated the 5-year survival data, and the OS was over 30% in patients who received the combination therapy, with a Complete Response (CR) rate was about 20%.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. The 5 year OS among patients receiving PD1 targeted immunotherapy is about 34%, with a median OS of 17-20 months. With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians, based on the long term data supporting the durability of responses with immunotherapies, but response rates are lower. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases, as the response rates are higher but are short lived. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.

Preclinical studies suggested that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses. The safety and efficacy of combining TECENTRIQ® with COTELLIC® (MEK inhibitor) and ZELBORAF® (BRAF inhibitor), in patients with BRAFV600-mutated metastatic melanoma, was evaluated in a Phase I study, with promising results, and a 28-day run-in period with COTELLIC® and ZELBORAF® was associated with an increase in proliferating CD4+ T-helper cells, without increasing the T-regulatory cells (Tregs). Tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response and Tregs remain a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. The aim of IMspire 150 trial was to determine if combining checkpoint inhibitor with two targeted therapies would improve efficacy.

IMspire150 is a pivotal, placebo-controlled, international, multicenter, double-blinded, Phase III trial, in which 514 treatment-naive patients with Stage IIIc and Stage IV, BRAF V600–mutant malignant melanoma were enrolled. Patients were randomly assigned 1:1 to treatment with the doublet combination or the triplet therapy. Doublet therapy given to the control group of patients consisted of ZELBORAF® 960 mg orally twice daily plus COTELLIC® at 60 mg orally, on days 1 to 21 of a 28 day cycle. In the experimental or triplet therapy group, there was a 28-day run-in with ZELBORAF® plus COTELLIC® alone, dosed similar to the control group (cycle 1), following which patients received TECENTRIQ® 840 mg IV on Days 1 and 15 of each 28 day cycle starting cycle 2, in combination with ZELBORAF® at a lower dose of 720 mg orally twice daily and COTELLIC® 60 mg orally once daily. Treatment was continued until disease progression, or unacceptable toxicity. Both treatment groups were well balanced, median patient age was 54 years, 58% were male and 94% of patients had Stage IV disease. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary end points included Objective Response Rates (ORR), Duration of Response (DOR), and Overall Survival (OS).

The combination of immunotherapy with targeted therapies was significantly superior to targeted therapies alone. At a median follow up of 18.9 months, the median PFS with the triplet combination was 15.1 months versus 10.6 months with the doublet therapy (HR=0.78; P=0.025). This represented a 22% reduction in the risk of disease progression. This benefit was observed across all subgroups including age, disease burden, LDH level, and extent of tumor involvement by organ site. Although Objective Response Rates were similar in both treatment groups, the median Duration of Response was 21.0 months with triplet combination versus 12.6 months for the doublet therapy. The OS data were not mature at the time of this analysis, but interim analysis however showed a median OS of 28.8 months with the triplet combination versus 25.1 months with doublet therapy. Both treatment groups had comparable toxicities. Among those patients receiving triplet combination, the most common toxicities were rash, fever, fatigue, nausea, pruritus, stomatitis, musculoskeletal pain, hepatotoxicity, edema, hypothyroidism, and photosensitivity.

It was concluded that in treatment-naive patients with advanced BRAF V600-mutant malignant melanoma, TECENTRIQ® in combination with ZELBORAF® and COTELLIC® significantly and clinically improved Progression Free Survival, when compared to placebo in combination with ZELBORAF® and COTELLIC®.

Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. McArthur GA, Stroyakovskiy D, Gogas H, et al. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.