Hem/Onc Updates – Page 40 – ChemoPrescribe LLC.

FDA Approves IO in Combination with Targeted Therapies for BRAF Positive Advanced Melanoma

August 6, 2020August 6, 2020 RR

SUMMARY: The FDA on July 30, 2020, approved TECENTRIQ® (Atezolizumab), in combination with COTELLIC® (Cobimetinib) and ZELBORAF® (Vemurafenib), for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. 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. 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. Patients with locally advanced or metastatic melanoma historically have had poor outcomes. With the development and availability of immune checkpoint inhibitors and BRAF and MEK inhibitors, this patient group now has significantly improved outcomes. BRAF-and-MEK-Inhibition-in-MAPK-Pathway

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and result in constitutive activation of the MAPK pathway.

ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF, demonstrated significant improvement in Progression Free Survival (PFS) and Overall Survival (OS), compared to Dacarbazine. Squamous cell carcinomas were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. MEK gene is downstream from RAF in the MAPK pathway. The addition of a selective inhibitor of MEK gene such as COTELLIC® (Cobimetinib) to a BRAF inhibitor such as ZELBORAF® has addressed some of these limitations, in previously published studies, with improvement in Objective Response Rates (ORR) and decrease in the incidence of cutaneous secondary cancers. coBRIM is a multicenter, randomized, Phase III study in which the efficacy and safety of COTELLIC® combined with ZELBORAF®, was evaluated in previously untreated patients, with advanced BRAF-mutated melanoma. The final analysis of this trial evaluated the 5-year survival data, and the OS was over 30% in patients who received the combination therapy, with a Complete Response (CR) rate was about 20%.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells. The 5 year OS among patients receiving PD1 targeted immunotherapy is about 34%, with a median OS of 17-20 months. With the approval of multiple therapeutic options for the management of patients with BRAF-mutant melanoma, treatment decisions have become increasingly complex. In patients with limited disease burden, immunotherapy with checkpoint inhibitors is favored by most clinicians, based on the long term data supporting the durability of responses with immunotherapies, but response rates are lower. On the contrary, BRAF-targeted agents are utilized in patients with extensive, symptomatic disease and active brain metastases, as the response rates are higher but are short lived. The optimal sequence of these therapeutic strategies in order to improve long-term patient outcome, has remained unclear.

Preclinical studies suggested that combining these two targeted therapies with a checkpoint inhibitor might overcome the limitations of each class and potentially lead to more durable responses. The safety and efficacy of combining TECENTRIQ® with COTELLIC® (MEK inhibitor) and ZELBORAF® (BRAF inhibitor), in patients with BRAFV600-mutated metastatic melanoma, was evaluated in a Phase I study, with promising results, and a 28-day run-in period with COTELLIC® and ZELBORAF® was associated with an increase in proliferating CD4+ T-helper cells, without increasing the T-regulatory cells (Tregs). Tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response and Tregs remain a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. The aim of IMspire 150 trial was to determine if combining checkpoint inhibitor with two targeted therapies would improve efficacy.

IMspire150 is a pivotal, placebo-controlled, international, multicenter, double-blinded, Phase III trial, in which 514 treatment-naive patients with Stage IIIc and Stage IV, BRAF V600–mutant malignant melanoma were enrolled. Patients were randomly assigned 1:1 to treatment with the doublet combination or the triplet therapy. Doublet therapy given to the control group of patients consisted of ZELBORAF® 960 mg orally twice daily plus COTELLIC® at 60 mg orally, on days 1 to 21 of a 28 day cycle. In the experimental or triplet therapy group, there was a 28-day run-in with ZELBORAF® plus COTELLIC® alone, dosed similar to the control group (cycle 1), following which patients received TECENTRIQ® 840 mg IV on Days 1 and 15 of each 28 day cycle starting cycle 2, in combination with ZELBORAF® at a lower dose of 720 mg orally twice daily and COTELLIC® 60 mg orally once daily. Treatment was continued until disease progression, or unacceptable toxicity. Both treatment groups were well balanced, median patient age was 54 years, 58% were male and 94% of patients had Stage IV disease. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary end points included Objective Response Rates (ORR), Duration of Response (DOR), and Overall Survival (OS).

The combination of immunotherapy with targeted therapies was significantly superior to targeted therapies alone. At a median follow up of 18.9 months, the median PFS with the triplet combination was 15.1 months versus 10.6 months with the doublet therapy (HR=0.78; P=0.025). This represented a 22% reduction in the risk of disease progression. This benefit was observed across all subgroups including age, disease burden, LDH level, and extent of tumor involvement by organ site. Although Objective Response Rates were similar in both treatment groups, the median Duration of Response was 21.0 months with triplet combination versus 12.6 months for the doublet therapy. The OS data were not mature at the time of this analysis, but interim analysis however showed a median OS of 28.8 months with the triplet combination versus 25.1 months with doublet therapy. Both treatment groups had comparable toxicities. Among those patients receiving triplet combination, the most common toxicities were rash, fever, fatigue, nausea, pruritus, stomatitis, musculoskeletal pain, hepatotoxicity, edema, hypothyroidism, and photosensitivity.

It was concluded that in treatment-naive patients with advanced BRAF V600-mutant malignant melanoma, TECENTRIQ® in combination with ZELBORAF® and COTELLIC® significantly and clinically improved Progression Free Survival, when compared to placebo in combination with ZELBORAF® and COTELLIC®.

Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial. McArthur GA, Stroyakovskiy D, Gogas H, et al. Presented at: the 2020 AACR Annual Virtual Meeting I; April 27-28, 2020. Abstract CT012.

The Transition to Biosimilars: Managing Payor Challenges

August 1, 2020August 1, 2020 RR

Written by Dr. Robert Rifkin | Sponsored by Mylan Pharmaceuticals

Biologic agents have long played a vital role in oncology. Not only does this class of agents represent the best of science, but it also accounts for a tremendous increase in spend of the healthcare dollar. As the field of biologic therapies advances, the biosimilarity exercise has become relevant. The premise of biosimilarity is to decrease healthcare costs and improve access to care.¹

This premise was first established with the affordable care act in the Biologics Price Competition and Innovation Act (BCPIA).² Since its inception, a new pathway for approval of biosimilars was tested and implemented. The 351 (K) regulatory pathway was first tested with biosimilar filgrastim (filgrastim–sndz), or Zarxio.³ Initially, upon product launch, a modest discount of 15% was employed. (15%) The uptake was slow; however, when the market adjusted and uptake accelerated, an approximate 30% discount was in play.

Several other biosimilars have now entered the supportive care space. Specifically, in the case of short acting filgrastim, there are now competitors Nivestym (Filgrastim-aafi) with several additional biosimilar filgrastims under development. Within the pegfilgrastim arena, the position of the originator, Neulasta, has now been challenged by 3 other long-acting filgrastims: Fulphila (pegfilgrastim-jmdb), Udenyca (pegfilgrastim-cbqv), and Ziextenzo (pegfilgrastim-bmez).⁴ These original, early supportive care biosimilars have helped to define the marketplace, test regulatory mechanisms, and dispel any myths regarding their adoption.⁴

Herceptin (trastuzumab) also faces competition as new biosimilars enter space. Multiple biosimilars have now launched in addition to the originator molecule, including: Herzuma (trastuzumab-pkrb), Kanjinti (trastuzumab-anns), Ogivri (trastuzumab-dkst), Ontruzant (trastuzumab-dttb), and Trazimera (trastuzumab-qyyp).⁵ For the trastuzumabs, the large number of biosimilar options provides both competition in the marketplace in addition to a potential new source of significant confusion with distribution, supply chain, and inventory management. It is relatively unlikely that any payor or formulary will carry all five biosimilar trastuzumabs currently available in addition to any other biosimilar options slated for release over the next year.

Additionally, the rituximab space has become increasingly complex. Beyond the originator molecule, we can now choice to use Truxima (ritiximab abbs), or Ruxience (rituximab-pvvr), and several more launches are anticipated. The space is further complicated by the availability of a subcutaneous form of Rituxan Hycela (rituximab/hyaluronidase human), the only biosimilar available in subcutaneous injection. Unsurprisingly, this has created some from payors as all labeled indications are not initially the same for each product. Moving forward, rituximab biosimilar labels will soon be equivalent, and competition will then drive the marketplace.

In the real world, there still exist very real barriers to adoption including a clinical, ease of use, and economic barriers. It is likely payors will interpose themselves into each one of these. Multiple biosimilars are now being approved for each originator molecule. This will ultimately result in a decline in cost. Payors and other stakeholders will then be faced with complicated decisions of maintaining the originator on the formulary, deleting it and placing a biosimilar in its place, or perhaps carrying two versions of the same molecule, with preference being given to one. Most likely, most formularies will carry originator in addition to one or more biosimilars concurrently depending on the provider and payer landscape. the originator and a preferred biosimilar concurrently.

Several articles have reviewed the concept of switching between the biosimilar and the originator, and to date no significant safety signals have arisen.⁶ The payor landscape is impacted by product availability and opportunities to switch. This demonstrated safety of switching has incrementally impacted the payor landscape. Pharmacy Benefit Managers (PBM) have also been interwoven into the payor conundrum, with discounts and rebates providing an additional layer of complexity.

Not only is the transition to biosimilars complicated for payors, but the transition must also include all stakeholders involved in the ultimate selection of a therapeutic biologic. Providers and patients need to be very well educated regarding the concept of biosimilarity. Other stakeholders, including pharmacists, advanced practice providers, nurses, and admixture technologists, must be thoroughly educated. The electronic health record also needs to be updated to reflect the increasing numbers of biosimilars now available – including the preferred therapeutic agents in each circumstance.

Payors and clinicians alike will need to develop biosimilar teams, drug contracting strategies with and without GPO’s, and a thorough evaluation of clinical economics for each biosimilar. Biosimilars will assume an increasingly important role in the delivery of cancer care and it is important to approach this from a patient journey point of view (Fig. 1).

Figure 1: Patient Journey⁷

By tracing this from beginning to end, a formula for success may be developed.

The combination of clinical confidence, patient confidence, and operational excellence will be required to be sure that we are prepared for biosimilars and ensure patient access. The patient’s journey is complicated and increasingly influenced by the payor and other stakeholders . Providers, consideration of the revenue cycle, RN educators, pharmacists, admixture technologists, and infusion RNs all must play together to ensure the success of biosimilars. In alignment with the patient journey, diagnosis and treatment selection will be accomplished by the provider. This will be followed by insurance authorization, treatment education, treatment scheduling, treatment admixture, and finally the delivery of the drug to the well-educated patient. There are many potentials for success as well as failure (Fig. 2).

Figure 2: Drug Preparedness – Success vs. Failure⁷

The cornerstone for all to succeed, as well as all of the affected stakeholders managing paired challenges, remains education. This cannot be overstated. Numerous websites have now appeared, both branded and unbranded, to help deliver biosimilar education. Such websites may be found at the FDA⁸ and the Center for Biosimilars.⁹

In conclusion, as all the stakeholders become thoroughly educated, the many challenges outlined above will continue to present themselves in real-time. The success and adoption of current and future biosimilars will continue to depend on the sound education of all stakeholders, including payors, in addition to improved cost savings and access. Biosimilar usage will be important to ensure long-term sustainability on the market, and as biosimilar uptake increases, healthcare cost reduction and improvements to care access may be achieved.

Sources

1. Pittman WL, Wern C, Glode AE. Review of Biosimilars and Their Potential Use in Oncology Treatment and Supportive Care in the United States.
2. https://www.fda.gov/media/78946/download
3. U.S. Food & Drug Administration. Zarxio (filgrastim-sndz) Approval Letter. Published online March 6, 2015. Accessed June 19, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125553Orig1s000Approv.pdf
4. Rugo H, Rifkin RM, Deckerc P, Bair AH, Morgan G. Demystifying Biosimilars: Development, Regulation and Clinical Use. Future Oncology. 15(7):777-790, 2019
5. AmerisourceBergen. Approval and launch dates for US biosimilars. Published June 19, 2020. Accessed June 25, 2020. http://gabionline.net/Reports/Approval-and-launch-dates-for-US-biosimilars?ct=t%28GONL+V20F19-6%29&mc_cid=2821e641cc&mc_eid=%5BUNIQID%5D
6. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching Reference Medications to Biosimilars: A Systematic Literature Review of Clinical Outcomes. Drugs 78(4): 463-78,2018.
7. Rifkin R, Busby L. Bringing Biosimilars to Community. Presented at McKesson Oncology University; 2019.
8. www.fda.gov
9. www.centerforbiosimilars.com/

ENHERTU® Improves Overall Survival in Previously Treated HER2-Positive Gastric Cancer

July 30, 2020July 30, 2020 RR

SUMMARY: The American Cancer Society estimates that in the US, about 27,600 new cases of Gastric cancer will be diagnosed in 2020 and about 11,010 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced Gastric and GastroEsophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Upon progression, Paclitaxel plus CYRAMZA® (Ramucirumab), an anti-VEGFR-2 antibody is recommended as second-line therapy, regardless of HER2 expression, based on OS and Progression Free Survival (PFS) data for this combination regimen. Trifluridine-tipiracil (LONSURF®) and Immune Checkpoint Inhibitors are treatment options for later lines of therapy and are associated with minimal prolongation in OS. Unlike treatment in metastatic breast cancer, re-treatment with Trastuzumab in combination with various different chemotherapy agents has not shown survival benefit in Gastric cancer. Further, Antibody-Drug Conjugate such as KADCYLA® (ado-trastuzumab emtansine), did not prolong median OS or improve Response Rates compared to chemotherapy, in patients with Gastric cancer who had progressed during or after treatment with Trastuzumab. Mechanism-of-Action-ENHERTU

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, minimizing systemic exposure.

DESTINY-Gastric01 is an open-label, randomized, multicenter, Phase II trial in which ENHERTU® was compared with chemotherapy in patients with HER2-positive advanced Gastric cancer. In this study 187 patients were randomly assigned in a 2:1 ratio to receive either ENHERTU® (N=125) or the treating physician’s choice of Irinotecan or Paclitaxel (N=62). Eligible patients had HER2-expressing advanced Gastric cancer or GastroEsophageal junction adenocarcinoma that had progressed after the receipt of at least two previous systemic therapies, which included a Fluoropyrimidine, a Platinum agent, and Trastuzumab (or approved biosimilar agent). Patients in the ENHERTU® group received the drug at a dose of 6.4 mg/kg as IV infusion every 3 weeks, whereas the physician’s choice group received either Irinotecan monotherapy 150 mg/m2 IV every 2 weeks, or Paclitaxel monotherapy 80 mg/m2 IV on days 1, 8, and 15 every 4 weeks. HER2 levels were documented as high if the score was 3+ on IHC, or 2+ on IHC with positive results on FISH, and documented as low if the score was 2+ on IHC with negative results on FISH, or a score of 1+ on IHC (negative). Treatment was continued until disease progression or unacceptable toxicities. Both treatment groups were well balanced. Approximately 72% of the patients had previously received CYRAMZA® (Ramucirumab), and 86% had received Taxanes. The median time since the last administration of Trastuzumab was 6.2 months. The Primary end point was the Objective Response Rate (ORR), according to Independent Central Review. Secondary end points included Overall Survival (OS), response duration, Progression Free Survival, and safety. The primary cohort consisted of patients with high-level HER2-positive disease, and was the focus of this analysis.

Treatment with ENHERTU® resulted in an ORR of 51%, compared to 14% in the physician’s choice group (P<0.001), according to Independent Central Review. An ORR lasting 4 weeks or more occurred in 43% of patients in the ENHERTU® group, as compared with 12% in the physician’s choice group. More than 80% of patients receiving ENHERTU® had a reduction in tumor size, compared with approximately half the patients receiving physician’s choice of chemotherapy. The median duration of confirmed objective response was 11.3 months in the ENHERTU® group, compared with 3.9 months in the physician’s choice group. Treatment with ENHERTU® resulted in a higher percentage of patients with confirmed disease control (86%), than physician’s choice of chemotherapy (62%). The ORR was higher among those with a HER2 score of 3+ on IHC, than among those with an IHC score of 2+ with positive results on FISH (58% versus 29%).
The Overall Survival was significantly longer in the ENHERTU® group compared to the physician’s choice group (median 12.5 months versus 8.4 months; HR=0.59; P=0.01). The estimated OS at 6 months was 80% in the ENHERTU® group and 66% in the physician’s choice group and at 12 months was 52% and 29%, respectively. In a prespecified subgroup analysis, OS benefit was greater with ENHERTU® compared to physician’s choice of chemotherapy, across most subgroups. The median PFS was 5.6 months in the ENHERTU® group and 3.5 months in the physician’s choice group (HR=0.47). The most common adverse events of Grade 3 or higher were cytopenias. ENHERTU® related Interstitial Lung Disease or pneumonitis was noted in 10% of patients and most events were Grade 1 or 2. Decrease in left ventricular ejection fraction or heart failure was not observed in either treatment groups.

It was concluded that treatment with ENHERTU® resulted in significant improvements in Objective Response Rates and Overall Survival, as compared with standard therapies, among patients with HER2-positive advanced Gastric or GastroEsophageal junction cancer. This benefit was seen even in patients who had disease progression while on Trastuzumab containing regimens.

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. Shitara K, Bang Y-J, Iwasa S, et al. for the DESTINY-Gastric01 Investigators. N Engl J Med 2020; 382:2419-2430

XTANDI® Improves Overall Survival in Nonmetastatic Castration-Resistant Prostate Cancer

July 30, 2020July 30, 2020 RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 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. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide).

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 (mCRPC). Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. The estimated mean survival of patients with CRPC is 9-36 months. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is often recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death. XTANDI-Mechanism-of-Action

XTANDI® (Enzalutamide) is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens. Previously published studies have shown that XTANDI® improved Overall Survival in metastatic CRPC, regardless of whether it was used before or after Docetaxel chemotherapy.

PROSPER trial is a multinational, double-blind, randomized, placebo-controlled Phase III study, conducted to assess the safety and efficacy of XTANDI® in patients with nonmetastatic CRPC. In this study, 1401 eligible patients were enrolled and randomized in a 2:1 ratio to receive XTANDI® 160 mg orally once daily (N=933) or placebo (N=468). Enrolled patients had rising PSA, with a PSA doubling time of 10 months or less, despite castrate levels of testosterone (0.50 ng/mL), while continuing to receive Androgen Deprivation Therapy (ADT) with either a gonadotropin-releasing hormone agonist or antagonist or with previous bilateral orchiectomy. A diagnosis of nonmetastatic CRPC was established based on conventional imaging such as CT scans, MRI and Bone scans. The median patient age was 73 years, and both treatment groups were well balanced. The Primary endpoint was Metastasis-Free Survival (MFS), defined as time from randomization to imaging-based progression, or time to death from any cause without evidence of imaging-based progression. Secondary endpoints included Overall Survival, time to PSA progression, PSA response rate and time to first use of a subsequent antineoplastic therapy, as well as health-related quality of life and frequency and severity of adverse events. At the primary analysis, the study met the Primary endpoint of MFS and treatment with XTANDI® significantly improved Metastasis-Free Survival. The authors in this publication reported results from the prespecified final analysis of Overall Survival.

The median Overall Survival was 67.0 months in the XTANDI® group and 56.3 months in the placebo group. XTANDI® plus Androgen Deprivation Therapy (ADT) lowered the risk of death by 27%, compared with placebo plus ADT (HR=0.73; P=0.001). This benefit was consistent across prespecified subgroups. XTANDI® was also associated with a delay in the use of a new subsequent antineoplastic therapy, and the median time to first use of new antineoplastic therapy was 66.7 months in the XTANDI® group and 19.1 months in the placebo group (HR=0.29). The most frequently reported Adverse Events with XTANDI® were fatigue and musculoskeletal events.

It was concluded that XTANDI® given along with Androgen Deprivation Therapy resulted in longer median Overall Survival, when compared with placebo plus ADT, among men with nonmetastatic, CRPC and a rapidly rising PSA level, with 27% lower risk of death. The authors however added that the classification of patients as having nonmetastatic disease may be impacted, with the availability of more sensitive imaging techniques, for earlier detection of metastasis.

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. Sternberg CN, Fizazi K, Saad F, et al. for the PROSPER Investigators. N Engl J Med 2020; 382:2197-2206

First Line KEYTRUDA® plus Chemotherapy Significantly Improves PFS in PD-L1-High Triple Negative Breast Cancer

July 23, 2020September 25, 2020 RR

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. 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 and African American females. 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 and often develop visceral metastases. 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. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival (PFS) of only 2-3 months.

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% to 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 triple-negative metastatic breast cancer.

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 vs 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 median follow up for patients assigned to receive KEYTRUDA® was 17.5 months and 15.5 months for the placebo group. The authors reported the results from an interim analysis conducted by an Independent Data Monitoring Committee (IDMC).

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). Formal statistical significance was not tested in the ITT population. Overall Survival data are pending. Adverse Events (AEs) were similar in both treatment groups, although immune-related AEs occurred at a higher incidence in the KEYTRUDA® arm.

It was concluded that KEYTRUDA® in combination with several chemotherapy regimens, showed a statistically significant and clinically meaningful improvement in PFS, compared with chemotherapy alone, in patients with previously untreated locally recurrent, inoperable or metastatic TNBC, whose tumors expressed PD-L1 with a Combined Positive Score (CPS) of 10 or more. This data may be particularly relevant for patients who may have received a taxane in the adjuvant setting within a year, and could be more appropriately treated with a non-taxane regimen, in combination with KEYTRUDA®.

KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortes J, Cescon DW, Rugo HS. et al. J Clin Oncol 38: 2020 (suppl; abstr 1000)

PSMA-Targeted Imaging for Biochemically Recurrent Prostate Cancer

July 23, 2020July 23, 2020 RR

The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse.

Rising PSA is therefore a sign of recurrent disease and identifying the site of recurrence can be of immense value for the clinician and can help determine the best course of therapy. The diagnostic accuracy of standard imaging tests, for the identification of sites of recurrence in patients with biochemical recurrence, is low. Almost 90% of the standard imaging tests such as CT/MRI and Bone Scan may be negative. More accurate non-invasive imaging techniques for the detection of recurrent tumor is therefore an unmet need. Prostascint, a Single Photon Emission Computerized Tomography (SPECT) radiopharmaceutical agent, was approved in 1999 for the diagnostic imaging of post-prostatectomy patients with a rising PSA. PET (Positron Emission Tomography) scans have largely superseded this study. FluDeoxyGlucose F18 (FDG), a glucose analogue is the most widely used PET radiotracer, but is not generally used as an imaging agent in prostate cancer. This is because good and reliable quality images are not feasible due to indolent growth of prostate cancers and the high urinary excretion of FDG. The other PET radiotracer that is available, Choline C11, has been shown to improve cancer detection in men with biochemical recurrent prostate cancer, but this agent has a short half life of 20 minutes, requires greater patient preparation including 6 hours of fasting prior to administration of Choline C11, delivers higher radiation dose to patients and image quality is poor. The FDA in 2016 approved AXUMIN® (Fluciclovine F18), a novel molecular radiopharmaceutical diagnostic agent, for PET imaging in men with suspected prostate cancer recurrence, based on elevated PSA levels, following prior treatment. This study however is less likely to be positive with PSA less than 1 ng/mL, unless the doubling time is rapid. There is also higher false positive rate within the intact or treated prostate gland, and uptake may be absent in densely sclerotic lesions. Current imaging modalities are therefore inadequate for localizing and characterizing occult disease in men with biochemically recurrent prostate cancer.

F-18 DCFPyL is a novel PET imaging agent that binds selectively with high affinity to Prostate-Specific Membrane Antigen (PSMA), which is overexpressed in prostate cancer cells. CONDOR is a prospective, multicenter, randomized, Phase III trial, conducted to evaluate the diagnostic performance of PET/CT imaging with F-18 DCFPyL, a radiopharmaceutical targeting the extracellular domain of PSMA. This study enrolled 208 men at 14 sites in the US and Canada, with a rising PSA level after definitive therapy and negative or equivocal standard-of-care imaging (eg, CT, MRI, bone scintigraphy). PET/CT imaging was performed 1-2 hours following administration of a single dose of F-18 DCFPyL. The median age was 68 yrs and the median time from diagnosis was 71 months. Approximately 50% of all patients had undergone Radical Prostatectomy, 35% underwent Radical Prostatectomy and Radiation Therapy, 15% had only received RadioTherapy, and 28% received at least one systemic therapy for their prostate cancer. Approximately 74% of patients had a total Gleason score below 8. All enrolled patients had biochemically recurrent metastatic Castration-Resistant Prostate Cancer, and a PSA of at least 0.2 ng/mL following radical prostatectomy, or at least 2 ng/mL over the nadir following prior Radiation Therapy, Cryotherapy or systemic therapy. The median PSA was 0.8 ng/mL, (PSA level at which most decisions about subsequent salvage focal or systemic therapies are made) and 31% of patients had a PSA of at least 2.0 ng/mL. All enrolled patients had no previous radiologic findings. The Primary endpoint was Correct Localization Rate of occult disease, as determined by three independent reviewers, and the Secondary endpoint was the impact of F-18 DCFPyL PET/CT imaging results on management of enrolled patients in this study.

The study met its Primary endpoint and the Correct Localization Rate of occult disease or the Positive Predictive Value ranged from 84.8% to 87% for the three independent reviewers. The Correct Localization Rate of occult disease was maintained regardless of PSA values and the F-18 DCFPyL PET/CT imaging detected disease even at the lowest of PSA values. Regarding the Secondary endpoint of impact of F-18 DCFPyL PET/CT imaging on treatment, 64% of patients had a change in management due to findings noted on the imaging study, of which 78% were attributable to positive findings on the imaging study, and 21.4% to negative findings on F-18 DCFPyL PET/CT imaging study. Specific changes in the treatment management included change in the goal of patients disease management from a noncurative approach to a curative salvage local therapy in 21% of patients, 28% changed from receiving salvage local therapy to systemic therapy or added systemic therapy, 23.9% changed from observation status to initiation of therapy and 4.4% changed from planned treatment to observation alone.

It was concluded that PSMA-targeted F-18 DCFPyL PET/CT imaging detected and localized occult disease in most men with biochemical recurrence, presenting with negative or equivocal findings on conventional imaging. Further, F-18 DCFPyL PET/CT imaging provided actionable information that led to change in treatment plans for the majority of patients, thus providing evidence that PSMA PET imaging may be valuable in men with recurrent or suspected metastatic prostate cancer.

Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study (CONDOR). Morris MJ, Carroll PR, Saperstein L, et al. DOI: 10.1200/JCO.2020.38.15_suppl.5501 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 5501-5501.

FDA Approves KEYTRUDA® for Tumor Mutational Burden-High Solid Tumors

July 16, 2020July 16, 2020 RR

SUMMARY: The FDA on June 16, 2020 granted accelerated approval to KEYTRUDA® (Pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic Tumor Mutational Burden-High (10 or more mutations/megabase) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment, and who have no satisfactory alternative treatment options. The FDA on the same day also approved the FoundationOne® CDx assay (Foundation Medicine, Inc.) as a companion diagnostic for KEYTRUDA®. 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.

Tumor Mutational Burden (TMB) is a measure of the somatic mutation rate within a tumor genome and is emerging as a quantitative indicator for predicting response to Immune Checkpoint Inhibitors such as KEYTRUDA®, across a wide range of malignancies. These non-synonymous somatic mutations in the tumor genome generate larger number of neo-antigens which are more immunogenic. Immune Checkpoint Inhibitors are able to unleash the immune system to detect these neoantigens and destroy the tumor. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic, coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/Megabase as High, and less than 10 mutations/Megabase, as Low. (A megabase is 1,000,000 DNA basepairs).

KEYNOTE-158 is a multicenter, non-randomized, open-label, Phase II basket trial investigating the antitumor activity and safety of KEYTRUDA® in multiple advanced solid tumors. The accelerated approval was based on data from a prospectively-planned, retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 study. Patients received KEYTRUDA® 200 mg IV every 3 weeks until unacceptable toxicity or documented disease progression. In this study, 1,050 patients were included in the efficacy analysis and TMB was analyzed in the subset of 790 patients with sufficient tissue for testing. Of these 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB 10 mutations /Megabase or more. The median age in this study population of 102 patients was 61 years, ECOG PS was 0-1, and 56% of patients had at least 2 prior lines of therapy. TMB status was assessed using the FoundationOne® CDx assay. Tumor response was assessed every 9 weeks for the first 12 months and every 12 weeks thereafter. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) in the patients who received at least one dose of KEYTRUDA®. The key Secondary outcome measures included Progression Free Survival (PFS), Overall Survival (OS), and safety.

In the 102 patients whose tumors were TMB-H, KEYTRUDA® demonstrated an ORR of 29%, with a Complete Response rate of 4% and a Partial Response rate of 25%. After a median follow up time of 11.1 months, the median DOR had not been reached. Among the responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. The median duration of exposure to KEYTRUDA® was 4.9 months. The most common adverse reactions for KEYTRUDA® were fatigue, decreased appetite, rash, pruritus, fever, nausea, diarrhea, cough, dyspnea, constipation, abdominal pain and musculoskeletal pain.

It was concluded that in patients with advanced solid tumors treated with KEYTRUDA® monotherapy, high TMB was associated with higher Objective Response Rates and median Duration of Response, with the Progression Free Survival favoring patients with high TMB. These data suggest that TMB may be predictive of the efficacy of KEYTRUDA® monotherapy in patients with a wide range of tumor types.

Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Marabelle A, Fakih MG, Lopez J, et al. Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253.

ENHERTU® Demonstrates Promising Clinical Activity in HER2 Positive Non-Small Cell Lung Cancer

July 16, 2020July 16, 2020 RR

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 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. 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including breast, gastric, lung and colorectal cancers. It is a growth-promoting protein and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. Other HER2 gene alterations such as HER2 mutations, as distinct molecular targets, have been identified in 2-4% of patients with NSCLC, specifically with adenocarcinoma histology. These acquired HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC, and is therefore an unmet need. Mechanism-of-Action-ENHERTU

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 HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. 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® (ado-Trastuzumab emtansine), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the 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, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens, based on the DESTINY-Breast01 trial.

DESTINY-Lung01 is an ongoing, global, multicenter, open-label, two-cohort, Phase II study, evaluating the safety and efficacy of ENHERTU® in 170 patients with HER2 mutant or HER2 overexpressing (defined as ImmunoHistoChemistry-IHC 3+ or IHC 2+), unresectable and metastatic non-squamous NSCLC. Eligible patients could not have received prior HER2-targeted therapy, with the exception of pan-HER TKIs. Patients were enrolled into 2 cohorts. The first cohort enrolled patients with HER2-expressing tumors as defined by IHC 3+ or 2+ (N = 42). The second cohort included patients whose tumors harbored a HER2 mutation as determined by a local laboratory test (N = 42). Enrolled patients had a median of two prior lines of therapy with majority of patients receiving platinum-based chemotherapy (90.5%), anti-PD-1 or PD-L1 treatment (54.8%) and 19% receiving Docetaxel. Patients received ENHERTU® 4.6 mg/kg every 3 weeks by intravenous infusion. The 42 patients included in the second cohort had a median age of 63 years, 64.3% of patients were female, and 45.2% had CNS metastases. For the majority of patients (90.5%), HER2 mutation was located in the kinase domain. The Primary endpoint was confirmed Objective Response Rate (ORR). Additional endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), and safety. The authors reported data for the cohort with HER2 mutations (second cohort), after a median follow up of 8.0 months.

The ORR was 61.9%, with 2.4% Complete Response, 59.5% Partial Response, and stable disease noted in 28.6% of patients. The Disease Control Rate was 90.5%. The median PFS was 14 months. The median Duration of Response and Overall Survival (OS) had not yet been reached at the time of data cut-off. The most common Grade 3 or higher treatment related Adverse Events were neutropenia and anemia. Confirmed treatment-related Interstitial Lung Disease (ILD) and pneumonitis were noted in approximately 12% of patients and were all Grade 2 and there were no deaths. Nonetheless, ILD is an important identified risk for patients treated with ENHERTU® and requires careful monitoring and management.

It was concluded that ENHERTU® demonstrated promising clinical activity in this interim analysis, with a high Objective Response Rate and durable responses, in a heavily pretreated population of patients with HER2-mutated NSCLC.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01. Smit EF, Nakagawa K, Nagasaka M, et al. J Clin Oncol 38: 2020 (suppl; abstr 9504).

PIQRAY® Effective after Progression on CDK Inhibition in Advanced Breast Cancer

July 9, 2020July 9, 2020 RR

The PhosphoInositide 3-Kinase (PI3K) pathway is an intracellular signaling pathway important in the regulation of cancer cell proliferation and metastasis. PI3K is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta, which play a unique role in the survival of different tumor types and establishment of supportive tumor microenvironments. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are primarily expressed in hematopoietic cells such as B and T cells. The PI3K alpha isoform is particularly important in breast cancer and plays an important role in tumorigenesis, supporting tumor angiogenesis and stromal interactions, making this a viable target. PIK3CA is an oncogene that codes for the alpha isoform of PI3K, (PI3Kα), more specifically for the alpha isoform of p110. The PI3k pathway is the most frequently altered pathway in human cancers including breast cancer, and has been implicated in disease progression in a significant number of patients with breast cancer. Activation of the PI3K pathway in breast cancer has been associated with resistance to endocrine therapy and disease progression. Approximately 40% of patients with Hormone Receptor positive (HR+), HER2-negative breast cancers, harbor activating mutations in the PIK3CA isoform of PI3K, which is the most common mutation in HR+ breast cancer. Patients with advanced breast cancer harboring PIK3CA mutations typically have a poor prognosis. This provides a strong rationale for targeting the PI3K pathway in breast cancer. Alpelisib-Mechanism-of-Action

PIQRAY® is an oral, alpha-specific PI3K inhibitor that specifically inhibits PIK3 in the PI3K/AKT kinase signaling pathway. Further, it was shown in preclinical studies that cancer cells with PIK3CA mutations are more sensitive to PIQRAY® than those without the mutation, across a broad range of tumor types. In the SOLAR-1 Phase III trial, there was a 35% improvement in Progression Free Survival (PFS) in patients randomized to PIQRAY® plus FASLODEX®, compared to the placebo plus FASLODEX® group, among postmenopausal patients with PIK3CA-mutated, HR+/HER2- negative, advanced breast cancer, who had progressed on or following prior Aromatase Inhibitor (AI) treatment with or without a CDK 4/6 inhibitor. However in this study, only 6% had received prior CDK4/6 inhibitor therapy and there is presently limited data available, to inform treatment decisions in patients who progress on AI and CDK 4/6 inhibitor combination.

BYLieve is an ongoing, prospective, open-label, Phase II, non-comparative trial, which evaluated the benefit of PIQRAY&reg in combination with endocrine therapy in patients with HR+, HER-negative, PIK3CA-mutated, advanced breast cancer, who progressed on or after a prior therapy including CDK inhibitor. This study included 3 patient cohorts– Cohort A included patients who received a CDK4/6 inhibitor plus an AI as immediate prior therapy, Cohort B included patients who received a CDK4/6 inhibitor plus FASLODEX® (Fulvestrant) as immediate prior therapy, and Cohort C included patients who progressed on/after an AI and received chemotherapy or endocrine therapy as immediate prior treatment.

The authors in this publication shared findings from Cohort A group of patients, who had received CDK4/6 inhibitor plus an AI as their immediate prior therapy. Cohort A enrolled 127 patients of whom 121 patients had centrally confirmed PIK3CA mutation. Patients in Cohort A received PIQRAY® 300 mg orally once daily along with FASLODEX® 500 mg IM on Day 1 and 15 of cycle 1 followed by Day 1 treatment, of each 28 day cycle thereafter. The median patient age was 58 years. Seventy percent (70%) of patients had received one prior metastatic regimen, none of the patients had received FASLODEX® as a first-line metastatic agent, and 60% of patients had secondary endocrine resistance. The median follow up was 11.7 months. The Primary endpoint was proportion of patients alive without disease progression at 6 months. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Overall Survival (OS), and safety.

The Primary endpoint was met and the proportion of patients with confirmed PIK3CA mutation and without disease progression at 6 months was 50.4%. The median PFS was 7.3 months. Among the 121 patients in Cohort A with a confirmed PIK3CA mutation, the response rate, which was all partial responses was 17.4%, and 45.5% achieved stable disease.

Although the BYLieve trial did not have a control group to allow comparing patients in Cohort A to patients receiving other standard therapies, the authors conducted a weighted/matched analysis between the patients in Cohort A of the BYLieve trial and a Real-World similar group of 95 patients with HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, who were treated with standard therapies. The Real-World patient data was obtained from the de-identified clinic-genomic database of Flatiron Health and Foundation Medicine. These 95 patients had received a wide range of regimens, with the most frequent being XELODA® (Capecitabine) monotherapy, FASLODEX® monotherapy, FASLODEX® plus IBRANCE® (Palbociclib), AFINITOR® (Everolimus) plus AROMASIN® (Exemestane), FASLODEX® plus FEMARA® (Letrozole), and IBRANCE® monotherapy.

Unadjusted results showed a median PFS of 7.3 months in BYLieve Cohort A versus 3.6 months in the Real-World cohort. Similar outcomes were noted when data were weighted by odds, propensity score matching, and exact matching.

It was concluded that the BYLieve trial is continuing to show clinically meaningful efficacy with a combination of PIQRAY® and FASLODEX® in HR+, HER2-negative, PIK3CA-mutated advanced breast cancer, post CDK inhibitor treatment, building further on the findings of SOLAR-1 trial. The matched analysis comparing BYLieve with Real-World Data in the post-CDK4/6 inhibitor setting, further supports use of PIQRAY® plus FASLODEX® for this patient group.

Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Rugo HS, Lerebours F, Ciruelos E, et al. J Clin Oncol 38: 2020 (suppl; abstr 1006).

Overall Survival Benefit with Frontline OPDIVO® plus YERVOY® and Limited Chemotherapy in NSCLC

July 9, 2020July 9, 2020 RR

SUMMARY: The FDA on May 26, 2020, approved the combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) and 2 cycles of Platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent Non-Small Cell Lung Cancer (NSCLC), with no Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 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. 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. Unleashing-T-Cell-Function-with-Combination-Immunotherapy

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.

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 versus Platinum-doublet chemotherapy 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. 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.

At a preplanned interim analysis after a minimum follow up 8.1 months, this trial demonstrated a statistically significant benefit in OS for patients treated with OPDIVO® plus YERVOY® and limited chemotherapy, compared to those who received chemotherapy alone. The median OS was 14.1 months versus 10.7 months, respectively (HR=0.69; P=0.0006). With longer follow up at 12.7 months, this OS benefit continued to improve in the immunotherapy plus chemotherapy group, with a median OS of 15.6 months versus 10.9 months, respectively (HR=0.66). The 1-year OS rates were 63% versus 47%. This clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology.

The median PFS was 6.8 months in the OPDIVO® plus YERVOY® and chemotherapy group and 5 months in the chemotherapy-only group (HR=0.70; P=0.0001). The ORR was 38% and 25%, respectively (P= .0003). The median response duration was 10 months in the OPDIVO® plus YERVOY® and chemotherapy group, and 5.1 months in the chemotherapy-only group. Grade 3-4 treatment related Adverse Events were reported in 47% of the patients receiving the immunotherapy plus chemotherapy combination versus 38% in the chemotherapy-only group.

It was concluded that CheckMate 9LA met its Primary endpoint of Overall Survival, and OPDIVO® plus YERVOY® with a limited course of chemotherapy should be considered as a new first line treatment option for patients advanced Non Small Cell Lung Cancer.

Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. Reck M, Ciuleanu T-E, Dols MC, et al. J Clin Oncol 38: 2020 (suppl; abstr 9501)

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