Category: Hem/Onc Updates

OPDIVO® plus CABOMETYX® Combination Doubles Progression Free Survival in Newly Diagnosed Advanced Kidney Cancer

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SUMMARY: The American Cancer Society estimates that 73,750 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2020 and about 14,830 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® is 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 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.MOA-of-CABOZANTINIB

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.

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 696O.

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

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SUMMARY: The FDA on September 4, 2020, granted accelerated approval to GAVRETO® (Pralsetinib) for adult patients with metastatic RET fusion-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA approved test. The FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for GAVRETO®. Lung cancer is the second most common cancer in both men and women MOA-of-GAVRETOand accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

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

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

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

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

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

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

FDA Approves DARZALEX® plus KYPROLIS® and Dexamethasone for Multiple Myeloma

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SUMMARY: The FDA on August 20, 2020, approved KYPROLIS® (Carfilzomib) and DARZALEX® (Daratumumab), in combination with Dexamethasone, for adult patients with Relapsed or Refractory multiple myeloma, who have received one to three lines of therapy. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32, 270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.Mechanism-of-Action-of-Daratumumab

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

The efficacy of KYPROLIS® and DARZALEX® along with Dexamethasone was evaluated in two clinical trials, CANDOR and EQUULEUS. CANDOR is a multicenter, open-label, Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0.0027). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. Toxicities were generally manageable and the incidence of Adverse Events leading to treatment discontinuation was similar in both treatment groups.

EQUULEUS is an open label, multicohort trial which evaluated the combination of KYPROLIS® administered weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 IV on cycle 1, day 1, and if tolerated, increased to 70 mg/m2 on Cycle 1 Day 8 and thereafter) along with DARZALEX® IV and Dexamethasone (KdD). Efficacy was based on Overall Response Rate (ORR). Of the 85 patients with Relapsed or Refractory multiple myeloma who had received 1 to 3 prior lines of therapy enrolled in the KdD cohort, the ORR was 81%, with response duration of 27.5 months.

It was concluded that a combination of KYPROLIS® along with Dexamethasone and DARZALEX® resulted in a significant PFS benefit over KYPROLIS® and Dexamethasone alone, with deeper responses, and the PFS benefit of KdD was maintained across prespecified, clinically important subgroups, particularly REVLIMID®-exposed and REVLIMID®-refractory patients. The authors added that KdD regimen should be considered as a novel, efficacious, and tolerable immunomodulatory-free treatment option for Relapsed/Refractory Multiple Myeloma patients.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Dimopoulos M, Quach H, Mateos M-V, et al. The Lancet 2020;396:186-197.

Precision Medicine in Pancreatic Cancer May Improve Overall Survival

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

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

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

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

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

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

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

First Line FOLFOXIRI Plus Bevacizumab May Be a Preferable Strategy for 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. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Patients with metastatic CRC, whose disease has progressed after treatment with standard therapies, have limited therapeutic options available, to treat their disease.

In the TRIBE trial, the triplet combination FOLFOXIRI (Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan) plus Bevacizumab significantly improved Progression Free Survival compared with the doublet combination FOLFIRI (Fluorouracil, Leucovorin and Irinotecan) plus Bevacizumab in patients with metastatic colorectal cancer. However, the actual benefit of first line treatment with three cytotoxic drugs compared with a preplanned sequential strategy of using doublet therapy, as well as the feasibility or efficacy of these therapies after disease progression has remained unclear. The authors in this study aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 and FOLFIRI doublets, in combination with Bevacizumab. It should be noted that FOLFOXIRI regimen is not FOLFIRINOX. FOLFOXIRI regimen does not require a bolus infusion of Fluorouracil, involves a different infusional dose and schedule, and includes Irinotecan and Leucovorin at lower doses than does FOLFIRINOX.

TRIBE2 is an open-label, randomized, multicenter, Phase III study in which first line FOLFOXIRI followed by reintroduction of the same regimen after disease progression, was compared with a sequence of mFOLFOX6 (Fluorouracil, Leucovorin, and Oxaliplatin) and FOLFIRI (Fluorouracil, Leucovorin, and Irinotecan) doublets, in combination with Bevacizumab, in patients with unresectable, previously untreated metastatic colorectal cancer. A total of 679 patients were randomly assigned 1:1 to the control group (N=340) or experimental group (N=339). Patients in the control group received first-line mFOLFOX6 (Oxaliplatin 85 mg/m2 IV along with Leucovorin 200 mg/m2 IV over 120 min, Fluorouracil 400 mg/m2 IV bolus, followed by Fluorouracil 2400 mg/m2 continuous infusion over 48 hours) plus Bevacizumab 5 mg/kg IV over 30 min starting on day 1. Patients in the experimental group received FOLFOXIRI (Irinotecan 165 mg/m2 IV over 60 min, Oxaliplatin 85 mg/m2 IV along with Leucovorin 200 mg/m2 IV over 120 min, Fluorouracil 3200 mg/m2 continuous infusion over 48 hours) plus Bevacizumab 5 mg/kg IV over 30 min starting on day 1. Treatment was repeated every 14 days for up to 8 cycles. Patients then received maintenance treatment with Fluorouracil and Leucovorin along with Bevacizumab every 14 days until disease progression. After disease progression on maintenance treatment, patients in the control group received FOLFIRI (Irinotecan 180 mg/m2 IV along with Leucovorin 200 mg/m2 IV over 120 min, Fluorouracil 400 mg/m2 IV bolus, followed by Fluorouracil 2400 mg/m2 continuous infusion over 48 hours) plus Bevacizumab 5 mg/kg IV over 30 min starting on day 1 every 2 weeks for 8 cycles. This was followed by Fluorouracil and Leucovorin along with Bevacizumab maintenance. After disease progression on maintenance treatment in the experimental group, FOLFOXIRI was reintroduced for up to 8 cycles, followed by Fluorouracil and Leucovorin along with Bevacizumab maintenance. Patient demographics, clinical and molecular baseline characteristics, were well balanced in both treatment groups. The Primary endpoint was Progression Free Survival 2 (PFS2), defined as the time from randomization to disease progression on any treatment given after first disease progression.

At a median follow up of 35.9 months, the median PFS2 19.2 months in the experimental group versus 16.4 months in the control group (HR=0.74; P=0.0005). The median PFS1 was 12 months versus 9.8 months respectively (HR=0.74, P=0.0002). The Objective Response Rate (ORR) to first line treatment was 62% in the experimental group versus 50% in the control group (P=0.0023). The median Overall Survival was 27.4 months in the experimental group versus 22.5 months in the control group (HR=0.82; P=0.032). The most common Grade 3 or 4 adverse events during first-line treatment in the experimental group were diarrhea and neutropenia. Serious adverse events occurred in 25% of patients in the experimental group versus 17% of patients in the control group. After first disease progression, there were no significant differences in frequency of Grade 3 or 4 adverse events between the control and experimental groups, except for a higher incidence of neurotoxicity in the experimental group (5% versus 0%).

It was concluded that first line treatment with FOLFOXIRI plus Bevacizumab followed by the reintroduction of the same regimen after disease progression is the best first-line treatment option for select group of patients with metastatic colorectal cancer, compared to sequential administration of chemotherapy doublets, in combination with Bevacizumab.

Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Cremolini C, Antoniotti C, Rossini D, et al. Lancet Oncol 2020;21:497-505

Novel Ultrasensitive Liquid Biopsy Detects Minimal Residual Disease in Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women 12%) will develop invasive breast cancer during their lifetime. Approximately 279,100 new cases of invasive breast cancer will be diagnosed in 2020 and about 42,690 individuals will die of the disease largely due to metastatic recurrence. Recurrent disease can occur early, but majority of patients with hormone receptor-positive breast cancer may develop recurrent disease decades, following their initial diagnosis. Once a diagnosis of metastatic breast cancer is established, it is generally incurable.

Systemic recurrence likely arises from micrometastatic disease present at initial diagnosis, which is undetectable by imaging or conventional blood tests. Adjuvant systemic therapy is recommended to eradicate micrometastatic disease and reduce the risk of cancer recurrence. However, current clinical tools are not accurate in identifying which patients would benefit from adjuvant systemic therapy and further are unable to, in real-time, predict whether the recommended therapies have achieved their therapeutic objective. Therefore, more sensitive techniques to detect micrometastatic disease are needed, so that patients receive the most appropriate and optimal therapy, with improved outcomes.

Recently published studies have shown that detection of circulating tumor DNA (ctDNA) in the peripheral blood may identify patients at risk of relapse following definitive therapy using digital droplet Polymerase Chain Reaction (ddPCR) assays. ctDNA refers to DNA fragments that are shed into the bloodstream by cancer cells after apoptosis or necrosis. The clinical sensitivity of this technique however is limited at the early postoperative time points, at which treatment decisions are usually made, and the lead time prior to clinical manifestation of overt metastatic disease has been relatively short. This is because presently available techniques track one or few mutations and are unable to detect MRD when the fraction of cancerous cell free DNA (cfDNA) in the bloodstream is low.

The authors developed an ultrasensitive blood test for tracking hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD), with a 1,000-fold lower error rate than conventional sequencing, to identify patients who might benefit from additional systemic treatment or de-escalation of therapy. The authors performed Whole-Exome Sequencing (WES) to define several hundred mutations from each patient’s tumor, and to limit potential errors, selected somatic SNVs (Single Nucleotide Variants) to track, using duplex sequencing in cfDNA and employing strict criteria. The detection of 2 or more mutations in a cfDNA sample was considered MRD-positive and any mutations found in a patient’s own genomic DNA was excluded.

For this study, the authors identified 142 patients who had been treated for Stage 0-III breast cancer with curative intent surgery, had postoperative blood and plasma samples available. Overall, 92% of patients received either neoadjuvant, or adjuvant chemotherapy, 76% received adjuvant endocrine therapy and 73% received adjuvant radiation treatment. Approximately 2% of patients had Stage 0 disease, 23% had Stage I, 48% had Stage II, and 27% had Stage III breast cancer at diagnosis. The MRD levels were tracked post-op (median 3.5 months) and 1 year out (median 14.2 months). The patients were monitored for distant recurrences for up to 13 years. A median of 57 mutations were targeted in each patient, identified via Whole-Exome Sequencing of primary tumor tissue and genomic DNA from whole blood. About 78% of patients had post-op samples available, while 86% had 1-year samples. The Primary objective of this study was to determine the predictive power of MRD testing and associated lead time to recurrence, in patients treated for early-stage breast cancer.

The median lead time (the time from a positive test to diagnosis of metastatic disease) between the first MRD-positive result and disease recurrence was 18.9 months in the patients with the most mutations tracked. This is significantly longer than what has been seen in prior studies. Distant disease recurrence was shown to be more likely if MRD was detected at the 1-year mark (HR=20.8; P<0.0001) compared with the post-op setting. Among these patients, the positive and negative predictive values for distant recurrence, was 0.70 and 0.77, respectively. Overall, the clinical sensitivities were 81% in patients with newly diagnosed metastatic breast cancer, 23% in the post-op setting, and 19% at the one year in early stage disease, and highest among patients with the most tumor mutations available to track. The authors noted that their testing methodology was 100-fold more sensitive than ddPCR, when tracking 488 mutations.

It was concluded that the ultrasensitive blood test developed by investigators for Minimal Residual Disease (MRD) could identify survivors who might benefit from additional systemic treatment versus de-escalation. MRD detection was strongly associated with distant recurrence and provided significant lead time to recurrence, enabling early therapeutic intervention in patients who may otherwise develop metastatic recurrence. The authors recommended that future blood-based Whole-Genome Sequencing assays should aim for extra sensitivity, to identify enough mutations to track in all patients.

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer. Parsons HA, Rhoades J, Reed SC, et al. Clin Can Res. DOI: 10.1158/1078-0432.CCR-19-3005. Published June 2020.

Association Between Immune Related Adverse Events and Recurrence Free Survival in Stage III Melanoma

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

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types.

Immune-related Adverse Events (irAEs) are commonly observed following treatment with ICIs. An association between irAEs and improved outcomes has been reported, among patients with malignant melanoma and lung cancer, treated with ICIs such as anti-CTLA-4 and anti-PD-1 antibodies. It however remains unclear whether immune-related Adverse Events (irAEs) indicate drug activity in patients treated with ICIs.

The European Organization for Research and Treatment of Cancer (EORTC) 1325/(KEYNOTE-054) trial is a randomized, double-blind, placebo-controlled Phase III study which enrolled 1019 patients with completely resected, Stage IIIA, IIIB or IIIC Melanoma. Patients were randomly assigned 1:1 to receive KEYTRUDA® 200 mg IV every three weeks (N=514) or placebo (N=505) as adjuvant therapy, for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. KEYTRUDA® 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.

This study met the Primary end point of Recurrence-Free Survival (RFS), in this high-risk Stage III melanoma patients. KEYTRUDA® was associated with significantly longer Recurrence-Free Survival (RFS) compared to placebo in the overall intent-to-treat population, with a 1-year RFS rate of 75.4% versus 61.0% respectively (HR for recurrence or death=0.57; P<0.001). This suggested that the risk of recurrence or death in the total population was 43% lower in the KEYTRUDA® group than in the placebo group.

The authors in this publication investigated the association between immune-related Adverse Events (irAEs) and Recurrence-Free Survival (RFS) in the KEYNOTE-054 clinical trial, adjusting for age, sex and stage of the disease and also investigated the influence of systemic steroid use on outcome. Of 1011 patients who received treatment with KEYTRUDA® therapy or placebo, 61.5% were men and 38.5% were women. About 25% were 65 years and older and 37% of patients were younger than 50 years. The onset of the first irAE occurred within the first 6 months of treatment for majority of the patients who experienced an irAE and the common irAEs included endocrine disorders such as hypothyroidism or hyperthyroidism, and vitiligo. The incidence of irAEs was 37.4% in the KEYTRUDA® group and 9% in the placebo group, and in each treatment group, the incidence of irAEs was similar for men and women, for younger and older patients, and across different disease stages.

Consistent with previously published results in the intent-to-treat population, a prolonged RFS was observed in the KEYTRUDA® group compared with the placebo group, among patients who started the treatment allocated at the time of randomization (HR=0.56). The occurrence of an irAE was associated with a longer RFS in the KEYTRUDA® group (HR=0.61; P=0.03), but not in the placebo group (HR=1.37; P=0.21). Compared with the placebo arm, the reduction in the hazard of recurrence or death was substantially higher (P=0.03) after the onset of an irAE (HR=0.37), than without or before the onset of an irAE (HR=0.62), in patients who started KEYTRUDA® treatment. Similar results were obtained in each sex group and when only endocrine AEs were considered. Steroid are known to be immune-suppressive and treatment with KEYTRUDA® was less effective when steroids were used after the onset of an irAE.

It was concluded from this secondary analysis that the occurrence of an irAE was associated with a longer Relapse-Free Survival, among patients treated with KEYTRUDA®.

Association Between Immune-Related Adverse Events and Recurrence-Free Survival Among Patients With Stage III Melanoma Randomized to Receive Pembrolizumab or Placebo. A Secondary Analysis of a Randomized Clinical Trial. Eggermont AM, Kicinski M, Blank CU, et al. JAMA Oncol. 2020;6:519-527.

Immunotherapy Benefits All Patient Groups with Advanced Cancer

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SUMMARY: The American Cancer Society estimates that in 2020, there will be an estimated 1.8 million new cancer cases diagnosed and 606,520 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

Immune Checkpoint Inhibitors enhance antitumor immunity by unleashing the T cells. However, this benefit may vary among patients and tumor types. Sex is a biological variable that affects immune responses. Women tend to mount stronger innate as well as adaptive immune responses, than men. (Innate immunity is inherently present in the body, whereas Adaptive immunity occurs in response to exposure to a foreign substance). This can translate into greater efficacy with vaccines and more rapid clearance of pathogens. Aging alters immune responses and adaptive immunity becomes less functional. Altered ECOG Performance Status has also been associated with poor immune response. Several other studies have been published looking at these variables, with conflicting results.

To address these discordant results, the authors performed a meta-analysis to examine the potential association of sex, age, and ECOG PS with immunotherapy survival benefit in patients with advanced cancer. This study was limited to randomized clinical trials that compared Overall Survival (OS) in patients with advanced cancer treated with ICI immunotherapy versus non-ICI control therapy. Data sources such as PubMed, Web of Science, Embase, and Scopus were searched and a total of 37 Phase II or III randomized clinical trials involving 23,760 patients were included in the analysis. Of these, 13 trials evaluated ICIs as first-line therapy. The most common cancer types studied were Non-Small Cell Lung Cancer (N= 14). The most common immune checkpoint inhibitors used were PD-1/PD-L1 inhibitors (N=25). The main Outcomes and Measures were the difference in survival benefit of ICIs between sex, age (less than 65 versus 65 years or more), ECOG PS (0 versus 1 or more), as well as the outcomes stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy (ICI alone or ICI combined with non-ICI) in the intervention arm.

The authors noted that Overall Survival benefit with ICI immunotherapy treatment was found for both men (HR=0.75) and women (HR=0.79), for both younger and less than 65 years (HR=0.77) and 65 years or older (HR=0.78) patients, and for both, patients with ECOG Performance Status 0 (HR=0.81) and PS greater than or equal to 1 (HR=0.79). There was no significant difference of relative benefit from immunotherapy over control therapy in patients of different sex (P=0 .25), age (P=0.94), or ECOG PS (P=0.74). Further, there was no significant difference found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

It was concluded that the results of this meta-analysis suggest that immunotherapy with ICIs may confer a survival benefit in the treatment of advanced cancer, regardless of patient sex, age, and performance status, and should not be restricted based on these characteristics.

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials. A Systematic Review and Meta-analysis. Yang F, Markovic SN, Molina JR, et al. JAMA Netw Open. 2020;3(8):e2012534. doi:10.1001/jamanetworkopen.2020.12534

VIDAZA® plus VENCLEXTA® for Elderly patients with AML

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SUMMARY: The American Cancer Society estimates that in 2020, 19,940 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,180 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard 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.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.VENCLEXTA_MOA

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both.

All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median patient age was 76 years. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group, and poor cytogenetic risk was reported in 36% and 39%, respectively. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively. The incidence of febrile neutropenia was higher in the VIDAZA® plus VENCLEXTA® group than in the control group. Infections of any grade occurred in 85% of the patients in the VIDAZA® plus VENCLEXTA® group and in 67% of those in the control group, and serious Adverse Events occurred in 83% and 73%, respectively.

It was concluded that among previously untreated patients with AML who were ineligible for intensive chemotherapy, those who received VIDAZA® plus VENCLEXTA® had significantly longer Overall Survival and higher remission rates, compared to those who received VIDAZA® alone. Whether VIDAZA® plus VENCLEXTA® will replace conventional induction chemotherapy for AML, remains to be seen.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. DiNardo CD, Jonas BA, Pullarkat V, et al. N Engl J Med 2020; 383:617-629

Favorable Outcomes with KADCYLA® in HER2+ Breast Cancer Irrespective of Mutational Status

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response (pCR) rate of 40-60%. Those without a pCR tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy. KATHERINE trial was conducted to address an unmet need, and evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy, in patients with residual invasive cancer at surgery.Mechanism-of-Action - KADCYLA

The KATHERINE trial is an open-label, Phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and Hormone Receptor positive disease was present in 72% of the patients. The Primary end point was invasive Disease Free Survival (iDFS-defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group, which translated to an absolute improvement of 11.3%. Invasive Disease Free Survival (iDFS), which was the Primary end point of the study, was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001).This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%.

The authors in this publication reported the exploratory analyses of the relationship between iDFS, and biomarkers potentially related to response. The authors focused on pathways that have been implicated in resistance to HER2 treatment such as pathways associated with PIK3CA mutations, as well as HER2 and PD-L1 expression in the post-neoadjuvant residual surgical samples.

In the first part of this biomarker analysis, a total of 1,363 available post-neoadjuvant surgery samples were analyzed through DNA sequencing for PIK3CA mutations. In the second part of this analysis, mRNA expression through RNA sequencing was determined on 1,059 tissue samples of which 244 were pre-neoadjuvant samples and 815 were post-neoadjuvant surgical samples. Because the post-neoadjuvant surgical samples were representative of the entire Intent-To-Treat (ITT) patient population, biomarker analysis for markers such as HER2, PD-L1, CD8, and predefined immune signatures including 3-gene, 5-gene, Teffector, chemokine signaling, and checkpoint inhibitor signatures, were performed by using post-neoadjuvant surgical samples.

The authors noted that in the ITT population (N=743), PIK3CA mutation status had no impact on outcomes when treated with KADCYLA®. Among those patients with mutated tumors who received KADCYLA® and HERCEPTIN®, the iDFS rates were 88.9% versus 77.9%, respectively (HR=0.54) and among those with non-mutated tumors the Invasive Disease Free Survival rates were 88.3% versus 77.0%, respectively (HR=0.48). There was no prognostic impact of PIK3CA mutations in this cohort of patients and the 3 year iDFS rates were almost identical between the mutated and non-mutated tumors.

The authors next looked at HER2 gene expression in the post-neoadjuvant surgical samples and noted that patients who had a tumors with high HER2 expression in the post-neoadjuvant residual surgical samples, and received subsequent treatment with HERCEPTIN®, had the worst outcomes with worse iDFS. This detrimental effect was not seen in the KADCYLA® group, suggesting that residual tumors that have a high HER2 expression in this setting are resistant to HERCEPTIN® but not to KADCYLA®.

When patients were evaluated based on their tumor PD-L1 expression, low PD-L1 expression in post-neoadjuvant residual tumors was associated with a worse outcome for those who received treatment with HERCEPTIN®, whereas treatment with KADCYLA® did not impact outcomes. These findings suggested that PD-L1 may be involved in some resistance mechanisms.

It was concluded that in the KATHERINE trial biomarker analysis, PIK3CA mutation status did not influence outcomes in either treatment groups. However, in the post-neoadjuvant HERCEPTIN® group, high HER2 expression and low PD-L1 expression was associated with less favorable outcomes. The benefit with KADCYLA® in this patient population was independent of all biomarkers assessed.

Biomarker data from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer. Denkert C, Lambertini C, Fasching PA, et al. J Clin Oncol. 2020;38(suppl 15):502. doi: 10.1200/JCO.2020.38.15_suppl.502