Category: Hem/Onc Updates

Late Breaking Abstract – ESMO 2018 Targeting PIK3CA Mutations Improves Outcomes in Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients.

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2 negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer.Alpelisib - Mechanism-of-Action

Alpelisib is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to Alpelisib than those without the mutation, across a broad range of tumor types. SOLAR-1 clinical trial was conducted to test this hypothesis.

SOLAR-1 is a global, double-blind, placebo-controlled, randomized phase III trial, which studied the benefit of Alpelisib in combination with FASLODEX® (Fulvestrant) among postmenopausal women and men with PIK3CA-mutated HR+/HER2 negative advanced or metastatic breast cancer, who had progressed on or following prior Aromatase Inhibitor treatment with or without a Cyclin-Dependent Kinase (CDK) 4/6 inhibitor. In this study, 572 patients were randomized in a 1:1 ratio to receive Alpelisib 300 mg orally daily or placebo once daily, in combination with FASLODEX® 500mg IM on days 1 and 15 of the first cycle and day 1 of each subsequent 28-day cycle. Patients were stratified based on visceral metastases and prior CDK4/6 inhibitor treatment. A total of 341 patients had PIK3CA mutations upon testing of the tumor tissue with 169 patients receiving the Alpelisib combination and 172 patients receiving FASLODEX® alone. Enrolled patients had received one or more prior lines of hormonal therapy, but no chemotherapy for advanced breast cancer. They had not previously received FASLODEX® or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy. Approximately half of the patients in each treatment group had lung or liver metastases and 6% had received prior CDK4/6 inhibitor therapy. The Primary endpoint was Progression Free Survival (PFS) for patients with the PIK3CA mutation. Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Clinical Benefit Rate, Health-Related Quality of Life, Efficacy in PIK3CA non-mutant cohort, Safety and Tolerability.

The Primary endpoint was met and at a median follow up of 20 months, the PFS was nearly twice as long in patients with PIK3CA mutations randomized to Alpelisib plus FASLODEX® compared to the placebo plus FASLODEX® group. The median PFS was 11.0 months in the Alpelisib group compared to 5.7 months in the placebo group (HR=0.65; P=0.00065). In patients with measurable, PIK3CA-mutated advanced breast cancer (N=262), the Overall Response Rate was 36% for the Alpelisib plus FASLODEX® group versus 16% for placebo plus FASLODEX® group (P=0.0002). There was no significant PFS benefit noted in the PIK3CA-nonmutant patient group receiving Alpelisib plus FASLODEX®. The most frequent toxicities with Alpelisib were hyperglycemia which could be managed with Metformin, nausea, decreased appetite and rash.

It was concluded that Alpelisib given along with FASLODEX® significantly improved Progression Free Survival compared to Placebo plus FASLODEX®, with manageable toxicities. The authors commented that this is the first study to show statistically significant, clinically meaningful PFS improvement with an alpha-specific PI3K inhibitor in PIK3CA-mutated HR+, HER2 negative advanced breast cancer, highlighting the importance of clinical genomics in advanced breast cancer. It however remains unclear whether Alpelisib should be incorporated into the current treatment paradigm upfront, along with endocrine therapy and a CDK 4/6 inhibitor, or sequentially following disease progression on a combination of endocrine therapy and a CDK 4/6 inhibitor. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. André F, Ciruelos EM, Rubovszky G, et al. Presented during the Presidential Symposium 1 at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3_PR.

Late Breaking Abstract – ASH 2018 IMBRUVICA® and RITUXAN® Combination Superior to FCR in Younger Patients with CLL

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SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies. Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab (FCR) has long been the gold standard and the most commonly used treatment regimen for younger, fit, treatment naïve patients with chronic lymphocytic leukemia. This is based on phase III trial data showing improvement in both Progression Free Survival (PFS) and Overall Survival (OS) compared with chemotherapy alone. FCR regimen however is associated with significant toxicities and cannot be tolerated by all CLL patients. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® in phase III trials showed improved PFS and OS when compared to Chlorambucil in previously untreated, elderly patients with CLL. Nonetheless, the efficacy of IMBRUVICA® as a first-line treatment for younger CLL patients (70 years or younger), compared to the most efficacious regimen such as FCR, is unknown.BCR-Signal-Pathways

E1912, led by the ECOG-ACRIN Research Group (ECOG-ACRIN), is a randomized phase III study in which IMBRUVICA® (Ibrutinib) plus RITUXAN® (Rituximab) was compared to Fludarabine, Cyclophosphamide, and RITUXAN® (FCR) chemotherapy regimen, in previously untreated patients aged 70 years or younger with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). In this trial, 529 patients were randomly assigned in a 2:1 ratio to receive IMBRUVICA® 420 mg orally daily until disease progression along with RITUXAN® 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, 500 mg/m2 on day 1 of cycles 3-7 (N=354) or six courses of Fludarabine 25 mg/m2 IV along with Cyclophosphamide 250 mg/m2 IV days 1-3 and RITUXAN® 50 mg/m2 IV on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, 500 mg/m2 on day 1 of cycles 2-6, given every 28 days (N=175). The median age was 58 years and 40% of the patients were 60 years of age or older. The Primary endpoint was Progression Free Survival (PFS) and the Secondary endpoint was Overall Survival (OS).

With a median follow up of 33.4 months, at the first interim analysis, IMBRUVICA® plus RITUXAN® significantly improved PFS compared to FCR (HR=0.35; P<0.0001), with a 65% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN® compared with FCR. The combination of IMBRUVICA® plus RITUXAN® also demonstrated improved OS (HR=0.17; P=0.0003) and this suggested that IMBRUVICA® plus RITUXAN® combination reduced the risk of death by 83% compared with FCR. In a subgroup analysis, the PFS benefit with IMBRUVICA® plus RITUXAN® was seen independent of age, sex, Performance Status (0-2), disease stage, as well as presence or absence of cytogenetic abnormality, deletion 11q23. At the time of this analysis, IMBRUVICA® plus RITUXAN® was also superior to FCR among IGHV unmutated patients (HR=0.26; P<0.0001), suggesting a 74% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN®, compared to FCR. A statistically significant benefit however was not observed among those with IGHV mutations, although there was a positive trend noted (HR=0.44; P=0.07). Treatment-related Grade 3 and 4 toxicities were significantly lower with IMBRUVICA® compared with FCR (58% versus 72%, respectively; P=0.004). FCR was more frequently associated with Grade 3 and 4 neutropenia (44% versus 23%) as well as infectious complications (18% versus 7%).

It was concluded that a combination of IMBRUVICA® and RITUXAN®, significantly improved PFS and OS, when compared to FCR, with fewer toxicities, among patients 70 years of age or under, with previously untreated CLL. The authors noted that these findings have immediate practice changing implications and establish IMBRUVICA® – based therapy as the most effective first-line therapy for untreated patients with CLL. Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912. Shanafelt TD, Wang V, Kay NE, et al. Presented at the 2018 ASH Annual Meeting. December 1-4, 2018; San Diego. Abstract LBA-4.

STIVARGA® Dose Optimization Improves Outcomes in Patients with Metastatic Colorectal Cancer

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. STIVARGA® (Regorafenib), is an oral multi-kinase inhibitor and inhibits multiple kinases including VEGF1, VEGF2, VEGF3, PDGFR, FGFR involved in tumor angiogenesis and KIT, RET, RAF-1, BRAF involved in oncogenesis. STIVARGA® is approved by the FDA for the treatment of patients with metastatic CRC, who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti-VEGF and anti-EGFR therapies, at a dose of 160 mg orally, once daily for the first 21 days of each 28-day cycle. The approval was based on a phase III trial in which patients receiving STIVARGA® had a statistically significant improvement in the Overall Survival (OS) and Progression Free Survival (PFS), compared to placebo.

The starting dose of STIVARGA® has been an obstacle and toxicities such as Palmar-Plantar Erythrodysesthesia Syndrome (PPES) commonly occurring during the first 2 weeks, as well as fatigue and hypertension have limited its use. Various dosing schedules have been implemented into clinical practice, despite the absence of reliable supportive data. There is therefore a need to optimize the dose of STIVARGA® in patients with refractory mCRC to maintain efficacy, while improving the tolerability profile. CORRELATE study looked at the data from the real-world setting of refractory mCRC regarding the dosing of STIVARGA® and safety, whereas the ReDos study evaluated a dose-escalation strategy, starting with a lower dose of STIVARGA®.

CORRELATE is a prospective, international observational study conducted in 13 countries to evaluate the use STIVARGA® in a real-world setting, based on safety and efficacy. The primary objective of this study was to assess safety. This final analysis describes the real-world dosing of STIVARGA® in mCRC.

Of the 1037 patients included in this study, 57% started treatment at 160 mg, 30% at 120 mg, and 13% at 80 mg or less. The mean dose administered was 75% of the approved dose. The median patient age was 65 years and majority of the patients had an ECOG performance status (PS) of 0-1 (87%). Dose reductions were more frequent in the 160 versus 120 mg group and treatment modifications were most commonly due to treatment related adverse events (66%). Most treatment discontinuations (49%) were due to radiologic disease progression, whereas 19% were due to STIVARGA® related adverse events. Treatment related adverse events of any grade occurred in 95% of patients, and 80% were attributed to STIVARGA®. Median overall survival (OS) was 7.6 months and the estimated 1-year OS was 34%.

It was concluded from this real-world, observational study that the starting dose of STIVARGA® for nearly half of patients was less than 160 mg/day and the common treatment related adverse events were generally consistent with the known safety profile of STIVARGA® in mCRC. Despite the dose modifications of STIVARGA®, there was no significant impact on its efficacy in terms of the median OS and median PFS.

ReDOS is a randomized phase II study in which STIVARGA® dose-escalation strategy beginning at a lower starting dose of 80 mg daily and ending at 160 mg daily was compared with the standard dose, in patients with refractory mCRC. In this dose escalation study, patients in Arm A (N=54) received STIVARGA® 80 mg daily, with weekly dose escalation up to 160 mg daily, if no significant drug-related toxicities were experienced, where as in Arm B (N=62), patients received the standard dose of STIVARGA® 160 mg daily, for 21 days of a 28-day cycle. The median age was 61 years and both treatment groups were well balanced. The Primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd cycle if there was no progression.

The study met its primary endpoint with 43% of patients on Arm A initiating the 3rd cycle versus only 25% of patients on Arm B (P=0.028). The median Overall Survival (OS) was improved in Arm A versus Arm B (9 months versus 5.9 months ; P=0.094). The median Progression Free Survival (PFS) was 2.5 months for Arm A and 2 months for Arm B (P=0.55). Overall grade 3 and 4 toxicities were lower on Arm A versus Arm B and multiple Quality Of Life parameters were improved in Arm A versus Arm B, at week 2 of the first cycle.

It was concluded that weekly dose escalation of STIVARGA® from 80 mg to 160 mg daily was superior to a starting dose of 160 mg daily. Based on this study, the NCCN has updated its ColoRectal Cancer (CRC) guidelines, recommending a weekly STIVARGA® dose-escalation strategy beginning at 80 mg and ending at 160 mg, for previously treated patients with metastatic ColoRectal Cancer.

Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study. O'Connor JM, Ducreux M, Petersen LN, et al. Ann Oncol. 2018;29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)-an ACCRU Network study. Bekaii-Saab TS, Ou FS, Anderson DM, et al. J Clin Oncol. 2018;36(suppl 4S; abstr 611)

Baseline Corticosteroid Use at Start of PD-1/PD-L1 Inhibitor Therapy Negatively Affects Outcomes in 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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 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. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced Non Small Cell Lung Cancer (NSCLC). It is now standard therapy for patients with lung cancer. Immuno-Oncology therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response.

Patients with NSCLC often are treated with corticosteroids for a variety of reasons including fatigue, dyspnea, decreased appetite, and symptomatic brain metastases. Corticosteroids by virtue of their immunosuppressive properties can potentially effect on T-cell function and for this reason, use of these agents before the start of therapy with PD-(L)1 blockade has been a uniform exclusion criterion in clinical trials of Immune Checkpoint Blockade therapies. It is however becoming increasing clear that corticosteroids use for the management of immune-related adverse events do not seem to negatively impact outcomes. Nonetheless, there are presently no data regarding the impact of corticosteroid use at baseline, on the efficacy of Immune Checkpoint Inhibitors. In this publication, the authors evaluated the potential impact of systemic corticosteroids at the start of Immune Checkpoint Blockade, on the efficacy of PD-(L)1 inhibitors.

The authors in this study identified patients with advanced NSCLC who were treated with single-agent PD-(L)1 inhibitor (Pembrolizumab, Nivolumab, Atezolizumab, or Durvalumab) from two institutions – Memorial Sloan Kettering Cancer Center (N=455) and Gustave Roussy Cancer Center (N=185), between April 2011 to September 2017. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. Information on the use of corticosteroids within 30 days of the start of PD-(L)1 blockade, type of corticosteroid used, indication and route of administration were collected for the MSKCC cohort. Patient characteristics, including age, gender, histology, ECOG Performance Status, and smoking history were collected for all patients. Efficacy outcomes following treatment with PD-(L)1 inhibitors blockade was determined by local radiologists and all patients were followed up until death or data lock.

It was noted that 14% (N=90) of the 640 patients treated with single-agent PD-(L)1 inhibitor received 10 mg or more of prednisone daily at the start of the treatment with a PD-(L)1 inhibitor. The most common indications for treatment with corticosteroids were dyspnea or other respiratory symptoms (33%), fatigue (21%), and brain metastases (19%). Patient characteristics were well balanced between those who did or did not receive corticosteroids, with two exceptions – patients with poor performance status and history of brain metastases were more common in those who received corticosteroids.

In the pooled cohort of patients from both participating institutions, patients receiving baseline corticosteroids compared with patients not receiving corticosteroids experienced a lower Objective Response Rate (7% versus 18%) and worse Progression Free Survival and Overall Survival (P<0.001). The authors performed a multivariable analysis in the pooled cohort (N = 640), incorporating smoking history, performance status, history of brain metastases, and corticosteroid use (Prednisone 10 mg or more versus less than 10 mg), at the start of PD-(L)1 blockade. Prednisone use 10 mg or more was associated with worse Progression Free Survival (P=0.03) and Overall Survival (P<0.001). In the Memorial Sloan Kettering Center cohort of patients, (data unavailable for the Gustave Roussy Cancer Center cohort), patients who discontinued corticosteroids 1-30 days before starting PD-(L)1 blockade had intermediate Progression Free Survival and Overall Survival compared to those who received corticosteroids on the day of PD-(L)1 blockade initiation and those who received no corticosteroids within 30 days of the start of therapy.

The authors concluded that among patients with Non Small Cell Lung Cancer treated with PD-(L)1 blockade, baseline corticosteroid use of 10 mg or more of prednisone equivalent was associated with inferior outcomes. Clinicians should exercise caution and minimize the use, duration, and dose of corticosteroids if immunotherapy with PD-(L)1 blockade is a future consideration. Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer. Arbour KC, Mezquita L, Long N, et al. J Clin Oncol. 2018;36:2872-2878

Radiotherapy plus ERBITUX® Inferior to Radiotherapy plus Cisplatin in HPV-Positive Oropharyngeal Squamous Cell Carcinoma

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SUMMARY: The Centers for Disease Control and Prevention estimates that in the US, there are more than 16,000 cases of Human PapillomaVirus (HPV)-positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) per year and there has been a significant increase in incidence during the past several decades, due to changes in sexual practices. They represent approximately 70% of all OPSCC in the United States and Canada. HPV-positive oropharyngeal squamous cell carcinoma is an entirely distinct disease entity from HPV-negative oropharyngeal squamous cell carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.Parts-of-the-Oropharynx

HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. Patients deemed unable to tolerate Cisplatin chemotherapy such as the elderly, and those with poor kidney function, receive ERBITUX® (Cetuximab), an Epidermal Growth Factor Receptor (EGFR) inhibitor with radiotherapy.

ERBITUX® is an EGFR targeted monoclonal antibody and the goal of this present study was to find an alternative to Cisplatin, and this study was designed to see if ERBITUX® with radiation would be less toxic than Cisplatin with radiation, without compromising survival among HPV-positive OPSCC patient population. RTOG 1016 is a randomized, multicentre, non-inferiority, phase III trial which included patients with Human PapillomaVirus (HPV)-positive Oropharyngeal Squamous Cell Carcinoma. This study enrolled 987 patients (N=987) at 182 centers in the US and Canada and enrollees had histologically confirmed HPV-positive Oropharyngeal carcinoma and clinical categories included T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0 groups. Patients were randomly assigned in a 1:1 ratio to receive either radiotherapy plus ERBITUX®, or radiotherapy plus Cisplatin. Treatment groups were well balanced and were stratified by T (T1–T2 vs T3–T4), N category (N0-N2a vs N2b-N3), and smoking history (10 pack-years or less vs more than 10 pack-years). Patients were randomized to receive either ERBITUX® at a loading dose of 400 mg/m2 IV 5-7 days before radiotherapy initiation, followed by ERBITUX® 250 mg/m2 IV weekly for seven doses (N=425) or Cisplatin 100 mg/m 2 on days 1 and 22 of radiotherapy (N=424). All patients received accelerated Intensity-Modulated RadioTherapy (IMRT) delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 hours apart). The Primary endpoint was Overall Survival.

The third and final interim analysis was done after a median follow-up of 4.5 years. Radiotherapy plus ERBITUX® did not meet the non-inferiority criteria for Overall Survival and the estimated 5-year Overall Survival was 77.9% in the ERBITUX® group versus 84.6% in the Cisplatin group, suggesting that the Overall Survival on the ERBITUX® arm was significantly inferior to the Cisplatin arm. Progression Free Survival (PFS) was also significantly lower in the ERBITUX® group compared with the Cisplatin group, with a 5-year PFS of 67.3% versus 78.4%, respectively. Five year locoregional failure rates were significantly higher in the ERBITUX® group compared with the Cisplatin group (17.3% versus 9.9%, respectively. Serious (grade 3-5) adverse events were similar for patients in both treatment groups and as expected, toxicities were different, with adverse events of renal toxicity, hearing loss, and bone marrow suppression more common in patients in the Cisplatin group, where as body rash was more common in the ERBITUX® group. All patients in this study were able to complete therapy at the time of this analysis.

It was concluded that this trial is the first randomized clinical trial specifically designed for patients with HPV-positive Oropharyngeal cancer, and among this patient group, radiotherapy plus ERBITUX® showed inferior Overall Survival and Progression Free Survival compared with radiotherapy plus Cisplatin. Radiotherapy plus Cisplatin should therefore be the standard of care for eligible patients with HPV-positive Oropharyngeal carcinoma. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Gillison ML, Trotti AM, Harris J, et al. Published:November 15, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)32779-X

Late Breaking Abstract – ASH 2018 Frontline DARZALEX® with REVLIMID® and Dexamethasone – A New Standard for Transplant-Ineligible Myeloma Patients

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 30,770 new cases will be diagnosed in 2018 and 12,770 patients are expected to die of the disease. Multiple Myeloma (MM) in 2018 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). REVLIMID® (Lenalidomide) based regimens are often prescribed for patients with newly diagnosed, transplant-ineligible Multiple Myeloma. REVLIMID®, a thalidomide analogue has immunomodulatory, tumoricidal, and antiangiogenic properties, and synergizes with Dexamethasone to enhance anti-myeloma activity. DARZALEX® (Daratumumab) is a human IgG1 monoclonal antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.Mechanism-of-Action-of-Daratumumab

The FDA in May, 2018 approved DARZALEX® in combination with VELCADE® (Bortezomib), a proteasome inhibitor, Melphalan, an alkylating agent and Prednisone (VMP regimen), for the treatment of patients with newly diagnosed Multiple Myeloma who are ineligible for Autologous Stem Cell Transplant (ASCT). VMP regimen however is mostly utilized in Europe and not in the US. In the POLLUX trial, addition of DARZALEX® to REVLIMID® and Dexamathasone (D-Rd) showed the greatest benefit, with a 63% reduction in risk of disease progression or death (HR=0.37; P<0.001) in patients with Multiple Myeloma who had at least one prior line of therapy, compared to REVLIMID® and Dexamathasone (Rd) . Based on the efficacy and tolerable safety profile of D-Rd, the authors conducted a phase III study (MAIA), comparing D-Rd to Rd in transplant-ineligible newly diagnosed Multiple Myeloma patients and reported the prespecified interim analysis of the study.

The MAIA study is a multicenter, international, open-label, phase III trial, which included 737 newly diagnosed Myeloma patients who were not candidates for high-dose chemotherapy and Autologous Stem Cell Transplant (ASCT), due to age 65 years or older or comorbidities. Patients were randomly assigned 1:1 to receive REVLIMID® 25 mg orally on days 1-21 of each 28-day cycle and Dexamethasone 40 mg once a week, with or without DARZALEX®. Patients assigned DARZALEX® (D-Rd regimen) received 16 mg/kg weekly for the first 8 weeks (cycles 1 and 2), every other week for 16 weeks (cycles 3 to 6), and then every 4 weeks (cycle 7 and beyond) until disease progression or unacceptable toxicity. Treatment groups were well balanced. The median patient age was 73 years and only 1% of patients were 65 years of age or less whereas 44% of patients were 75 years or older. Cytogenetic risk level could be determined in 642 patients of the total population. Eighty-six percent (86%) of these patients were standard risk and 14% were considered high risk. The Primary end point was Progression Free Survival (PFS). Key Secondary endpoints included Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity rate (10-5 sensitivity), and Safety.

The prespecified interim analysis occurred with a median follow up of 28 months. DARZALEX® regimen significantly improved PFS with the median PFS not reached with D-Rd compared with 31.9 months in the Rd group (HR=0.55; P<0.0001). This represented a 45% reduction in the risk of progression or death in patients treated with D-Rd. D-Rd also resulted in deeper responses with a Complete Response (CR) or better rate of 47.6% in the D-Rd group compared with 24.7% in the Rd group (P<0.0001). The Very Good Partial Response (VGPR) or better rate was 79.3% in the D-Rd arm compared with 53.1% in the Rd arm (P<0.0001). The MRD-negative rate was more than threefold higher with D-Rd versus Rd at 24% versus 7%, respectively. Higher rates of neutropenia, and leukopenia were observed in the D-Rd arm and the safety profile was consistent with previously reported DARZALEX® studies.

The authors concluded that the addition of DARZALEX®, to REVLIMID® and Dexamethasone significantly reduced the risk of progression or death by 45% in newly diagnosed Multiple Myeloma patients who are transplant-ineligible and these results support D-Rd as a new standard of care for this patient group. Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA). Facon T, Kumar SK, Plesner T, et al. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract LBA-2.

Axillary Radiotherapy is an Alternative to Complete Lymph Node Dissection in Early-Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Axillary lymph node evaluation is an important part of breast cancer staging and the presence of axillary lymph metastases decreases the 5-year survival rate by 28-40%. Axillary lymph node status remains the most powerful predictor of breast cancer recurrence and survival. Axillary Lymph Node Dissection (ALND) was first advocated in the 18th century as part of the treatment of invasive breast cancer and has been standard practice until 2 decades back. ALND can be associated with significant morbidities such as upper limb lymphedema, pain, and sensitivity disorders and this can have a major psychological impact on breast cancer patients. Sentinel Lymph Node Biopsy (SLNB) which was introduced into clinical practice in the mid 1990’s, however has now become the standard for Stage I and II breast cancer. The sentinel node is the first lymph node(s) to which cancer cells are most likely to metastasize from a primary tumor. With the introduction of intraoperative lymphatic mapping in the 1990s, Sentinel Lymph Node Biopsy (SLNB) has now gained general acceptance and if the sentinel node is negative for metastatic disease or only has minimal disease, then no further axillary surgery is indicated. Unlike Axillary Lymph Node Dissection (ALND), SLNB is associated with a lower incidence of lymphedema/ seroma at the surgery site, paresthesias and restriction of joint movement. Nine randomized clinical trials have not shown any difference in mortality among patients who underwent ALND or SLNB for either lymph node metastases or negative sentinel lymph nodes, validating Sentinel Lymph Node Biopsy (SLNB). The American Society of Clinical Oncology (ASCO) first published guidelines on the use of SLNB for patients with early stage breast cancer in 2005, based on one randomized clinical trial. Since then, ASCO updated Clinical Practice Guideline based on additional information from 9 randomized clinical trials and13 cohort studies pertinent to SLNB and ALND.

Patients with T1-2 tumors with positive Sentinel Lymph Node Biopsy usually undergo complete ALND and there is increasing controversy about whether ALND is always necessary. AMAROS is a multicenter, randomized phase III trial, sponsored by the European Organisation for Research and Treatment of Cancer (EORTC), in which the effectiveness of complete Axillary Lymph Node Dissection (ALND) was compared with axillary Radiation Therapy (RT), in patients with invasive breast cancer. The rationale was that Radiation Therapy uses high-energy x-rays to damage tumor cells and may be a less invasive treatment and causes fewer side effects than complete ALND. This study was conducted to evaluate whether axillary RT could yield comparable outcomes to ALND with fewer adverse side effects, in this patient population. This trial enrolled 4806 patients with early-stage, clinically node-negative breast cancer of whom 1425 patients had a positive sentinel lymph node biopsy. Of these patients, 744 were randomly assigned to undergo complete ALND, whereas 681 patients received axillary RT. Both treatment groups were well balanced. The first 5-year follow up data published in 2013 showed that upper extremity lymphedema occurred significantly less often in those who received Radiotherapy compared with those who underwent complete ALND, and recent Quality of life and morbidity data supported these earlier findings.

The authors herein presented the 10 year follow up data of the AMAROS trial. It was noted that at 10 years, 1.82% of patients assigned to axillary RT had an axillary recurrence compared with 0.93% of those assigned to complete ALND, and this suggested that there was no significant difference (P=0.36). Further, there was no significant difference in the distant metastasis–free survival or Overall Survival between the two treatment groups. The distant metastasis–free survival was 78.2% among those assigned to axillary RT and 81.7% among those assigned to complete ALND and Overall Survival in the two treatment groups was 81.4% and 84.6%, respectively. It was noted that there was a higher 10-year cumulative incidence of second primaries among patients assigned to axillary RT compared with those assigned to complete Axillary Lymph Node Dissection (12% versus 8.3%). It remains unclear whether the addition of the radiation will increase the risk of second primary cancers.

It was concluded that axillary Radiotherapy is noninferior to complete Axillary Lymph Node Dissection in terms of locoregional control and this trial suggests that some patients with a positive sentinel lymph node biopsy may be appropriate candidates for axillary Radiotherapy. Rutgers, E. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10-year results of the EORTC AMAROS trial. Presented at the 2018 San Antonio Breast Cancer Symposium; December 4-8; San Antonio, Texas.(Abstract GS4-01)

Adjuvant KADCYLA® Superior to HERCEPTIN® in High Risk HER2-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.Mechanism-of-Action - KADCYLA

The present study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy. These high risk patients have an unfavorable prognosis, compared to those who have no residual cancer following neoadjuvant therapy. The KATHERINE trial is an open-label, phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®.

This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and hormone receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The median duration of follow up was 41.4 months in the KADCYLA® group and 40.9 months in the HERCEPTIN® group.

At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group. Invasive Disease Free Survival which was the Primary end point of the study was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001). This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%. Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the KADCYLA® group and in 15.9% of the HERCEPTIN® group. A consistent benefit was seen across all prespecified subgroups. Adverse events were consistent with the known safety profile of KADCYLA®, with more toxicities associated with KADCYLA® than with HERCEPTIN®. Additional follow-up will be necessary to determine the Overall Survival benefit with adjuvant KADCYLA®.

It was concluded that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, substituting KADCYLA® for adjuvant HERCEPTIN® reduced the risk of recurrence of invasive breast cancer or death was 50%, with the benefit seen across all patient subgroups. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. (published online December 5, 2018). New Engl Jour Med. doi: 10.1056/NEJMoa1814017

TECENTRIQ® in Combination with Chemotherapy Improves Overall Survival in Extensive Stage 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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Patients with extensive stage SCLC are often treated with a combination of Carboplatin or Cisplatin with Etoposide as first line treatment and the tumor response rates are as high as 60-80%. However, majority of the patients relapse within months of completing initial therapy, with a median Overall Survival of approximately 10 months. Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic and could respond to immune-checkpoint inhibitors. This hypothesis was subsequently confirmed in patients with refractory or metastatic SCLC.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody that directly binds to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells and blocks the interaction of PD-L1 with PD-1 and B7.1 receptors and thereby enables the activation of T cells and restores tumor-specific T-cell immunity. In a phase I trial, TECENTRIQ® monotherapy demonstrated durable responses, with an acceptable safety profile in patients with relapsed or refractory SCLC. The authors in this study combined checkpoint inhibition with cytotoxic chemotherapy for synergy and improved efficacy. Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The IMpower133 trial is a multinational, randomized, double-blind, placebo-controlled phase III trial which evaluated the benefit of TECENTRIQ® plus Carboplatin and Etoposide in chemo naïve patients with extensive-stage Small-Cell Lung Cancer. Enrolled patients were randomized in a 1:1 ratio and the induction phase consisted of four cycles of Carboplatin AUC 5 mg/ml/min IV on day 1 and Etoposide 100 mg/m2 IV on days 1-3 of each 21-day cycle, with either TECENTRIQ® 1200 mg IV day 1 of each cycle (N=201) or placebo (N=202). The induction phase was followed by a maintenance phase during which patients received either TECENTRIQ® or placebo (based on previous random assignment) and treatment was continued until disease progression or unacceptable toxicities. The median age was 64 yrs and PD-L1 testing was not a requirement. Prophylactic cranial irradiation was permitted during the maintenance phase of treatment but thoracic radiation therapy was not permitted. The Primary end points were Overall Survival (OS) and Progression Free Survival and Secondary end points included Objective Response Rate (ORR) and Duration of Response.

At a median follow up of 13.9 months, the median OS was 12.3 months in the TECENTRIQ® group compared to 10.3 months in the placebo group (HR=0.70; P=0.007). This suggested a 30% reduction in the risk of death when TECENTRIQ® was added to chemotherapy. The 1-year OS rate was 51.7% in the TECENTRIQ® group and 38.2% in the placebo group. The median Progression Free Survival was also longer in the TECENTRIQ® group than in the placebo group (5.2 months versus 4.3 months, HR=0.77; P=0.02). Survival benefits were consistently seen across patient subgroups. The safety profile of TECENTRIQ® plus Carboplatin and Etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed in this trial.

It was concluded that in this multinational trial, the addition of TECENTRIQ® to chemotherapy in the first line treatment of extensive stage Small-Cell Lung Cancer resulted in significantly longer Overall Survival and Progression Free Survival, when compared to chemotherapy alone. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. Horn L, Mansfield AS, SzczÄ™sna A, et al. for the IMpower133 Study Group. N Engl J Med 2018; 379:2220-2229

FDA Approves VITRAKVI®, A Novel Tumor Agnostic Therapy for TRK Fusion-Positive Cancers

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SUMMARY: The FDA on November 26, 2018, granted accelerated approval to VITRAKVI® (Larotrectinib) for adult and pediatric patients with solid tumors that have a NeuroTrophic Receptor tyrosine Kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. This is the second tissue-agnostic FDA approval for the treatment of cancer. Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. The FDA in May 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) solid tumors. This was the first FDA approval of a systemic cancer treatment, based on a specific genetic biomarker, independent of tumor origin (first tissue/site-agnostic approval).

A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”). ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug. 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. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors. Next-generation sequencing has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRKA, TRKB, and TRKC are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies but in more than 90% of certain rare tumor types, such as salivary gland tumors, a form of juvenile breast cancer, and infantile fibrosarcoma.Tropomyosin-Receptor-Kinase-Signaling-Pathway

The approval of VITRAKVI®, a potent and highly selective, oral, small molecule inhibitor of all three TRK proteins was based on data from three multicenter, open-label, single-arm clinical trials – LOXO-TRK-14001, a phase I study involving adults, SCOUT, a phase I-II study involving children and NAVIGATE, a phase II study involving adolescents and adults. The authors in this development program included patients of any age and with any tumor type who had chromosomal fusion involving NTRK genes (Age and Tumor agnostic therapy). Positive NTRK gene fusion status was prospectively determined in local laboratories using NGS or Fluorescence In Situ Hybridization (FISH). Treatment efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The Primary end point for the combined analysis was the Overall Response Rate (ORR) according to Independent review. Secondary end points included Duration of Response, Progression Free Survival, and safety.

The ORR was 75%, including 22% Complete Responses and 53% Partial Responses. At the time of database lock, median Duration of Response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. The safety of VITRAKVI® was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (20% or more) with VITRAKVI® were fatigue, nausea, vomiting and abnormal liver function studies. None of the patients on VITRAKVI® discontinued therapy, due to a drug-related adverse event.

It was concluded that TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults and VITRAKVI® had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of age of the patient or tumor type. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. Drilon A, Laetsch TW, Kummar S, et al. N Engl J Med 2018; 378:731-739