Association between Antibiotic Use and Colorectal Cancer

SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the overall death rate has continued to drop, deaths from CRC among people younger than 55 years have increased 1% per year from 2008 to 2017, with 12% of CRC cases diagnosed in people under age 50. The proportion of the total number of patients diagnosed with CRC under the age of 50 yrs rose from 10% in 2004 to 12.2% in 2015 (P<0.0001). Younger adults presented with more advanced stage of disease (Stage III/IV) than those 50 yrs or older (51.6% versus 40.0% respectively). Based on these findings, the American Cancer Society in 2018 updated its guidelines to include a “qualified recommendation” to begin CRC screening at the age of 45 yrs. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet, which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking.

Preclinical studies have suggested that there is a very complex interplay of the immune system with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation.

There has been a significant increase in the global antibiotic consumption and colorectal cancer (CRC) rates in individuals aged less than 50 years since the late 1980s. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may influence CRC genesis in older patients and negate the benefits of immunotherapy and influence treatment outcomes. Quinolones and Sulfonamides/Trimethoprim antibiotics used to treat a wide range of infections have been associated with these right side colon cancers. It has been postulated that gut flora with more abundant Fusobacteria and Bacteroidetes may contribute to CRC development. The limited effect of Quinolones and Sulfonamides on anaerobic bacteria would therefore favor anaerobic bacteria such as Fusobacteria species and Bacteroidetes species, which may play a role in CRC development. The purpose of this analysis was to investigate antibiotics use in relation to subsequent CRC risk.

The authors conducted a matched case-control study using data from Swedish population from July 2005 to December 2016. Swedish personal Identity numbers enabled multiregister linkage and matching. The CRC cases identified using the Swedish Colorectal Cancer Register, were matched with controls from the Total Population Register. Data on antibiotics use were extracted from the Swedish Prescribed Drug Register, and other variables of interest were taken from the Swedish Inpatient Register and the Longitudinal Integration Database for Health Insurance and Labor Market Studies. All primary CRC cases were classified as proximal colon cancer (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure), distal colon cancer (descending, sigmoid colon), or rectal cancer (rectosigmoidal junction, rectum). Stages of CRC were categorized as early stage (Stage I-II) and late stage (Stage III-IV) based on TNM Classification. This nationwide, population-based study with a matched case-control design included 40,545 newly diagnosed CRC cases (67% in the colon and 33% in the rectum) and 202720 controls (for each CRC case, 5 controls were selected from the Total Population Register). Approximately 53% were men and 47% were women. Prespecified subgroup analyses (sex, age, and anatomical tumor site) were performed, and those with antibiotic use, within 2 years of CRC diagnosis were excluded. Antibiotics use reported as defined daily doses, was categorized as no use (no reported use of antibiotics during the study period), low (1-10 days), moderate (11-60 days), high (61-180 days), and very high (more than 180 days) use.

It was noted in this analysis that there was a positive dose-response association between antibiotics use and colon cancer. The CRC risk was mostly confined to proximal colon cancer for moderate use and for very high use, versus no use (P<0.001). The association between antibiotics use and risk of proximal colon cancer was more obvious among patients 50 years and older at the time of diagnosis, compared with patients younger than 50 years. There was an inverse association between antibiotics use and rectal cancer, probably reflecting differences in the bacterial flora at those two sites. When stratified by tumor stage, the positive association between antibiotics use and risk of proximal colon cancer was more pronounced in Stage I-II cancer compared with Stage III-IV cancer. In contrast, the inverse association in rectal cancer was limited to Stage III-IV. Quinolones and Sulfonamides and/or Trimethoprims were associated with increased risk of proximal colon cancer whereas Nitrofurantoins, Macrolides and/or Lincosamides, and notably, Metronidazoles and/or Tinidazoles (which exclusively inhibit anaerobic bacteria) were inversely associated with rectal cancer. Antibiotics across all classes generally had an inverse association for rectal cancer in women. There was no association noted between Methenamine hippurate, a urinary tract antiseptic not affecting the gut microbiota, and CRC risk.

It was concluded from this analysis that there was a consistent association between antibiotics use and higher subsequent risk of proximal colon cancer and an inverse association for rectal cancer in women. The authors added that these findings strengthen the evidence from previous investigations and provide new insights into site-specific carcinogenesis, as well as indirect support for the role of gut microbiota. This study provides further reasons to reduce, where possible, frequent and unnecessary antibiotic prescribing.

Antibiotics use and subsequent risk of colorectal cancer: A Swedish nationwide population-based study. Lu SSM, Mohammed Z, Haggstrom C, et al. JNCI: Journal of the National Cancer Institute, djab125, https://doi.org/10.1093/jnci/djab125

Durable Survival Benefit with First Line OPDIVO® plus YERVOY® and a Limited Course of Chemotherapy

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

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. OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. In the CheckMate-227, Part 1, Phase III trial, a combination of OPDIVO® plus YERVOY®, significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with OPDIVO® plus YERVOY® could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

CheckMate-9LA is a randomized, open-label, multi-center, Phase III trial which evaluated the benefit of a combination of OPDIVO® plus YERVOY®, and 2 cycles of Platinum-doublet chemotherapy (experimental arm) versus Platinum-doublet chemotherapy (control arm) for 4 cycles, followed by optional Pemetrexed maintenance therapy, as a first-line treatment in patients with metastatic or recurrent NSCLC, regardless of PD-L1 status and histology. In this study, 719 adults treatment naïve patients with histologically confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive OPDIVO® 360 mg every 3 weeks plus YERVOY® 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group.

The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and efficacy by PD-L1 subgroups. PFS2 was a pre-specified exploratory endpoint and was defined as time from randomization, to objectively documented progression after the next line of therapy, or to death from any cause, whichever occurred first. At a preplanned interim analysis after a minimum follow up 8.1 months, this trial met its primary and secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histologies.

The authors in this publication reported updated efficacy and safety outcomes, along with Progression-Free Survival (PFS) after next line of treatment (PFS2), Treatment-Related Adverse Events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental treatment group due to TRAEs, from the CheckMate 9LA Phase III trial. The minimum follow up for OS was 24.4 months. The majority of patients (93%) received two cycles of chemotherapy and 13% completed the maximum 2 years of immunotherapy treatment. The median number of doses was 9.0 for OPDIVO® and 4.0 for YERVOY®. In the control arm, 75% of patients received four cycles of chemotherapy and 67% patients who had non-squamous tumor histology receiving Pemetrexed maintenance. About 29% patients in the control arm had completed the full four cycles of chemotherapy without optional Pemetrexed maintenance therapy. The median duration of therapy was 6.1 months in the experimental arm and 2.5 months in the control arm.

With a median follow up of 30.7 months, OPDIVO® plus YERVOY® with a limited course of chemotherapy continued to prolong Overall Survival (OS), when compared to chemotherapy (Median OS 15.8 versus 11.0 months; HR=0.72). The 2-year OS rate was 38% versus 26%. This OS benefit was observed across most key subgroups including those with PD-L1 expression of less than 1%, more than 1%, as well as by histology. More importantly, patients with pretreated CNS metastases at baseline had a median OS of 19.9 months in the experimental group versus 7.9 months in the control group, respectively (HR=0.47).

PFS continued to be prolonged in the experimental group compared to the control group, with an Hazard Ratio of 0.67 and 2-year PFS rates of 20% versus 8%, respectively. The ORR was 38% in the experimental group and 25% in the control group (P=0.0003). 34% versus 12% of all responses respectively, were ongoing at 2 years. The median PFS2 in all randomized patients was 13.9 months in the experimental group and 8.7 months in the control group (HR=0.66). Again, PFS2 also favored the experimental arm over the control arm in subgroups by PD-L1 expression, and by histology.

No new safety signals were observed and majority of Grade 3/4 toxicities were mostly observed during the first two treatment cycles in the experimental group. In patients who discontinued all components of the experimental treatment (OPDIVO® plus YERVOY® with chemotherapy) due to toxicities (N=61), the median OS was 27.5 months and 56% of responders had an ongoing response, more than 1 year after discontinuation of therapy. After discontinuing the experimental regimen, patients remained treatment-free for a median of 11.9 months and had a 48% chance of being treatment-free at 1 year.

The researchers concluded that with a 2-year minimum follow-up, OPDIVO® plus YERVOY® with two cycles of chemotherapy provided durable efficacy benefits over conventional chemotherapy, with a manageable safety profile. They added that this treatment regimen remains an efficacious first line treatment of advanced Non Small Cell Lung Cancer.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. Reck M, Ciuleanu T-E, Cobo M, et al. https://doi.org/10.1016/j.esmoop.2021.100273

Late Breaking Abstract – ESMO 2021: Adjuvant KEYTRUDA® for High Risk Stage II Melanoma

SUMMARY: The American Cancer Society’s estimates that for 2021, about 106,110 new cases of melanoma will be diagnosed in the United States and 7,180 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for Stage I disease and 90% for Stage II disease. The current standard of care for patients following resection of high-risk Stage II disease is observation, even though patients with Stage IIB and IIC disease presenting with high-risk features (depth of invasion, T-category, ulceration) have 5 and 10 year melanoma-specific survival similar to that of patients with Stage IIIA and IIIB disease.

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. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. The FDA in 2019, approved KEYTRUDA® for the adjuvant treatment of patients with melanoma, with involvement of lymph node(s) following complete resection (Stage III). The present study was conducted to evaluate the role of adjuvant immunotherapy in patients with high risk Stage II melanoma.

KEYNOTE-716 is a randomized, double-blind, Phase III trial, in which 976 patients aged 12 years or older, with completely resected cutaneous Stage IIB or IIC melanoma, and no lymph node involvement, were randomly assigned 1:1 to receive KEYTRUDA® 200 mg (2 mg/kg for pediatric patients) or placebo, every 3 weeks for 17 cycles (up to 1 year). Patients were stratified by T category 3b, 4a, 4b (adults) and with a separate stratum for pediatric patients. Approximately 65% had Stage IIB disease and 35% had Stage IIC disease. There was no prespecified analysis for PD-L1 or BRAF status in this study, as there was inconsistent and small amounts of tissue available for testing. This was the first part (Part 1) of this double-blind study. The Primary endpoint was Relapse Free Survival (RFS) per investigator assessment, and Safety. The second part (Part 2) of this study was open-label design, and adults and pediatric patients were eligible to receive up to 35 additional cycles of treatment, only if they had recurrence after receiving the placebo or completed 17 cycles of KEYTRUDA®. Patients in the KEYTRUDA® group who experienced disease recurrence within 6 months of completing the treatment were excluded from Part 2 of the study. Secondary end points included Distant Metastasis-Free Survival, Overall Survival (OS) and Quality of Life. The researchers herein reported the results at the interim analysis of Part 1 of this study, and Part 2 data are not yet mature.

At median follow up of 14.4 months, the study met its Primary end point of RFS at the first protocol-specified analysis. KEYTRUDA® significantly prolonged RFS compared to placebo (HR=0.65; P=0.00658). At the time of this analysis, 11.1% of patients on KEYTRUDA® had a recurrence, compared to 16.8% of those receiving placebo. The 12-month RFS rate was 90.5% for KEYTRUDA® versus 83.1% for placebo. Median RFS was Not Reached in either group at the time of this analysis. Quality of Life scores were similar between the KEYTRUDA® and placebo groups at all time points.

It was concluded that adjuvant KEYTRUDA® for resected Stage IIB and IIC melanoma decreased the risk of disease recurrence or death by 35% compared with placebo, and was associated with significantly prolonged Relapse Free Survival and a favorable benefit-risk profile. KEYNOTE-716 is the first randomized Phase III trial of an anti-PD-1 therapy in resected Stage II melanoma, and these findings represent an important milestone for this patient group.

LBA3_PR – Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Luke JJ, Rutkowski P, Queirolo P, et al. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346. 10.1016/annonc/annonc741.

Late Breaking Abstract – ESMO 2021: Keytruda® Plus Chemotherapy in Advanced Cervical Cancer

SUMMARY: The American Cancer Society estimates that for cervical cancer in the US for 2021, about 14,480 new cases of invasive cervical cancer will be diagnosed and about 4,290 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to develop cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.

Patients with persistent, recurrent, or metastatic cervical cancer often receive Platinum-based chemotherapy, (Cisplatin or Carboplatin along with Paclitaxel) plus Bevacizumab. The addition of Bevacizumab to chemotherapy improved the median Overall Survival from 13.3 months to 17 months in a randomized study.

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In the KEYNOTE-158 trial, the Objective Response Rate (ORR) with single agent KEYTRUDA® in previously treated recurrent or metastatic cervical cancer patients with PD-L1 positive tumors was 14.3%. KEYNOTE-826 trial was conducted to assess whether adding KEYTRUDA® to Platinum-based chemotherapy with or without Bevacizumab would improve efficacy, as compared with chemotherapy with or without Bevacizumab, as first line therapy for persistent, recurrent, or metastatic cervical cancer.

KEYNOTE-826 is a global, multicenter, double-blind, randomized Phase III trial, in which 617 women with recurrent, persistent, or metastatic cervical cancer were randomly assigned in a 1:1 ratio to receive KEYTRUDA® 200 mg IV or placebo, every 3 weeks for up to 35 cycles. Patients in both treatment groups received Paclitaxel 175 mg/m2 IV and the investigator’s choice of Cisplatin 50 mg/m2 or Carboplatin AUC 5 IV every 3 weeks. Chemotherapy was limited to 6 cycles, although patients with ongoing clinical benefit without unacceptable side effects could continue beyond 6 cycles. Bevacizumab at a dose of 15 mg/kg IV every 3 weeks was allowed at the investigator’s discretion. Enrolled patients were not previously treated for advanced disease and were not considered curable. The median patient age was 50 years, and close to two thirds of the patients had persistent or recurrent disease with distant metastases. Patients were stratified according to metastatic disease at diagnosis, planned Bevacizumab use and PD-L1 Combined Positive Score (CPS) less than 1, 1-9 and 10 or more. All the treatment groups were well balanced and about 63% of patients in each treatment group received Bevacizumab. Eighty eight percent (88%) of patients had PD-L1 CPS 1 or more at baseline, and 51% had CPS 10 or more. Approximately 72% of the patients had Squamous Cell Carcinoma, 56% received previous chemoradiotherapy with or without surgery, and 20% had previously untreated metastatic disease at trial entry. The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). The median follow up for the first interim analysis was 22.0 months.

The median PFS in those patients with a PD-L1 CPS of 1 or more (N=548) was 10.4 months in the KEYTRUDA® group and 8.2 months in the placebo group (HR for disease progression or death=0.62; P<0.001). This represented a 38% reduction in the risk of disease progression or death in the KEYTRUDA® group. The PFS in all enrolled patients (N=617) was 10.4 months and 8.2 months, respectively (HR=0.65; P<0.001). The PFS in patients with a PD-L1 CPS of 10 or more (N=317) was 10.4 months and 8.1 months, respectively (HR=0.58; P<0.001).

The OS at 24 months was significantly longer in the KEYTRUDA® group, compared to the placebo group, among patients with a PD-L1 CPS of 1 or more, and was 53% in the KEYTRUDA® group and 41.7% in the placebo group (HR for death= 0.64; P<0.001), 50.4% and 40.4% among all enrolled patients (HR=0.67; P<0.001), and 54.4% and 44.6% among patients with a PD-L1 CPS of 10 or more (HR=0.61; P=0.001), respectively. The confirmed Response Rates were also higher and Duration of Response longer in all patient groups receiving KEYTRUDA®, compared to placebo. Side effects with the combination therapy were manageable and were as expected, based on known adverse events with the individual drugs.

It was concluded that the addition of KEYTRUDA® to chemotherapy, with or without Bevacizumab, significantly prolonged Progression Free and Overall Survival, among patients with persistent, recurrent, or metastatic cervical cancer.

Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. Colombo N, Dubot C, Lorusso D, et al. for the KEYNOTE-826 Investigators. September 18, 2021. DOI: 10.1056/NEJMoa2112435.

Late Breaking Abstract – ESMO 2021: ENHERTU® Superior to KADCYLA® in Patients with HER2 Positive Metastatic Breast Cancer

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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA® given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure.

In the DESTINY-Breast 01 Phase II registration trial involving patients with HER2-positive metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, the Objective Response Rate (ORR) was 60.9%, with 6% Complete Responses and 54.9% Partial Response, with a median response duration of 14.8 months. The median PFS was 16.4 months. This benefit was consistent across all key subgroups, including patients who had previously received PERJETA® therapy.

DESTINY-Breast 03 is a global, multicenter, open-label, randomized Phase III study, in which the efficacy and safety of ENHERTU® was compared with KADCYLA®, in patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a Taxane. In this study, 524 pts were randomized 1:1 to receive ENHERTU® 5.4 mg/kg (N=261) or KADCYLA® 3.6 mg/kg (N=263) once every 3 weeks. The median patient age was 54 years and patients in both treatment groups were comparable in terms of baseline characteristics including age, HER2-positivity status, ECOG Performance Status, prior treatment for breast cancer, brain metastases, and prior cancer therapy with agents including Trastuzumab. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, PFS by investigator, and Safety.

At the time of the prespecified interim analysis of this study, the median follow up was approximately 16 months and the median PFS by BICR review was Not Reached with ENHERTU® and was 6.8 months with KADCYLA® (HR=0.28; P= 7.8 × 10−22). This represented a very statistically significant 72% reduction in the risk for progression or death with ENHERTU® compared to KADCYLA®. The investigator-assessed PFS was similar (25.1 versus 7.2 months, HR=0.26, P<0.0001). This PFS benefit was observed as early as 4 weeks and remained consistent throughout the follow up period. PFS was significantly higher with ENHERTU® in all prespecified key subgroups, including Hormone Receptor status, prior treatment with PERJETA®, visceral disease, number of prior lines of therapy, and the presence or absence of brain metastases. Majority of patients in the ENHERTU® group experienced a reduction in tumor size, and the ORR was significantly higher among patients in the ENHERTU® compared to those who received KADCYLA® (79.7% versus 34.2%; P<0.0001), with a near doubling of the Complete Response rate in the ENHERTU® group, at 16.1% compared to 8.7% in the KADCYLA® group. The estimated 12-month Overall Survival rate was 94.1% versus 85.9% respectively (HR=0.56; P=0.007), but was not considered significant as it did not cross the prespecified boundary for significance, likely due to the immaturity of the dataset.

Adjudicated treatment related Interstitial Lung Disease/pneumonitis was more common in the ENHERTU® compared with the KADCYLA® treatment arm, at rates of 10.5% and 1.9%, respectively and most of the events were Grade 1 or 2 in severity, and none at Grade 4 or 5 in either treatment group. Interstitial Lung Disease profile was of less concern, than was seen in previous trials of ENHERTU® in more heavily pretreated patients. All Left Ventricular Ejection Fraction decreases were Grade 1 or 2 and were seen in 2.7% of the ENHERTU® group and in 0.4% of KADCYLA® group.

The researchers concluded that ENHERTU® demonstrated a highly statistically significant and clinically meaningful improvement in Progression Free Survival, when compared to KADCYLA®, in patients previously treated with Trastuzumab and Taxane for HER2-positive metastatic Breast cancer, with manageable toxicity and a significant improvement in Interstitial Lung Disease profile. The authors added that these data support ENHERTU® becoming the standard of care for second line treatment of HER2-positive metastatic breast cancer.

Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Cortés J, Kim SB, Chung WP, et al. Presented at: European Society for Medical Oncology 2021 Virtual Congress. September 16-21, 2021; virtual. Abstract LBA1.

PSMA Targeted Therapy Improves Overall Survival in Metastatic Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen) and the estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

Prostate-Specific Membrane Antigen (PSMA) is a type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer.

Lu-177-PSMA-617 is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with Lu-177-PSMA-617 targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell. The antitumor activity and safety of Lu-177-PSMA-617 have been established previously in a Phase II study (Lancet Oncol. 2018;19:825-833).

VISION is an international, randomized, open-label Phase III study in which the benefit of Lu-177-PSMA-617 was evaluated in men with PSMA-positive mCRPC, previously treated with second generation Androgen Receptor signaling pathway inhibitor (XTANDI®-Enzalutamide or ZYTIGA®-Abiraterone acetate), and 1 or 2 taxane chemotherapy regimens. In this trial, 831 patients were randomized 2:1 to receive Lu-177-PSMA-617, 7.4 GBq every 6 weeks for 6 cycles plus Standard of Care as determined by the treating physician (N=551), or Standard of Care only (N=280). Both treatment groups were well balanced and this trial excluded patients treated with XOFIGO® (Radium-223). Enrolled patients had a castrate level or serum/plasma testosterone of lower than 50 ng/dL, and PET imaging with 68 Ga-PSMA-11 was used to determine PSMA positivity by central review. The Primary endpoints were radiographic Progression Free Survival (rPFS) by Independent Central Review (ICR) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and time to first Symptomatic Skeletal Event (SSE). The median study follow up was 20.9 months.

Lu-177-PSMA-617 plus Standard of Care significantly improved rPFS by 60%, compared to Standard of Care alone (median rPFS 8.7 versus 3.4 months, HR=0.40; P<0.001). The median OS was also significantly improved by 38% with Lu-177-PSMA-617 plus Standard of Care compared to Standard of Care alone (median OS 15.3 versus 11.3 months, HR=0.62; P<0.001). All key secondary endpoints including Objective Response Rate, Disease Control Rate, and time to first Symptomatic Skeletal Event were statistically significant, and in favor of Lu-177-PSMA-617 plus Standard of Care.

It was concluded that radioligand therapy with Lutetium-177–PSMA-617 significantly improved radiographic Progression Free Survival and Overall Survival when added to Standard of Care, compared with Standard of Care alone, in men with PSMA-positive metastatic Castration Resistant Prostate Cancer.

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Sartor O, de Bono J, Chi KN, et al. N Engl J Med 2021; 385:1091-1103.

KEYTRUDA® in Combination with Chemotherapy Improves Overall Survival in Triple Negative Breast Cancer

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. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

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. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first line treatment of advanced TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-Paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety.

The authors had previously reported that KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82).

The researchers have now reported the Overall Survival results after a median follow up of 44.1 months. The OS in the subgroup of patients with PD-L1 CPS of 10 or more was significantly better with first line KEYTRUDA® plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively; HR=0.73; P=0.0093). This represented a 27% reduction in the risk of death with the KEYTRUDA® combination. Among this subgroup, factors significantly associated with superior outcomes included age 65 yrs and older, use of Paclitaxel as the on-study chemotherapy, no prior adjuvant therapy, de novo metastasis, Disease Free Interval of 12 months or more, and less than 3 metastatic sites. However, this OS benefit was not noted in the subgroup of patients with PD-L1 CPS scores of 1 or less. In this subgroup, the median OS was 17.6 months in the KEYTRUDA® group and 16 months in the placebo group (HR=0.86; P=Not Significant). The same was true among the Intention-To-Treat (ITT) population, including all randomized patients regardless of PD-L1 tumor status. In this patient group, the median OS was 17.2 months in the KEYTRUDA® group and 15.5 months in the placebo group, and this was not statistically significant (HR=0.89).

The authors concluded that these updated results support KEYTRUDA® in combination with chemotherapy as a new standard-of-care treatment regimen for patients with locally recurrent unresectable or metastatic Triple Negative Breast Cancer, whose tumors express PD-L1, with CPS of 10 or more.

KEYNOTE-355: Final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Cortes J, Cescon DW, Rugo HS. et al. European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA16. Presented on September 19, 2021.

FDA Approves EXKIVITY® for Metastatic Non Small Cell Lung Cancer with EGFR exon 20 Insertion Mutations

SUMMARY: The FDA on September 15, 2021, granted accelerated approval to EXKIVITY® (Mobocertinib), for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic device to select patients with the above mutations for EXKIVITY® treatment.

The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC, and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

EXKIVITY® is a novel oral EGFR TKI, that was designed to address the unmet need in patients with EGFR exon 20 insertion mutant positive NSCLC. EXKIVITY® was designed to potently inhibit oncogenic variants containing activating mutations in exon 20, with selectivity over Wild Type EGFR.

The present FDA approval of EXKIVITY® was based on an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. This trial was conducted in three parts- Dose escalation or Part 1, to determine the safety profile of EXKIVITY®, Expansion phase or Part 2, to evaluate the antitumor activity of EXKIVITY® in seven histologically and molecularly defined cohorts, and Extension phase or Part 3, to evaluate efficacy of EXKIVITY® in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations, and who have been previously treated.

So, this 3-part, multicenter study has dose-escalation/expansion and extension (EXCLAIM) cohorts. Patients with EGFR exon 20 insertion positive metastatic NSCLC, with ECOG status 0-1, and one or more prior lines of therapy for locally advanced/metastatic disease, received EXKIVITY® 160 mg orally daily, until disease progression or intolerable toxicity. Efficacy was evaluated in 114 patients whose disease had progressed on or after Platinum-based chemotherapy. Among these platinum pretreated patients, the median age was 60 years, 66% were female, 60% were Asian, and 59% had 2 or more prior systemic therapies. The main efficacy outcome measures were confirmed Objective Response Rate (ORR) assessed by blinded Independent Review Committee (IRC) and Duration of Response.

At a median follow up of 14.2 months, the ORR was 28%, with a median Duration of Response of 17.5 months. The median Progression Free Survival was 7.3 months and the median Overall Survival was 24 months. Clinically meaningful improvements were observed for dyspnea, coughing, chest pain, and these benefits were evident by cycle 2, and maintained throughout treatment. The most common adverse reactions were rash, nausea, stomatitis, vomiting, diarrhea, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.

It was concluded that EXKIVITY® is the first and only oral therapy specifically designed to target EGFR exon 20 insertions, and the present FDA approval is an important addition, designed for this patient population.

Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. Ramalingam SS, Zhou C, Kim TM, et al. J Clin Oncol. 2021;39(suppl 15):9014. DOI:10.1200/JCO.2021.39.15_suppl.9014.

Updated Overall Survival with KISQALI® plus FASLODEX® in Advanced Breast Cancer

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. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. Cyclin Dependent Kinases (CDK) 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.

Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) 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-RIBOCICLIB

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest.

In the MONALEESA-2 Phase III trial, KISQALI® in combination with FEMARA® (Letrozole) was compared to FEMARA® alone, in postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior therapy for their advanced breast cancer. The addition of KISQALI® to FEMARA® significantly prolonged Progression Free Survival (PFS), compared to FEMARA® alone. In the MONALEESA-7 Phase III study, KISQALI® in combination with Tamoxifen or a Non-Steroidal Aromatase Inhibitor plus ZOLADEX® (Goserelin) was compared with placebo in combination with Tamoxifen or an Aromatase Inhibitor plus ZOLADEX®, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer, who had not previously received endocrine therapy for advanced disease. In this study of premenopausal women, KISQALI® plus endocrine therapy significantly improved PFS and OS, compared with placebo plus endocrine therapy. The MONALEESA-7 trial recently reported an exploratory updated OS analysis with a median follow up of 53.5 months. In this analysis, KISQALI® plus endocrine therapy showed a clinically relevant and significant median OS benefit of 58.7 months compared with 48.0 months in the placebo plus endocrine therapy group.

MONALEESA-3 is a multicenter, international, randomized, double-blind, placebo-controlled Phase III study which compared the efficacy of KISQALI® in combination with FASLODEX® with FASLODEX® alone, among postmenopausal women with HR-positive, HER2-negative advanced breast cancer, who received no prior endocrine therapy or only one line of prior endocrine therapy for advanced disease. In this trial, 726 women were randomized, of whom 367 were treatment-naïve and 345 patients had received up to one line of prior endocrine therapy for advanced disease. Patients were randomized 2:1 to receive KISQALI® plus FASLODEX® (N=484) or placebo plus FASLODEX® (N=242). Treatment consisted of KISQALI® 600 mg orally daily 3 weeks on and 1 week off and FASLODEX® 500 mg IM on day 1 of each 28-day cycle, with an additional dose given on day 15 of cycle 1. Patients were stratified by the presence or absence of lung or liver metastases and prior endocrine therapy (first line versus second line). The median age in both groups was 63 years. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Overall Response Rate (ORR), and Safety. The authors had previously reported that in the MONALEESA-3 trial, there was a significant OS benefit for KISQALI® plus FASLODEX® versus placebo plus FASLODEX®, with an median OS of Not Reached (NR) versus 40.0 months (HR=0.72; P=0.00455).

The researchers in this publication reported an exploratory OS analysis update for MONALEESA-3, with an extended follow up (median, 56.3 months) in order to analyze the long-term OS benefit of KISQALI® plus FASLODEX® versus placebo plus FASLODEX®, similar to MONALEESA-7 trial. There was a significant OS benefit with a median OS of 53.7 months in the KISQALI® group versus 41.5 months in the placebo group (HR=0.73). The estimated 4-year survival rates were 54% and 45% for KISQALI® and placebo, respectively, while the 5-year survival rates were estimated to be 46% and 31% respectively. Subgroup analysis according to prior lines of endocrine therapy showed that patients in the first line subgroup had an median OS of Not Reached in the KISQALI® group and 51.8 months in the placebo group (HR=0.64). In the second line setting, the median OS was 39.7 months in the KISQALI® group versus 33.7 months in the placebo group (HR=0.78). No new safety signals were observed.

It was concluded that this extended follow up analysis of MONALEESA-3 is the longest reported follow up for any CDK4/6 inhibitor clinical trial in the postmenopausal women, and demonstrated a durable Overall Survival benefit with KISQALI® plus FASLODEX®, compared to FASLODEX® alone, in patients with HR-positive, HER2-negative advanced breast cancer. Further, this benefit was maintained when KISQALI® was given both as first line as well as second line therapy, and across subgroups of patients studied.

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Slamon DJ, Neven P, Chia S, et al. Annals of Oncology 2021; 32:1015-1024.

Infection Risk in Multiple Myeloma Patients Receiving New Generation Therapies

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). 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 will eventually relapse, requiring multiple lines of therapy for disease control. The availability of newer agents has transformed Multiple Myeloma into a chronic disease. Patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Infection is a leading cause of morbidity and mortality in patients with Multiple Myeloma. In a study of over 3000 newly diagnosed Multiple Myeloma patients, approximately 50% of early deaths (deaths occurring in less than 6 months following diagnosis) were associated with infections (J Clin Oncol. 2005;23:9219-9226). The increased susceptibility to infection in this patient group has been attributed to disease-related deficits in the innate or adaptive immune system, including hypogammaglobulinaemia, qualitative and quantitative abnormalities of dendritic cells, T cells, and Natural Killer cells, as well as renal function impairment, and therapies administered at different stages of the disease. Further, the introduction of new therapeutic agents such as Proteasome Inhibitors (PIs), Immunomodulatory drugs and monoclonal antibodies, with novel mechanisms of action, for first and later lines of therapy, for both Hematopoietic Stem Cell Transplantation eligible and ineligible patients, has significantly improved survival, but has also changed the spectrum of infections in patients with Multiple Myeloma. The epidemiology and risks for infection with the use of new therapeutic agents however remains unclear. The present study was conducted to determine patterns, risks and outcomes of infections in patients with Multiple Myeloma, managed with new therapeutic agents and monoclonal antibodies.

In this study, patients with Multiple Myeloma treated with second generation therapies and other monoclonal antibodies were identified from pharmacy and clinical databases, collected from 2 major tertiary referral centers for Multiple Myeloma management in Australia. Agents considered new generation therapies included Pomalidomide, Carfilzomib, Isatuximab, Daratumumab and Elotuzumab. Following commencement of new generation therapy, 60% of the patient’s had previously received Autologous Stem Cell Transplantation and 93% of the patient’s had Relapsed or Refractory Multiple Myeloma. Patients were then followed for episodes of infection, from the commencement of therapy with any newer agents, until completion of treatment, death or end of study, which ever occurred first. Prophylaxis with antibiotics for bacterial infections was not routinely used, but antiviral prophylaxis with Valaciclovir was used when patients received therapy with Proteasome Inhibitors. Patients received prophylaxis with Trimethoprim/Sulfamethoxazole for Pneumocystis jirovecii pneumonia when steroid doses exceeded 16-20 mg of Prednisone equivalent per day.

Each episode of infection was classified as Microbiologically Defined (MDI) when pathogens were isolated on microbiological testing, Clinically Defined (CDI) when sites of infection were identified but no pathogens were isolated on microbiological testing, and Fever of Unknown Focus (FUF) when patients had febrile episodes with no pathogen or site identified. Univariate and multivariate analyses were performed to determine risk factors for infection.

A total of 148 patients with Multiple Myeloma were followed for a median of 13.2 months, and 345 infection episodes were identified. Of these, 29% (100 out of 345) were defined as Microbiologically Defined Infections, 58% (200 out of 345) were defined as Clinically Defined Infections, and 13% (45 out of 345) were defined as Fever of Unknown Focus. Of those with Microbiologically Defined Infections, 50% of infections were attributed to viruses, whereas 45% were attributed to bacterial infection. Respiratory Syncytial Virus was the most frequently isolated virus accounting for 24% of episodes, followed by Rhinovirus at 16% and Influenza virus at 14%. E. coli was the most frequently isolated bacteria at 20%, followed by Haemophilus influenza at 11%. The most common infection site was the respiratory tract (56.8%), hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. Treatment with Proteasome Inhibitors resulted in 16.8 times increased risk for infections, combination of IMiD and PI was associated with 13.44 times higher risk, monoclonal antibody combination therapy was associated with 10.44 times higher risk, and more than 4 lines of therapy was associated with 7.72 times higher risk for infections (P<0.05).

It was concluded from this study that majority of infections are caused by viruses, in patients with Multiple Myeloma treated with newer therapeutic agents. Treatment with a Proteasome Inhibitor and more than 4 lines of therapy were associated with higher risk for infection.

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Lim C, Sinha P, Harrison SJ, et al. Clinical Lymphoma, Myeloma & Leukemia. 2021;21:444-450.