Author: RR

FDA Approves OPDIVO® plus CABOMETYX® in Newly Diagnosed Advanced Kidney Cancer

RR

SUMMARY: The FDA on January 22,2021, approved the combination of OPDIVO® (Nivolumab) and CABOMETYX® (Cabozantinib) as first line treatment for patients with advanced Renal Cell Carcinoma (RCC). The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is significant unmet need for improved therapies for this disease. SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/smooth vessel cell wall, and is capable of specifically binding to tyrosine kinases, inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® has been the standard first line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, Phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival (OS) was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.

The FDA in 2018, approved combination immunotherapy, OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab), for the treatment of intermediate or poor-risk, previously untreated advanced Renal Cell Carcinoma (RCC), based on significantly higher Overall Survival (OS) and Objective Response Rates (ORR), compared with SUTENT® (CheckMate 214). Subsequently, two studies, a combination of BAVENCIO® (Avelumab) and INLYTA® (Axitinib) – JAVELIN Renal 101, and KEYTRUDA® (Pembrolizumab) and INLYTA® (KEYNOTE-426), demonstrated superior OS, compared to SUTENT®, and for the first time set the stage for the use of a combination of checkpoint inhibitor and targeted therapy in this patient population.MOA-of-CABOZANTINIB

OPDIVO®, an anti-PD-1 checkpoint inhibitor and CABOMETYX® (Cabozantinib), a small-molecule Tyrosine Kinase Inhibitor, are both approved as single agents, for the second-line treatment of Renal Cell Carcinoma. The rationale for combining these two agents is that OPDIVO® unleashes the immune system and restores antitumor immune response, whereas CABOMETYX® has both antiangiogenic and immunomodulatory properties and may counteract tumor-induced immunosuppression.

CheckMate 9ER study is a multinational, randomized, Phase III trial, in which a combination of OPDIVO® plus CABOMETYX® was compared with single agent SUTENT®, in treatment naïve patients with advanced clear cell Renal Cell Carcinoma. This study included 651 treatment naïve patients with advanced Renal Cell Carcinoma with a clear cell component, who were randomly assigned in a 1:1 ratio to receive OPDIVO® 240 mg IV every 2 weeks along with CABOMETYX® 40 mg orally daily (N=323) or SUTENT® 50 mg orally daily in 4-week-on, 2-week-off cycles (N=328). Treatment was continued until disease progression or unacceptable toxicity. Patients with any IMDC (International Metastatic RCC Database Consortium) risk score were included. Patients with sarcomatoid tumor features were allowed. Patients were stratified by IMDC risk score and tumor PD-L1 expression. The median patient age was 62 years, 58% of patients were in the IMDC intermediate risk category and 75% of patients had tumor PD-L1 expression of less than 1%. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and safety.

At a median follow up of 18.1 months, the median PFS was 16.6 months with OPDIVO® plus CABOMETYX® combination versus 8.3 months with single agent SUTENT® (HR=0.51; P<0.0001), suggesting a doubling of PFS, with a 49% reduction in the risk of disease progression or death. The median Overall Survival, a secondary endpoint, was not reached in either treatment group, but at this first analysis, patients randomized to the OPDIVO® plus CABOMETYX® combination had significantly longer OS, than those receiving SUTENT® (median Not Reached; HR=0.60; P=0.001), suggesting a 40% reduction in the risk of death. These benefits were seen consistently across pre-specified subgroups defined according to IMDC risk categories and PD-L1 expression. The Objective Response Rate (ORR) was also significantly higher and doubled among patients receiving the OPDIVO® plus CABOMETYX® combination, compared to those receiving SUTENT® (55.7% versus 27.1%, P<0.0001). Complete response rates were also higher among those receiving the OPDIVO® plus CABOMETYX® combination (8.0% versus 4.6%), with a shorter median time to response, and longer duration of response. Grade 3 or more Adverse Events were higher among those receiving OPDIVO® plus CABOMETYX® combination, compared to those receiving SUTENT® (60.6% versus 50.9%).

It was concluded that a combination of OPDIVO® plus CABOMETYX® demonstrated superior Progression Free Survival, Overall Survival and Overall Response Rate, compared to SUTENT®, in treatment naïve patients with advanced Renal Cell Carcinoma, and provides a new treatment option for this patient group.

Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Choueiri TK, Powles T, Burotto M, et al. Ann Oncol. 2020;31(4). Abstract 6960.

Maintenance Therapy with NINLARO® in Transplantation Ineligible Multiple 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, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation, can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Transplant (ASCT) and to date is the only drug approved for this indication. REVLIMID® maintenance however is associated with the development of second new primary malignancies and tolerability issues.

Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Just like normal cells make proteins, so do cancerous cells. But the proteins made by the cancerous cells are ineffective and in excess. Myeloma cells depend on the Proteasomes to facilitate this metabolic function, to regulate their growth and survival. Proteasome Inhibitors (PIs) inhibit Proteasome function and are a backbone of multiple myeloma treatment. VELCADE® (Bortezomib), a Proteasome Inhibitor has shown promising activity in early clinical trials, as maintenance treatment post-ASCT. The limitations with VELCADE® as maintenance therapy include, parenteral administration and tolerability. There is therefore an unmet need for an effective oral PI maintenance therapy that is convenient for the patients, with acceptable toxicities. NINLARO® (Ixazomib) unlike VELCADE® is a second generation, oral, Proteasome Inhibitor, which disrupts protein metabolism in myeloma cells, by inhibiting Proteasomes and has an antiproliferative and pro-apoptotic effect. In the TOURMALINE-MM3 Phase III trial study, weekly NINLARO® maintenance treatment in responding patients after ASCT resulted in a significant reduction in the risk of progression and death, and was associated with a favorable safety profile.

TOURMALINE-MM4 is an International, randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate the efficacy and safety of NINLARO® as maintenance therapy in transplant-ineligible patients after standard-of-care induction therapy. In this study, patients were randomly assigned 3:2 to receive NINLARO® 3 mg orally (N=425) or matching placebo (N=281) on days 1, 8, and 15 of 28-day cycles, as maintenance treatment for 24 months. The dose of NINLARO® was increased to 4 mg from cycle 5, if tolerated during cycles 1-4. Eligible patients had newly diagnosed multiple myeloma, not undergoing Autologous Stem Cell Transplantation (ASCT) and had achieved better than or equal to Partial Response after 6-12 months of standard induction therapy. The median patient age was 73 years and enrolled patients were stratified by induction regimen (PI-containing versus non-PI therapy), preinduction disease Stage (I or II versus III), age at randomization (less than 75 years versus 75 years or older) and response to initial therapy at screening (Complete Response-CR or Very Good Partial Response-VGPR versus Partial Response-PR). About 62% were in CR or VGPR at study entry. The Primary endpoint was Progression Free Survival (PFS). The key Secondary endpoint was Overall Survival (OS).

With a median follow up for PFS of 21.1 months, the median PFS since randomization was 17.4 versus 9.4 months (HR=0.659; P<0.001), suggesting a 34.1% reduction in risk of progression or death with NINLARO® versus placebo. Patients who achieved Complete or Very Good Partial Response postinduction benefitted the most with NINLARO® maintenance treatment, with a median PFS of 25.6 versus 12.9 months with placebo (HR=0.586; P<0.001). NINLARO® maintenance was well tolerated in this elderly population of transplantation-ineligible patients and 70.7% of patients tolerated the 3 mg dose of NINLARO® sufficiently well to escalate the dose to 4 mg. Overall rates of adverse events were similar between groups, and adverse events in the NINLARO® group were mostly grade 1-2 severity and included GI toxicities, rash, and peripheral neuropathy. No new safety signals were seen. There was no increase in new primary malignancies and there was no impact on patients’ self-reported quality of life.

It was concluded that TOURMALINE-MM4 is the first randomized Phase III trial to specifically investigate an induction-agnostic maintenance option for transplantation-ineligible patients with NDMM, and oral NINLARO® maintenance treatment prolonged Progression Free Survival with no unexpected toxicity in this patient population.

Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial. Dimopoulos MA, Spicka I, Quach H, et al. J Clin Oncol. 2020;38:4030-4041.

XALKORI® (Crizotinib)

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The FDA on January 14, 2021 approved XALKORI® for pediatric patients 1 year of age and older and young adults with Relapsed or Refractory, systemic Anaplastic Large Cell Lymphoma (ALCL) that is ALK-positive. The safety and efficacy of XALKORI® have not been established in older adults with Relapsed or Refractory, systemic ALK-positive ALCL. XALKORI® is a product of Pfizer Inc.

Adjuvant VERZENIO® with Endocrine Therapy in High Risk 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 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-ABEMACICLIB-A-CDK4-and-CDK6-Inhibitor

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

VERZENIO® is presently approved by the FDA as monotherapy as well as in combination with endocrine therapy for patients with HR-positive, HER2- negative advanced breast cancer. The addition of VERZENIO® to FASLODEX® resulted in a statistically significant improvement in Overall Survival among patients with HR-positive, HER2-negative advanced breast cancer, who had progressed on prior endocrine therapy. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk early breast cancer.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, histologic Grade 3, or centrally tested high proliferation rate (Ki-67 of 20% or more). Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5 to 10 years of physicians choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease Free Survival (IDFS), and Secondary end points included distant Relapse Free Survival, Overall Survival, and safety. At a preplanned interim analysis, the addition of VERZENIO® to endocrine therapy resulted in a 25% reduction in the risk of developing a Invasive Disease Free Survival (IDFS) event, relative to endocrine therapy alone. Following the positive interim analysis, patients continued to be followed for IDFS, distant recurrence, and Overall Survival. The current study describes outcomes following an extended follow up of this trial, with a median follow up time of 19 months.

At the time of this primary outcome analysis, 1,437 patients (25.5%) had completed the two-year treatment period and 3,281 patients (58.2%) were in the two-year treatment period. The combination of VERZENIO® plus endocrine therapy continued to demonstrate superior Invasive Disease Free Survival (IDFS) compared to endocrine therapy alone, with a 28.7% reduction in the risk of developing invasive disease (P=0.0009; HR=0.713). The 2-year IDFS in the combination group was 92.3% and 89.3% in the endocrine therapy alone treatment group. This IDFS benefit with VERZENIO® was consistently noted in all prespecified subgroups. Further, there was an improvement in the 2-year distant Relapse Free Survival rate among patients who received the combination treatment compared with those who received endocrine therapy alone (93.8% versus 90.8%, respectively). Overall Survival data was immature at the time of analysis.

The researchers also evaluated outcomes among 2,498 patients with centrally assessed high tumor Ki-67 status. Among patients in this cohort, those who received the combination treatment had a 30.9% decreased risk of invasive disease compared with those who received endocrine therapy alone (P=0.01; HR=0.691) and the 2-year IDFS rates in the combination group and the endocrine therapy alone group were 91.6% and 87.1%, respectively. There were no new safety signals observed with VERZENIO®.

It was concluded that at the time of this primary outcome analysis, VERZENIO® combined with endocrine therapy continued to demonstrate a clinically meaningful improvement in Invasive Disease Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer.

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Presented at the 2020 San Antonio Breast Cancer Symposium, December 8-11. Abstract. GS1-01.

PET-Directed Therapy for Limited Stage Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common Non-Hodgkin Lymphoma diagnosed in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 yrs or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

Approximately 25-30% of DLBCL present as limited stage. Three cycles of Rituximab (RITUXAN®) along with CHOP plus Radiation Therapy (RT) is the standard treatment approach for limited stage DLBCL based on SWOG S0014 study. Data from retrospective studies suggested that 80% of patients were PET negative after 3 cycles of R-CHOP (defined as Deauville score 1-2), on a mid-treatment interim PET/CT scan, and only 8% of them relapsed after receiving 1 additional cycle of R-CHOP without RT.

S1001 is a prospective, Phase II, Intergroup, National Clinical Trials Network, PET-directed study, designed to tailor therapy for patients with limited-stage DLBCL after 3 cycles of R-CHOP. The goal of this study was to eliminate toxicities associated with RT, for the majority of patients with a negative PET scan after 3 cycles of R-CHOP and to improve the outcome in the minority of patients with a positive interim PET scan.

This study included 132 eligible, treatment naïve, Stage I/II, CD20-positive, DLBCL patients, with nonbulky (less than 10 cm) disease. All patients received 3 cycles of standard R-CHOP treatment given every 3 weeks, with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m2 IV, Vincristine 1.4 mg/m2 (capped at 2 mg) IV, and Prednisone 100 mg orally daily for 5 days. Patients had an interim PET scan between days 15 and 18 of cycle 3, which was centrally reviewed in real time. Patients with a negative PET, defined as Deauville score 1-3, proceeded with 1 additional cycle of R-CHOP. Patients with a positive PET (Deauville score 4-5) initiated 36 Gy of involved field radiation therapy, plus an additional boost of up to 9 Gy to FDG-avid areas, within 5 weeks of cycle 3 of R-CHOP. Three to 6 weeks after completing radiation therapy, patients received ZEVALIN® (Ibritumomab tiuxetan) administered per standard protocol, with Rituximab 250 mg/m2 IV given on day 1 and day 7, 8, or 9, and ZEVALIN® 0.4 mCi/kg on day 7, 8, or 9, after Rituximab. A final PET scan was performed 12 weeks after treatment completion. Patients were followed up with clinical examination and testing, including CT scans every 6 months for the first 2 years and then annually for up to 7 years or death.

The median age was 62 years, 62% of patients had Stage I disease, 17% had B symptoms, 43% had extranodal involvement, 66% had exclusive involvement of the head and neck region, and 10% had fully resected disease at baseline. Stage-modified IPI score was 0 in 27%, 1 in 42%, 2 in 28%, and 3 in 4% of the patients. Overall, 72% of the patients had DLBCL-Not Otherwise Specified, 17% had high-grade B-cell lymphoma–Not Otherwise Specified, and 3% had high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit lymphoma or triple-hit lymphoma). Among 87 patients for whom Cell of Origin could be assessed, 68% had Germinal Center B-cell (GCB), 23% had Activated B-Cell (ABC), and 9% were unclassifiable.

With a median follow up of 4.92 years, only 6 of 132 eligible patients progressed, and 3 died as a result of lymphoma, for a 5-year Progression Free Survival (PFS) estimate of 87% and an Overall Survival (OS) estimate of 89%. Eighty-nine percent of the patients with a negative interim PET/CT received R-CHOP × 4, whereas only 11% had a positive interim PET/CT and required radiation-based therapy, with both groups having excellent outcomes.

The authors concluded that, this largest prospective study in the US of limited-stage DLBCL establishes R-CHOP × 4 alone as the new standard treatment for the absolute majority of patients.

Positron Emission Tomography–Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001. Persky DO, Li H, Stephens DM, et al. J Clin Oncol. 2020;38:3003-3011

First Line KEYTRUDA® Superior to Chemotherapy in Metastatic MSI-H/dMMR 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 were diagnosed in the United States in 2020 and about 53,200 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have family histories of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. The FDA in 2017 granted accelerated approval to KEYTRUDA® for patients with advanced MSI-High or dMMR solid tumors, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. This has led to routine MSI-H/dMMR testing in advanced solid tumors.

KEYNOTE-177 is an International, multicenter, randomized open-label, Phase III trial conducted, to evaluate the efficacy and safety of KEYTRUDA® versus Standard-of-Care (SOC) chemotherapy, as first-line therapy for dMMR or MSI-H metastatic ColoRectal Cancer (mCRC). In this study, a total of 307 patients with MSI-H/dMMR mCRC as determined locally, and with ECOG PS of 0 or 1 were randomly assigned 1:1 to first-line treatment with KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=153) or investigator’s choice of mFOLFOX-6 or FOLFIRI every 2 weeks, with or without Bevacizumab or Cetuximab (N=154). Chemotherapy regimens were chosen prior to randomization. Treatment was continued until disease progression, unacceptable toxicity or completion of 35 cycles (for KEYTRUDA® only). The median patient age was 63 years and both treatment groups were well balanced. The co-Primary endpoints of the study were Progression Free Survival (PFS) and Overall Survival (OS). Key Secondary endpoints included Overall Response Rate (ORR) and Safety. Patients with confirmed disease progression on chemotherapy were given the option to crossover, to receive treatment with KEYTRUDA®.

At the second interim analysis, after a median follow up of 32.4 months, it was noted that KEYTRUDA® was superior to chemotherapy with a median PFS of 16.5 months versus 8.2 months for chemotherapy (HR=0.60; P=0.00002). The estimated restricted mean survival time after 24 months of follow up was 13.7 months in the KEYTRUDA® group as compared with 10.8 months in the chemotherapy group. Progression Free Survival was consistently longer with KEYTRUDA® than with chemotherapy across prespecified subgroups. The confirmed ORR was 43.8% with KEYTRUDA® versus 33.1% with chemotherapy, with Complete Responses in 11% and 4%, respectively. Among patients with an Overall Response, 83% in the KEYTRUDA® group had ongoing responses, as compared with 35% in the chemotherapy group at 24 months. The median Duration of Response was not reached in the KEYTRUDA® group and was 10.6 months in the chemotherapy group. Following disease progression, 36% of patients assigned to the chemotherapy group crossed over to the KEYTRUDA® group. This study is being continued to evaluate OS. Grade 3-5 treatment related Adverse Event rates were 22% in the KEYTRUDA® arm and 66% in the chemotherapy group.

The authors concluded that when compared to chemotherapy, first-line therapy with KEYTRUDA® provided a clinically meaningful and statistically significant improvement in Progression Free Survival, among patients with MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related Adverse Events. The authors added that KEYTRUDA® should be the new standard of care for this patient group.

Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. Andre T, Shiu K-K, Kim TW, et al. for the KEYNOTE-177 Investigators. N Engl J Med 2020;383:2207-2218.

Genomics Identify Patients with Smoldering Myeloma at Risk of Developing Multiple Myeloma

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. Smoldering Multiple Myeloma or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years.

The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3 g/dL, IgA M-spike of at least 2 g/dL or a urinary Bence Jones protein level of more than 1 g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values.

Identifying SMM patients who are at a high risk for progression to Multiple Myeloma can allow for early intervention to prevent end-organ damage and potentially achieve long-term remission. Current prognostic models rely solely on clinical markers and do not fully capture the risk of SMM progression. The authors in this study hypothesized that genetic alterations can predict the risk of progression from SMM to overt Multiple Myeloma (MM).

The researchers conducted a multicenter study on bone marrow samples from 214 patients at the time of diagnosis with SMM, using Next-Generation Sequencing (NGS) technologies. This study included an external validation cohort of 72 patients with SMM, whose tumor DNA has been previously sequenced. Whole-Exome Sequencing was performed on 166 tumor samples, and deep targeted sequencing on 48 tumor samples. This study excluded patients who presented at diagnosis with MM related findings such as hypercalcemia, renal impairment, anemia, or bone lytic lesions or who had any myeloma-defining event. Patients with light-chain and nonsecretory SMM were however included. The median patient age was 62 years. Patients were followed up for a median of 6.8 years to identify which of these patients developed myeloma, and the researchers then cross-linked the molecular and clinical data to explore whether certain genomic abnormalities increased the risk of progression to myeloma.

It was noted that most of the genetic alterations necessary for progression to MM were already present by the time of diagnosis of SMM and were all independent risk factors of progression, after accounting for clinical risk staging. They included alterations of the MAPK pathway (KRAS and NRAS Single Nucleotide Variants-SNVs), DNA repair pathway (deletion 17p, TP53, and ATM SNVs) and amplification or translocation of MYC gene.

Patients who harbored MYC aberrations (translocations or amplifications) had the shortest median Time to Progression (8.4 versus 51.6 months; P<0.001) followed by those with MAPK pathway mutations (14.4 versus 60 months; P<0.001) and DNA repair pathway alterations (15.6 versus 50.4 months; P=0.004). These findings were validated in the external cohort of 72 patients with SMM whose tumor DNA had been previously sequenced and the researchers found that patients with any of the high-risk genetic alterations also had a higher risk of progression to MM. APOBEC (“apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like”) associated mutations were enriched in patients who progressed to MM, and were associated with a shorter time to progression.

It was concluded that the genetic alterations with Smoldering Multiple Myeloma are essentially the same as full-fledged myeloma suggesting that by the time Smoldering Multiple Myeloma is diagnosed, most of the molecular abnormalities found in myeloma have already occurred. The authors added that genomic predictors of progression could identify patients at high risk of progression to Multiple Myeloma and thus improve on the precision of current clinical models. However, the role played by tumor microenvironment in the risk of disease progression, remains to be determined.

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. Bustoros M, Sklavenitis-Pistofidis, Park J, et al. J Clin Oncol 2020;38:2380-2389.