Early Adjuvant Chemotherapy Dose Reductions Can Impact Breast Cancer Survival

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 invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Patients with early stage breast cancer often receive adjuvant chemotherapy and this is even more so true for HER positive and triple negative (ER, PR and HER negative) breast cancer patients, who are at an increased risk to develop recurrent disease. Meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has shown a 20-25% relative risk reduction in breast cancer mortality with first-generation adjuvant chemotherapy regimens such as CMF (Cyclophosphamide/Methotrexate/Fluorouracil) and additional survival benefit with the Anthracyclines and Taxane based regimens.

Chemotherapy dose reductions are often considered for patients with obesity, BSA of more than 2.0 m2, age over 65 years, comorbidities such as kidney disease or diabetes, and febrile neutropenia. ASCO guidelines recommend full weight-based chemotherapy doses in the treatment of obese patients. Dose reductions to less than 85% of the optimal (total cumulative) chemotherapy dose (mg/m2) and cycle delay have shown inferior survival outcomes in both prospective and some retrospective studies. However, it is unclear if dose reductions made for third-generation Anthracycline/Taxane-based regimens as well as sequential regimens such as Taxanes following Anthracycline based regimens, has an impact on survival.

The authors therefore performed a retrospective analysis to evaluate the effect of Total Cumulative Dose (TCD) of adjuvant chemotherapy, on breast cancer outcomes, in women diagnosed with Stage I-III, Hormone Receptor positive or negative, HER2-negative breast cancer, treated with adjuvant FEC (5-FU 500 mg/m2, Epirubicin 100 mg/m2, Cyclophosphamide 500 mg/m2) for 3 cycles followed by Docetaxel 100 mg/m2 for 3 cycles (FEC-D chemotherapy regimen) from 2007 through 2014. Using the historical cutoff of 85% as the optimal Total Cumulative Dose (TCD), this study focused on data from the Alberta Cancer Registry on 1,302 women with Stage I to III breast cancer.

The TCD for cycles 1-6 of less than 85% or 85% and more was calculated. The majority of patients (84%) received 85% or more of the TCD across all six cycles. Sixteen percent (16%) received reduced doses (less than 85% of TCD). Those receiving a TCD of 85% or more were more likely to be younger (median age of 54 yrs) and premenopausal, with a lower number of comorbidities, compared with those with a TCD of less than 85%. The average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy, to explore the effects of early (FEC) versus late (Docetaxel only) dose reduction. The median follow up was 60 months.

It was noted that the amount of chemotherapy delivered had a significant impact on survival. Patients receiving a TCD of 85% or more had a 5-year Disease Free Survival (DFS) of 85.9% versus 79.2% for those receiving a lower TCD (P=0.025). The 5-year Overall Survival (OS) was also superior at 88.8% versus 80.7% (P<0.001), respectively. When the researchers split the lower TCD group into two cohorts based on dose reduction during cycles 1-3 versus cycles 4-6, they found that outcomes were not compromised when dose reduction occurred only during the later cycles (which were the only cycles to include Docetaxel), suggesting that late dose reductions in chemotherapy may not have as much of an impact on DFS and OS, compared with early dose reductions. The authors hypothesized that majority of cancer cells that are sensitive to chemotherapy are eradicated during the first few treatments, rather than in the later treatments. Further, the amount of Docetaxel that was prescribed in the last three cycles may be higher than needed for the FEC-D regimen. Menopausal status, use of G-CSF and dose delay of 14 days or more, were not shown to affect OS.

It was concluded that early dose reductions in adjuvant FEC-D chemotherapy results in inferior outcomes, with adverse affect on DFS and OS. Conversely, late reductions in chemotherapy dose (Docetaxel only) appear to have minimal impact on survival. Based on this data, the authors recommended that Medical Oncologists should strive to deliver full-dose FEC when prescribing adjuvant FEC-D chemotherapy for breast cancer. Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer. Veitch Z, Khan OF, Tilley D, et al. J Natl Compr Canc Netw. 2019;17:957-967.

Late Breaking Abstract – ASTRO 2019 Detectable HPV Circulating Tumor DNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression

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. They represent approximately 70% of all OPSCC in the United States and Canada. HPV is a non-enveloped, double-stranded, DNA virus that infects epithelial cells and majority of the HPV subtypes cause epithelial lesions such as warts or papillomas, which are of low malignant potential. However, there is a subset of high-risk HPV that can cause cancer by integrating its DNA into the host genome, with the resulting expression of two important oncogenes E6 and E7 in the host cell. The E6 oncogene binds and degrades tumor suppressor TP53 via ubiquitin-mediated processes thereby preventing the host cell from engaging in cell cycle checkpoints and enduring an apoptotic response. The E7 oncogene binds to and destabilizes tumor suppressor retinoblastoma (pRb) resulting in transcription of genes involved in proliferation and cell cycle progression. One of the main molecular pathways amplified through E7 is the CDKN2A/p16 gene pathway, which results in the overexpression of p16 protein. E7 also induces cellular proliferation by disrupting the activity of Cyclin Dependent Kinase inhibitors p21 and p27. In essence, HPV infection induces failures in cell cycle checkpoints, resulting in genetic instability and over time, progression of premalignant lesions to invasive Squamous Cell Carcinoma. Unlike tobacco induced HNSCC where TP53 and pRb pathways are nullified due to mutation and epigenetic alterations, in HPV-related HNSCC, wild-type TP53 and pRb are functionally inactivated by the viral oncogenes.

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 infection. The HPV-positive primary Squamous Cell Carcinoma tends to be smaller in size, with early nodal metastases, and HPV status particularly in OroPharyngeal Squamous Cell Carcinoma is an independent prognostic factor for Overall Survival (OS) and Progression Free Survival (PFS). These patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Further, HPV positive patients demonstrate higher Response Rates to chemoradiation as well as an improved Overall Survival. However, approximately 20% of patients diagnosed with HPV-positive OPSCC experience cancer progression within 5 years.

The role of circulating tumor DNA (ctDNA) as a cancer biomarker in the post-operative surveillance of patients with HPV-associated OPSCC has remained unclear. The authors in this study aimed to investigate ctDNA detectability rates by post-op risk category and association with prognosis in this patient population. The researchers prospectively collected and tested serum samples from 29 patients with HPV-associated OPSCC who had not yet undergone treatment, for assay validation. As a control, 7 HPV negative OPSCC patients were included. A cohort of 46 patients with HPV-associated OPSCC who had undergone surgery for the disease had serum samples collected prior to beginning adjuvant therapy. The serum collected from this total group of 82 patients (N=29+7+46) was analyzed in a blinded fashion for E6/E7 HPV ctDNA using ddPCR multiplex assay (HPV 16, 18, 31, 33), and HPV ctDNA detectability was compared statistically across groups. Associations of patient and tumor characteristics with recurrence were assessed and estimates of Progression Free Survival (PFS) and Overall Survival (OS) were made using the Kaplan-Meier (KM) method.

The researchers found that ctDNA was detectable in 27 of 29 patients who had not yet undergone treatment, for a sensitivity rate of 93%, whereas none of the 7 HPV-negative patients had detectable ctDNA, for a specificity rate of 100%. Post-op serum was collected at a median of 25 days after surgery prior to beginning adjuvant therapy and ctDNA was detectable in 43% of patients including 47% with high-risk features (Extra Nodal Extension or R1-microscopic residual tumor). All detected ctDNA was HPV type 16.

At a median follow up of 20 months for the post-op HPV-OPSCC cohort, 24% of these patients had recurrent disease. Among those who recurred, 64% had detectable ctDNA compared with 35% whose disease did not recur (P=0.1). There was a significant association between detectable ctDNA and 24-month Progression Free Survival (45% versus 84%; P=0.04) and Overall Survival (80% versus 100%; P=0.02). Overall, detectable ctDNA, T4 tumors, and more than 4 positive lymph nodes were positively associated with disease recurrence.

It was concluded that detectable HPV circulating tumor DNA is a highly sensitive and specific means of determining HPV-status and was significantly associated with worsened Progression Free Survival and Overall Survival among post-op patients with Human Papilloma Virus (HPV)-associated OroPharyngeal Squamous Cell Carcinoma. HPV circulating tumor DNA as a cancer biomarker may also assist in risk stratification, treatment assessment, and surveillance. Detectable HPV ctDNA in Post-Operative Oropharyngeal Squamous Cell Carcinoma Patients is Associated with Progression. Routman DM, Chera BS, Jethwa KR, et al. International Journal of Radiation Oncology • Biology • Physics 2019;105, 682-683. LBA5

Single Agent XOSPATA® for FLT3 Mutated AML

SUMMARY: The American Cancer Society estimates that in 2019, 21,450 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,920 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy. Even with the best available therapies, the 5 year Overall Survival in patients 65 years of age or older is less than 5%.

Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients, based on risk and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.MUTATED-FLT3-INDUCES-LIGAND-INDEPENDENT-PATHWAY-ACTIVATION

The Fms-Like Tyrosine kinase 3 (FLT3) is a cytokine receptor tyrosine kinase in the PDGF family of growth factor receptors. It is located on the cell surface (transmembrane) of early hematopoietic stem and progenitor cells and regulates their proliferation and differentiation. It plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. FLT3 mutations occur most often as Internal Tandem Duplications (FLT3-ITD) or point mutations at codon D835 (FLT3-Tyrosine Kinase Domain or TKD). Approximately 80% of AML patients with a FLT3 mutation will have the FLT3-ITD, and about 15% will have both FLT3-ITD and FLT3-TKD, and about 5% will have FLT3-TKD alone. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations are predicted to have poor outcomes with shorter remission duration and significantly decreased leukemia-free and Overall Survival. FLT3-TKD can confer resistance to other Tyrosine Kinase Inhibitors and frequently do not respond to salvage chemotherapy.

XOSPATA® (Gilteritinib) is a highly selective oral FLT3/AXL Tyrosine Kinase Inhibitor with activity against both FLT3-ITD and FLT3-TKD mutations. Tyrosine Kinase AXL has been implicated in FLT3 inhibitor resistance. Another FLT3 inhibitor, RYDAPT® (Midostaurin), is also approved, but in combination with standard Cytarabine and Daunorubicin-based chemotherapy for patients with newly diagnosed FLT3-mutated AML. However, for patients with relapsed or refractory AML, RYDAPT® has not conferred durable clinical benefit as a single agent. Unlike XOSPATA®, RYDAPT® is a not selective and is a multikinase inhibitor and inhibits FLT3, PDGFR, c-KIT (CD 117), VEGFR, and protein kinase C. Single-agent XOSPATA®, in a phase 1-2 study, resulted in a 41% composite Complete Remission rate (Complete Remission with or without normal hematologic recovery), among patients with relapsed or refractory FLT3-mutated AML. Based on this information, the authors conducted a multicenter, randomized trial comparing XOSPATA® with conventional salvage chemotherapy regimens in patients with relapsed or refractory FLT3-mutated AML.

The ADMIRAL trial is an international, multicenter, randomized, Phase III study in which 371 patients with relapsed or refractory FLT3 mutated AML were randomly assigned in a 2:1 ratio to receive either XOSPATA® 120 mg orally once daily or salvage chemotherapy, in 28-day cycles. The median age was 62 years, approximately 60% of the patients had relapsed AML and 39% had primary refractory disease. Over 85% of patients had received previous induction therapy with Anthracyclines but not FLT3 inhibitors. The two Primary end points were Overall Survival and the percentage of patients who had Complete Remission with full or partial hematologic recovery. Secondary end points included Event-Free Survival (freedom from treatment failure – relapse or lack of remission or death) and the percentage of patients who had Complete Remission. The median duration of follow up for Overall Survival was 17.8 months.

The median Overall Survival in the XOSPATA® group was significantly longer than that in the chemotherapy group (9.3 months versus 5.6 months) with a 36% reduction in the risk of death, compared to salvage chemotherapy (HR for death=0.64; P<0.001). The median Event-Free survival was 2.8 months in the XOSPATA® group and 0.7 months in the chemotherapy group (HR for treatment failure or death=0.79). The percentage of patients who had Complete Remission with full or partial hematologic recovery was 34.0% in the XOSPATA® group and 15.3% in the chemotherapy group and the Complete Remission rates were 21.1% and 10.5%, respectively. The median Overall Survival as well as Complete Remission rates were similar among those with FLT3 ITD mutations alone and those with FLT3 TKD mutations, when treated with XOSPATA®. Further, longer survival was observed with XOSPATA® than with chemotherapy across all cohorts of patients with co-mutations, particularly in those patients with double mutation (DNMT3A and NPM1), and baseline levels of AXL expression did not influence survival with XOSPATA®. Serious adverse events occurred less frequently in the XOSPATA® group than in the chemotherapy group and the most common adverse events of Grade 3 or higher were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).

It was concluded that treatment with single agent XOSPATA® resulted in significantly longer Overall Survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. Perl AE, Martinelli G, Cortes JE, et al. N Engl J Med 2019; 381:1728-1740

Late breaking Abstract – ESMO 2019 OPDIVO® Improves Overall Survival in Advanced Esophageal Cancer Regardless of PD-L1 Expression

SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis, with a 5-year relative survival rate of 8% or less.

The FDA in July 2019 approved KEYTRUDA® (Pembrolizumab) for patients with recurrent, locally advanced or metastatic Squamous Cell Carcinoma of the Esophagus (ESCC), whose tumors express PD-L1 (Combined Positive Score-CPS of 10 or more). This approval was based on the Phase III KEYNOTE-181 global trial in which KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher. The median Overall Survival in the Intent-To-Treat population was however was not statistically significant.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in a Phase II study showed promising antitumor activity and safety profile among patients with advanced refractory Squamous Cell Carcinoma of the Esophagus (ESCC). ATTRACTION-3 is a multicentre, randomized, open-label, Phase III trial in which 419 patients with unresectable advanced or recurrent ESCC refractory or intolerant to one prior Fluoropyrimidine/Platinum-based chemotherapy, regardless of PD-L1 expression, were enrolled. Patients were randomly assigned (1:1) to either OPDIVO® 240 mg IV every 2 weeks (N=210) or investigator’s choice of Paclitaxel 100 mg/m2 IV once per week for 6 weeks then 1 week off or Docetaxel 75 mg/m2 IV every 3 weeks (N=209). Both treatment groups were well balanced and nearly 90% of the patients were male and 96% were Asian. Approximately 85% of patients were current or former smokers, about half of patients had prior surgery and about 70% had prior radiotherapy. Approximately 50% of patients had tumor PD-L1 expression of 1% or more. The Primary endpoint was Overall Survival (OS), in the intent-to-treat population that included all randomized patients.

At a minimum follow-up of 17.6 months, OPDIVO® showed a statistically significant improvement in OS, with a 23% reduction in the risk of death, compared to chemotherapy. The median Overall Survival was 10.9 months in the OPDIVO® group versus 8.4 months in the chemotherapy group (HR for death=0.77, P=0.019). The proportion of patients alive at 18 months was numerically larger with OPDIVO® versus chemotherapy (31% vs 21%). The OS benefit with OPDIVO® over chemotherapy was noted across tumor PD-L1 expression levels (PD-L1 1% or more, HR=0.69; PD-L1 less than 1%, HR=0.84). The Objective Response Rate was similar in both treatment groups (19% vs 22%). However the median duration of response with OPDIVO® was 6.9 months, versus 3.9 months with chemotherapy, suggesting that the responses were substantially more durable with OPDIVO® compared to chemotherapy. There was no significant difference in the Progression Free Survival between the treatment groups. Grade 3 or 4 adverse events occurred in 18% of the OPDIVO® group and 63% of the chemotherapy group.

It was concluded that OPDIVO® was associated with a significant improvement in Overall Survival with a favorable safety profile compared with chemotherapy, in previously treated patients with advanced Esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression, and represents a potential new standard second-line treatment option for this patient group. Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): the phase 3 ATTRACTION-3 study. Cho BC, Kato K, Takahashi M, et al. Presented at ESMO 2019: September 27-October 1, 2019; Barcelona, Spain. Abstract LBA 11.

ZEJULA® (Niraparib)

The FDA on October 23, 2019 approved ZEJULA® for patients with advanced Ovarian, Fallopian tube, or Primary Peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with Homologous Recombination Deficiency (HRD)-positive status. HDR is defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability in patients with disease progression greater than six months after response to the last Platinum-based chemotherapy. ZEJULA® is a product of Tesaro, Inc.

DARZALEX® (Daratumumab)

The FDA on September 26, 2019 approved DARZALEX® for adult patients with Multiple Myeloma in combination with VELCADE® (Bortezomib), THALOMID® (Thalidomide), and Dexamethasone in newly diagnosed patients who are eligible for Autologous Stem Cell Transplant (ASCT). DARZALEX® is a product of Janssen Biotech, Inc.

NCCN updates Colorectal Cancer Testing and Treatment Guidelines

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 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable with a 5-year survival rate of 11%.

The 2019 NCCN guideline update for colon cancer has expanded the scope of personalized medicine and clinical diagnostics by incorporating biomarker testing to guide treatment. With the identification of new biomarkers and expansion of biomarker testing to guide treatment among patients with colorectal cancer, studies are underway to classify colorectal cancer (CRC) based on comprehensive gene expression profiles. The Consensus Molecular Subtypes (CMS) is one of the most robust transcriptome-based classification of colorectal cancer (CRC). The CMS subtype may influence the efficacy of chemotherapy and CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs. The CRC Subtyping Consortium (CRCSC) initiated by 15 institutions analyzed more than 30 different gene expression sets across multiple platforms and sample preparation methods and identified four different molecular subtypes, CMS1, CMS2, CMS3 and CMS4. This covers approximately 87% of all CRC cases, thus leaving approximately 13% of cases molecularly uncharacterized.

CMS1: Approximately 14 percent of all CRC are considered CMS1, of which approximately 12 percent are sporadic (non-inherited), while the remaining patients have inherited disease (Lynch Syndrome). Tumors are located in the proximal colon, have a high BRAF V600E mutation rate and are associated with impaired DNA mismatch repair (MMR). Patients in this group tend to have a lower rate of relapse and if relapse does occur, they are associated with poor outcomes (about 9 months). The 5-year survival rate for this group is about 73%.

CMS2: This is the most common CRC subtype with approximately 39% of the CRC patients belonging to this group. Majority of the tumors are located in the left colon and tumors are characterized by the initial loss of APC, a tumor suppressor gene, followed by an activating mutation in KRAS and loss of TP53. Patients in this group have higher survival rates (35 months) after relapse. The 5-year survival rate for this group is 77%, the best among the four different CRC subtypes.

CMS3: Approximately 13 percent of CRC patients belong to this group. KRAS mutations are most frequently found in this patient group (68%) and approximately 3% of patients in this group overexpress HER2. Patients in this group have the second highest survival rates, with a 5-year survival rate of 75%.

CMS4: These tumors are characterized by MSS (MicroSatellite Stable) with frequent mutation of genes such as APC, KRAS, PIK3CA, and TP53. Patients in this group often have poor prognosis as they are diagnosed at advanced stages. They have little or no benefit from systemic adjuvant therapy and those with metastatic disease are often resistant to EGFR inhibitors, independent of KRAS mutation status. They have the worst 5-year Overall Survival (62%) of any molecular subtype.

The following are the key 2019 NCCN guideline updates 

KRAS, NRAS and BRAF Mutation Testing

All patients with metastatic colorectal cancer should have tumor tissue genotyped for KRAS, NRAS and BRAF mutations individually or as a part of Next Generation Sequencing (NGS) panel

MicroSatellite Instability (MSI) or MisMatch Repair (MMR) Testing

1) The presence of BRAF V600E mutation in the setting of absence of MLH1 would preclude the diagnosis of Lynch Syndrome in a majority of cases. However, approximately 1% of cancers with BRAF V600E mutation and loss of MLH-1 are Lynch Syndrome and therefore, caution should be exercised, in excluding patients with a strong family history from germline screening in the case of BRAF V600E mutations

2) ImmunoHistoChemistry (IHC) refers to staining of tumor tissue for protein expression of the four mismatch repair MMR genes, MLH1, MSH2, MSH6, and PMS2, known to be mutated in Lynch Syndrome. A normal IHC test implies that all 4 MMR proteins are normally expressed or retained. An abnormal or positive IHC test implies loss or absence of expression of one or more of the 4 MMR proteins. When IHC is reported as positive, caution should be exercised to ensure that positive IHC refers to absence of mismatch expression and not presence of expression. Loss of expression by IHC in any of the MMR genes should then be followed up with genetic testing. Abnormal MLH1 on IHC should be followed by tumor testing for BRAF V600E mutation. The presence of BRAF V600 E mutation is consistent with sporadic cancer.

mFOLFOXIRI + EGFR

mFOLFOXIRI with EGFR inhibitor VECTIBIX® (Panitumumab) or ERBITUX® (Cetuximab) was added as a treatment option for unresectable stage IV mCRC that are left-sided and are KRAS/NRAS/BRAF wild-type.

mFOLFOX + EGFR

The combination regimen FOLFOX + VECTIBIX® or ERBITUX® was added for KRAS/NRAS/BRAF wild-type tumors.

Immunotherapy

Patients with advanced or metastatic CRC who are not appropriate candidates for intensive therapy may be offered OPDIVO® (Nivolumab) or KEYTRUDA® (Pembrolizumab), as a single agent or a combination of OPDIVO® and YERVOY® (Ipilimumab), only for tumors that are MMR deficient and MSI High (Category 2B). These same immunotherapy options are also listed in the guidelines as second and third-line options for MMR deficient and MSI High patients.

NTRK Gene Fusion

Tumors should be tested for Neurotrophic Receptor Tyrosine Kinase (NTRK) gene fusion, and VITRAKVI® (Larotrectinib) is now a second-line treatment option for patients with metastatic CRC that is NTRK gene fusion positive.

BRAF and MEK

BRAF wild-type was added as an indication for treatment, where KRAS and NRAS wild-type are noted. Combination therapies added to the guidelines as second-line options include

1) TAFINLAR® (Dabrafenib) targeting BRAF plus MEKINIST® (Trametinib) targeting MEK along with ERBITUX® or VECTIBIX® which are EGFR targeted monoclonal antibodies

2) BRAFTOVI® (Encorafenib) targeting BRAF plus MEKTOVI® (Binimetinib) targeting MEK along with ERBITUX® or VECTIBIX®.

NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer. Messersmith WA. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Late Breaking Abstract – ESMO 2019 First-Line Treatment with TAGRISSO® Improves Overall Survival in EGFR-Positive NSCLC

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 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 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.EGFR-Tyrosine-Kinase-Inhibitors

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.

FLAURA, which is a randomized, double blind, Phase III clinical trial, was conducted to compare the efficacy and safety of first line TAGRISSO® to TARCEVA® or IRESSA® (the latter two are considered standard first line therapies), in NSCLC patients with sensitizing EGFR mutations. This study randomized 556 advanced NSCLC treatment naïve patients, with EGFR Exon 19 Deletions or Exon 21 (L858R) substitution mutations, in a 1:1 ratio, to TAGRISSO® 80 mg orally once daily (N=279) or Standard of Care EGFR-TKI, IRESSA® 250 mg or TARCEVA® 150 mg, orally once daily (N=277). Patients were stratified by mutation status (Exon 19 vs 21 mutations) and race (Asian vs non-Asian). Patients with CNS metastases who were neurologically stable, were allowed in this study. The Primary endpoint was Progression Free Survival (PFS) and Overall Survival (OS) was a Secondary endpoint.

The median PFS was 18.9 months with TAGRISSO®, compared to 10.2 months for the standard therapy (HR=0.46; P<0.001), suggesting a 54% reduction in the risk of disease progression, compared with Standard of Care. TAGRISSO® extended the median Time To Progression by about 9 months. This PFS benefit was consistent across all subgroups of patients, including those with and without CNS metastases at study entry. The Objective Response Rate (ORR) with TAGRISSO® was 80% compared with 76% for TARCEVA® and IRESSA®. The median Duration of Response with TAGRISSO® was 17.2 months versus 8.5 months in the comparator arm.

The authors now reported the Overall Survival (OS) results from the Phase III FLAURA trial. Approximately, 25% of patients in the comparator group had crossed over to the TAGRISSO® group upon disease progression. Despite this crossover, the OS was significantly prolonged with TAGRISSO® with a median OS of 38.6 months compared with 31.8 months for the comparator arm (HR=0.799; P=0.046), representing a 20% reduction in the risk of death with TAGRISSO®. At the time of final data cutoff for the study, about 54% of patients remained alive at 3 years in the TAGRISSO® group compared with 44% in the comparator group, and 28% of patients enrolled in the trial were still receiving TAGRISSO® at three years versus 9% on either TARCEVA® or IRESSA®. Treatment with TAGRISSO® also resulted in a statistically significant and clinically meaningful 52% reduction in the risk of CNS disease progression or death, compared to the comparator arm (HR=0.48; P=0.014). Fewer patients in the TAGRISSO® group experienced Grade 3 or more Adverse Events compared to the comparator arm. Approximately 30% of patients in both treatment groups did not receive subsequent therapy after progression.

It was concluded that 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. Osimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Ramalingam SS, Gray JE, Ohe Y, et al. Presented at 2019 ESMO Congress, Barcelona, Spain, September 28 to October 1, 2019. Abstract LBA5_PR.