Tag: Rectal Cancer

FDA Approves BRAFTOVI® in Combination with ERBITUX® for Metastatic Colorectal Cancer

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SUMMARY: The FDA on April 8, 2020, approved BRAFTOVI® (Encorafenib) in combination with ERBITUX® (Cetuximab) for the treatment of adult patients with metastatic ColoRectal Cancer (CRC) with a BRAF V600E mutation, detected by an FDA-approved test, after prior therapy. Colorectal Cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC), whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.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. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. It should be noted that BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than Malignant Melanoma.

BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The combination of BRAFTOVI® along with anti-EGFR monoclonal antibody ERBITUX® (Cetuximab) showed promising activity in early-phase clinical trials.

The present FDA approval was based on BEACON CRC (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) trial, which is an international, multicenter, randomized, open-label, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI® (Binimetinib), was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC, whose disease has progressed after one or two prior regimens. Eligible patients were required to have BRAF V600E mutation-positive metastatic CRC (detected by the Qiagen therascreen® BRAF V600E RGQ PCR kit), with disease progression after one or two prior regimens. In this trial, 665 patients were randomly assigned in a 1:1:1 ratio to receive either triplet therapy of BRAFTOVI® 300 mg orally daily, MEKTOVI® 45 mg orally twice daily, and ERBITUX® 400 mg/m2 IV as an initial dose, then 250 mg/m2 IV weekly (N=224), doublet-therapy of BRAFTOVI® and ERBITUX® administered in the same doses and on the same schedule as the triplet regimen (N=220) or investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan (N=221). Patients were stratified according to previous Irinotecan use and treatment was administered in 28-day cycles until disease progression. The co-Primary end points were Overall Survival (OS) in the triplet-therapy group as compared with the control group and Secondary end points included OS in the doublet-therapy group as compared with the control group, as well as Progression Free Survival, Duration of Response, and Safety in all groups. This study was not powered to compare the triplet-therapy group against the doublet-therapy group. The Overall Response Rate (ORR) and Duration of Response were assessed by blinded Independent Central Review in the subset of the first 220 patients assigned to receive either BRAFTOVI® and ERBITUX® or the control group.

The median OS was 8.4 months in the BRAFTOVI® plus ERBITUX® group, compared to 5.4 months in the control group (HR=0.60; P=0.0003), and this represented 40% reduction in the risk of death among the BRAFTOVI® plus ERBITUX® group. Median PFS was 4.2 months in the BRAFTOVI® plus ERBITUX® group compared to 1.5 months in the control group (HR=0.40; P< 0.0001). The ORR was 20% and 2% respectively. The median Duration of Response was 6.1 months for the BRAFTOVI® plus ERBITUX® group and Not Reached in the control arm. The median OS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR for death=0.52; P<0.001). This represented 48% reduction in the risk of death in the triplet-therapy group. Both the triplet and doublet regimens reduced the risk of Quality of Life (QoL) deterioration by about 45% by different QoL assessment instruments, compared with the control regimen. The most common adverse reactions in the BRAFTOVI® plus ERBITUX® group were fatigue, nausea, diarrhea, dermatitis acneiform, abdominal pain, decreased appetite, arthralgia, and rash.

It was concluded from the BEACON CRC trial that a combination of BRAFTOVI®, MEKTOVI® and ERBITUX® as well as a combination of BRAFTOVI® plus ERBITUX® resulted in significantly longer Overall Survival and a higher Response Rate than standard therapy, in patients with metastatic Colorectal Cancer, with the BRAF V600E mutation.
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. Kopetz S, Grothey A, Yaeger R, et al. N Engl J Med 2019; 381:1632-1643

Improved Quality of Life and Efficacy with BRAFTOVI®, MEKTOVI® and ERBITUX® Triplet Therapy in Patients with BRAF V600E-Mutant 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 147,950 new cases of CRC will be diagnosed in the United States in 2020 and about 53,200 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab), as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC), whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 5-20% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.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. The BRAF V600E mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. However, BRAF V600E-mutated CRC is inherently less sensitive to BRAF inhibition than melanoma. BRAFTOVI® (Encorafenib) is a BRAF inhibitor and has target binding characteristics that differ from other BRAF inhibitors such as ZELBORAF® (Vemurafenib) and TAFINLAR® (Dabrafenib), with a prolonged target dissociation half-life and higher potency. The combination of BRAFTOVI® along with anti-EGFR monoclonal antibody ERBITUX® (Cetuximab) showed promising activity in early-phase clinical trials. 
The BEACON CRC (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) trial is an international, multicenter, randomized, open-label, Phase III study in which the efficacy and safety of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI® (Binimetinib), was compared with the investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan, in patients with BRAF V600E-mutant mCRC, whose disease has progressed after one or two prior regimens. In this trial, 665 patients were randomly assigned in a 1:1:1 ratio to receive either triplet therapy of BRAFTOVI® 300 mg orally daily, MEKTOVI® 45 mg orally twice daily, and ERBITUX® 400 mg/m2 IV as an initial dose, then 250 mg/m2 IV weekly (N=224), doublet-therapy of BRAFTOVI® and ERBITUX® administered in the same doses and on the same schedule as the triplet regimen (N=220) or investigators’ choice of ERBITUX® combined with either Irinotecan or Fluorouracil, Folinic acid, and Irinotecan (N=221). Patients were stratified according to previous Irinotecan use and treatment was administered in 28-day cycles until disease progression. The co-Primary end points were Overall Survival (OS) in the triplet-therapy group as compared with the control group and Secondary end points included OS in the doublet-therapy group as compared with the control group, as well as PFS, Duration of Response, and Safety in all groups. This study was not powered to compare the triplet-therapy group against the doublet-therapy group.
At the time of prespecified interim analysis, with a median duration of follow up for survival at 7.8 months across the three groups, the median OS was 9.0 months in the triplet-therapy group and 5.4 months in the control group (HR for death=0.52; P<0.001). This represented 48% reduction in the risk of death in the triplet-therapy group. The confirmed Response Rate was 26% in the triplet-therapy group and 2% in the control group (P<0.001). The median OS in the doublet-therapy group was 8.4 months (HR for death versus control=0.60; P<0.001).
The authors in this updated analysis focused on the patient-reported Quality of Life (QOL) assessments from this study. QOL assessments using 4 validated QOL measures were secondary endpoints in the trial. They included EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer (FACT C), EuroQol 5D 5L, and Patient Global Impression of Change (PGIC). The risk of QOL deterioration was reduced by 45% (HR=0.55) and 44% (HR=0.56), using EORTC QLQ C30 and FACT C assessments respectively, in favor of the triplet regimen over control. Similar findings were observed when the doublet-therapy regimen was compared with the regimen in the control group, and when QOL assessments were made using the other two QOL measures (EuroQol 5D 5L and PGIC). There was however no significant differences in QOL when the triplet and doublet regimen groups were compared.
It was concluded based on this updated analysis of the BEACON CRC trial, that among patients with BRAF V600E-mutant metastatic Colorectal Cancer, a combination of BRAFTOVI® plus ERBITUX® with or without a MEK inhibitor MEKTOVI®, demonstrated longer maintenance of QOL on patient-reported assessments, compared to the current standard of care. Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). Kopetz S, Grothey A, Van Cutsem E, et al. J Clin Oncol. 2020;38(suppl 4; abstr 8).

Dramatic Increase in ColoRectal Cancer Incidence among Young Adults

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Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than 50 years of age, according to data in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. Based on these findings, the American Cancer Society in 2018 updated its guidelines to include a “qualified recommendation” to begin CRC screening at the age of 45 yrs. 

In a recently published retrospective study, the proportion of the total number of patients diagnosed with CRC under the age of 50 yrs rose from 10% in 2004 to 12.2% in 2015 (P<0.0001). Younger adults presented with more advanced stage of disease (Stage III/IV) than those 50 yrs or older (51.6% versus 40.0% respectively). When racial and ethnic groups were stratified by sex, among men with a diagnosis of CRC before age 50, non‐Hispanic whites showed a proportional increase in diagnosis (P<0.0001), whereas among women, both Hispanic whites (P<0.05) and non‐Hispanic whites (P<0.001) had increases in the proportion of CRC diagnosed before age 50. The rates of CRC diagnosis in young adults increased over time, regardless of income level (P<0.001).The highest proportion of young adult CRC diagnoses occurred in the highest income group. The proportion of CRC cases diagnosed in younger individuals rose in urban areas (P<0.001), but not in rural areas. Health Care Providers should be mindful of these data, when screening guidelines are discussed with patients. 

MicroRNA-31-3p Expression is a Predictive Biomarker of Anti-EGFR Efficacy in Patients with RAS Wild-type Metastatic Colorectal Cancer

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Advanced ColoRectal Cancer (CRC) is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor RAS mutations. It is now becoming clear that among these pan RAS wild type tumors, a predictive biomarker, MiR-31-3p expression in tumors, may further determine who would benefit from Anti-EGFR targeted therapy.
In a recently published study (Clin Cancer Res 2018), tumors with Low MiR-31-3p expression benefited from ERBITUX® combination compared to AVASTIN® for PFS (HR=0.74;P=0.05), OS (HR=0.61;P<0.01) and Objective Response Rate (P<0.01). There was however no difference in outcomes among High MiR-31-3p expressors between the two treatment groups. This study suggested that only low MiR-31-3p expressing tumors among the pan RAS wild type CRC patients benefit from Anti-EGFR targeted therapies.

American Cancer Society Updates Colorectal Cancer Screening Guideline for Average Risk Adults

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The ACS recently updated Colorectal Cancer Screening Guideline using prevailing evidence as well as microsimulation modeling analyses. The new guideline does not prioritize among screening test options. This is because test preferences vary among individuals and the guidelines development committee emphasized that screening rates could be improved by endorsing the full range of tests without preference. Adults born around 1990 have twice the risk of colon cancer and four times the risk of rectal cancer compared with adults born around 1950, who have the lowest risk. In the updated guideline, screening is recommended earlier, starting at age 45 years and may be performed  with either a high-sensitivity stool-based test or a structural (visual) exam, depending on patient preference and test availability.

FDA Approves OPDIVO® for MSI-H or dMMR Metastatic Colorectal Cancer

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The FDA on July 31, 2017, granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients 12 years and older with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic ColoRectal Cancer, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Patients with metastatic ColoRectal Cancer who have dMMR or MSI-H tumors are less likely to respond to conventional chemotherapy and OPDIVO® demonstrated durable responses and disease control in this heavily pretreated patient group.

Three Months of Adjuvant Therapy Adequate for Stage III Colon Cancer

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The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. They concluded that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer. Three months of adjuvant chemotherapy is adequate for patients with T1-3, N1 disease. This study data was presented at 2017 ASCO Annual Meeting.

Chemoradiation Alone without Surgery does not Compromise Survival in Selected Patients with Rectal Cancer

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SUMMARY: The American Cancer Society estimates 39,910 new cases of Rectal Cancer will be diagnosed in the United States in 2017. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable and often treated with a combination of neoadjuvant (preoperative) chemoradiation and surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in Rectal Cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent Fluoropyrimidine based chemotherapy as a radiosensitizer, followed by postoperative chemotherapy, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine). Complete Response is seen in approximately 25% of the patients who receive chemoradiation. However, 15% to 25% of these patients develop local recurrence. Surgery following chemoradiation may result in long term complications and may necessitate temporary or permanent colostomy in addition to sexual and urinary dysfunction.

The International Watch & Wait Database Consortium was established in 2014 by EURECCA (the European Registration of Cancer Care) and the Champalimaud Foundation in Lisbon. This Consortium which includes 35 institutions in 11 countries was established mainly to collect all available data and expand knowledge on the benefits, risks and oncological safety of organ preserving strategies, in Rectal Cancer. This database as of August 2016 included 775 patients and majority of these patients had stage T2/3 disease (92%) with clinical N0/1 nodal status (75%). Ninety percent of these patients (N=679) had a clinical Complete Response following induction therapy with chemoradiation. These patients did not undergo surgery and were followed up for a median of 2.6 years.

It was noted that 25% of all patients had local recurrence and 84% of these occurred in the first 2 years of follow up. Local recurrence was endoluminal in 96% of the patients and in the loco-regional lymph nodes in 4%. Distant metastasis occurred in 7% of the patients. The 3-year Overall Survival rate was 91% among all patients, and was 87% for patients who experienced local recurrence. These findings are comparable to survival rates seen in patients with a Complete Response, who undergo standard surgery.

It was concluded that in this largest series of patients to date with Rectal Cancer, a “watch-and-wait” strategy to treating Rectal Cancer without surgery, following Complete Response to chemoradiation, resulted in outcomes comparable to historical controls. As more information is gathered, it is important that restaging be performed in all patients with Rectal Cancer who undergo chemoradiotherapy, to prevent unnecessary surgical procedures, and give patients the option for a watch-and-wait approach. The International Watch & Wait database (IWWD) for rectal cancer: An update. van der Valk M for the International Watch and Wait Database Consortium. J Clin Oncol 35, 2017 (suppl 4S; abstract 521)

Short Course Neoadjuvant Radiation Therapy Effective and Less Toxic in Advanced Rectal Cancer

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SUMMARY: The American Cancer Society estimates 39,220 new cases of Rectal cancer will be diagnosed in the United States in 2016. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable with a combination of neoadjuvant (preoperative) chemoradiation, surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in Rectal cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent Fluoropyrimidine based chemotherapy as a radiosensitizer, followed by postoperative chemotherapy, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine).

The authors in this study evaluated the efficacy of a short course of neoadjuvant radiation therapy for patients with unresectable cT3 or cT4 Rectal adenocarcinoma. The trial included 515 patients who were randomly assigned either to the control group (N=254), in which patients received RT at 50.4 Gy delivered in 28 fractions, given simultaneously with a regimen of 5-FU bolus, Leucovorin and ELOXATIN® (Oxaliplatin) or the experimental group (N=261) in which patients received a short Five day course of Radiotherapy at 5 Gy per day (Total 25 Gy), followed by three courses of FOLFOX4 delivered over 48 hours, during weeks 3, 5, and 7. Both treatment groups underwent surgery approximately 12 weeks after radiation was started and about 6 weeks following neoadjuvant treatment. ELOXATIN® inclusion in the chemotherapy regimen was at the discretion of the treating physician, due to increase in toxicity. Nonetheless, 70% of the patients had received ELOXATIN® at the end of the study. It should be noted that the NSABP protocol R-04 demonstrated that the addition of ELOXATIN® in the neoadjuvant chemotherapy regimen did not improve outcomes but resulted in significant toxicity. The median follow up was 35 months.

The primary endpoint of the rate of curative resection (R0) was 71% in the control group versus 77% in the experimental group. Pathological Complete Response rates were 11.5% in the control group and 16% in the experimental group. The 3 year Overall Survival rates for the control versus experimental group were 65% vs 73% and Disease Free Survival for the control versus experimental group were 52% vs 53%. These differences were not statistically significant. The local failure rates were similar in both treatment groups (22%).

The authors concluded that a short course of radiotherapy combined with three cycles of chemotherapy post radiation, can be more convenient with lower toxicity and this regimen would be an appealing option for patients with locally advanced Rectal cancer, with metastases in liver or lungs, for whom chemotherapy to control systemic disease can be started much earlier, following a short course of radiation therapy. Neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancer: Results of a Polish II multicentre phase III study. Bujko K, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 489)