TAFINLAR® and MEKINIST® versus OPDIVO® plus YERVOY® for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

SUMMARY: The American Cancer Society estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 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.

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 results in constitutive activation of the MAPK pathway.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. TAFINLAR® plus MEKINIST® led to long-term survival benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, from two randomized Phase III COMBI-d and COMBI-v trials.

A combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) showed durable improved outcomes among patients with unresectable or metastatic melanoma and approximately 50% of patients were alive at 6.5 years (J Clin Oncol 39, 2021. suppl 15; abstr 9506). The FDA granted approval for this combination in 2015 for the treatment of patients with metastatic melanoma, regardless of tumor BRAF mutation status.

It has been noted that BRAF/MEK inhibitor therapy tends to produce high tumor response rates and prolonged median Progression Free Survival (PFS), whereas OPDIVO® /YERVOY® tends to have its major impact on Duration of Response. However, the optimal treatment sequence for patients with treatment-naive BRAFV600-mutant metastatic melanoma, between combination OPDIVO®/YERVOY® checkpoint inhibitor immunotherapy and combination TAFINLAR® plus MEKINIST® molecularly targeted therapy, has remained unclear. Recently published tumor biology studies have suggested that resistance to BRAF/MEK-inhibitor therapy results in an immunosuppressive tumor microenvironment that is void of functional CD103+ dendritic cells, preventing effective antigen presentation to the immune system, and that immunotherapy may enhance BRAF-mutated melanoma responsiveness to targeted therapy.

DREAMseq (EA6134) is a two-arm, two-step, open-label, randomized Phase III trial, which investigated the anti PD-1/CLTA-4 immunotherapy combination of OPDIVO® plus YERVOY® followed by the anti-BRAF/MEK targeted therapy combination of TAFINLAR® plus MEKINIST®, versus the reverse sequence, in patients with advanced BRAF V600-mutant melanoma. This study was conducted to determine which treatment sequence produced the best efficacy.

In this study, 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomly assigned to receive either combination OPDIVO® plus YERVOY® (arm A=133) or TAFINLAR® plus MEKINIST® (arm B=132) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, TAFINLAR® plus MEKINIST® (arm C=27) or OPDIVO® plus YERVOY® (arm D=46). The two initial treatment arms were balanced and more patients on arm B had BRAF V600K-mutant tumors than those on arm A (25.2% versus 12.1%). The median patient age was 61 years and eligible patients had histologically confirmed, BRAF V600-mutant unresectable Stage III or IV melanoma with measurable disease. The Primary end point was 2-year Overall Survival (OS). Secondary end points included 3-year OS, Objective Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), crossover feasibility, and Safety.

The study was stopped early by the Independent Data Safety Monitoring Committee because statistical significance was achieved for the Primary endpoint. The 2-year OS for those starting on arm A was 71.8% and arm B was 51.5% (P=0.01). Step 1 Progression Free Survival favored arm A (P=0.054). The Objective Response Rates were arm A: 46%, arm B: 43%, arm C: 47.8%, and arm D: 29.6%. The median Duration of Response was not reached for arm A, and 12.7 months for arm B (P<0.001). Crossover occurred in 52% of patients following documented disease progression. Grade 3 or more toxicities occurred with similar frequency between treatment groups and adverse events related to regimens were as expected.

It was concluded from this study that for patients with advanced BRAF V600-mutant metastatic melanoma, the treatment sequence beginning with the immune checkpoint inhibitor combination of OPDIVO® plus YERVOY® resulted in superior Overall Survival and longer Duration of Response, compared with the treatment sequence beginning with TAFINLAR® plus MEKINIST®, and should therefore be the preferred treatment sequence for most of these patients.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. Atkins MB, Lee SJ, Chmielowski B, et al. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

RNF43 Mutations Predict Response to Anti-BRAF/EGFR Combination Therapy in BRAF V600E Metastatic Colorectal Cancer

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 151,030 new cases of CRC will be diagnosed in the United States in 2022 and about 52,580 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations, which is recognized as a marker of poor prognosis in this patient group. These patients predominantly present with right-sided proximal tumors, tend to have aggressive disease with a higher rate of peritoneal metastasis, and do not respond well to standard treatment intervention. Approximately 30% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Further, in striking contrast to patients with melanoma harboring BRAF V600E mutations in whom there is a 70% Objective Response Rate with BRAF inhibitor monotherapy, there is little or no clinical benefit with the same treatment among BRAF V600E mutant CRC patients.

Preclinical studies have shown that inhibiting BRAF in colorectal tumors can transiently reduce Mitogen-Activated Protein (MAP) kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. In the Phase III BEACON Colorectal Cancer study, a combination of BRAF inhibitor BRAFTOVI® (Encorafenib) and EGFR antagonist ERBITUX® (Cetuximab), with or without concomitant MEK inhibition improved Response Rates, Overall Survival and Progression Free Survival in patients with metastatic CRC with a BRAF V600E mutation. The FDA approved this doublet therapy in 2020 for this patient group. Despite this improved efficacy, a significant percentage of patients do not respond this therapy and among those who respond, the responses noted in CRC are still not as robust as has been in BRAF-mutant metastatic melanomas treated with anti-BRAF therapy. This suggests that there may be other factors modulating treatment response, including molecular determinants, that need to be identified, to optimize clinical management of these patients.

BRAF V600E mutated tumors in CRC are also associated with specific molecular features, including a low frequency of APC mutations and a high rate of mutations in the tumor suppressor gene RNF43 (Ring Finger Protein 43). RNF43 is a E3 ubiquitin ligase which negatively regulates Wnt signaling by inducing degradation of the Wnt receptors. It has been postulated that the a cross-talk between the MAPK and WNT signaling pathways may modulate the antitumor activity of anti-BRAF/EGFR therapy.

The researchers in this study sought to explore which genes were enriched for somatic mutations in responder and non-responder groups, among patients with BRAF V600E mutant CRC, treated with anti-BRAF/EGFR combination therapy. This study included 166 patients (N=166) with BRAF V600E mutant CRC of whom 98 patients received treatment with anti-BRAF/EGFR combination therapy (N=46 in the Discovery cohort and N=52 in the Validation cohort). The Control cohort (N=68) consisted of BRAF V600E mutant CRC patients treated with chemotherapy with or without antiangiogenic therapy, and were not exposed to anti-BRAF therapy. Whole-Exome Sequencing (WES) and/or targeted gene sequencing was performed on baseline tumor and/or plasma cell-free DNA (cfDNA) samples of all included patients, and over 20,000 genes were analyzed.

It was noted that RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic CRC tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.

The researchers concluded that these findings suggest that RNF43 may be a potential stratification biomarker that could help with decision making, in patients with MicroSatellite-Stable, BRAF V600E–mutant metastatic Colorectal cancer. They added that RNF43 gene may be a predictive biomarker of a response to treatment with anti-BRAF/EGFR combination therapy in this patient group.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF V600E metastatic colorectal cancer. Elez, E, Ros J, Fernandez J, et al. Nature Medicine 2022;28:2162–2170.

Improved Outcomes with Early Switch to Fulvestrant Plus Palbociclib in ESR1 Mutated 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 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 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 most of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of ER+/HER2- metastatic breast cancer as first-line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER+ breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).

Fulvestrant (FASLODEX®) is an estrogen antagonist and like Tamoxifen binds to estrogen receptors (ERs) competitively, but unlike Tamoxifen causes rapid degradation and loss of ER protein (ER down regulator) and is devoid of ER agonist activity. Palbociclib (IBRANCE®) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. Palbociclib is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. The FDA in February 2016, approved Palbociclib in combination with Fulvestrant, for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy.

Patients with ESR1 mutations on Fulvestrant had improved Progression Free Survival (PFS) compared with Exemestane (AROMASIN®) in the SoFEA trial. The combination of Palbociclib and Fulvestrant improved PFS compared with Fulvestrant plus placebo in both ESR1 mutant and ESR1 wild-type patients, in the PALOMA3 trial.

The PADA-1 study aimed to show the efficacy of an early change in therapy based on a rising ESR1 mutation in the peripheral blood, while assessing the global safety of the combination Fulvestrant and Palbociclib. PADA-1 is a prospective, randomized, open-label, multicentre, Phase III trial in which 1017 patients with ER-positive, HER2-negative advanced breast cancer were included. These patients were monitored for a rising ESR1 mutation in the peripheral blood, while on first-line treatment with an Aromatase Inhibitor (Letrazole 2.5 mg, Anastrozole 1 mg or Exemestane 25 mg orally once daily, taken continuously) and Palbociclib 125 mg orally once daily on days 1-21 of a 28-day treatment cycle, at enrollment and every 2 months thereafter. Blood samples were monitored for several ESR1 mutations which included E380, P535, L536, Y537, and D538. The median time from trial enrollment to detection of the ESR1 mutation was 14.2 months. Patients with newly present or rising ESR1 mutation in the peripheral blood circulating tumor DNA and no synchronous disease progression (N=172) were randomly assigned (1:1) to continue with the same therapy (N=84) or to switch to Fulvestrant 500 mg IM on day 1 of each 28-day cycle and on day 15 of cycle 1, along with Palbociclib as previously dosed (N=88). Baseline characteristics were similar in both treatment groups. The median patient age was 61 years, and one-third of patients had prior treatment with an Aromatase Inhibitor. Patients were stratified according to visceral involvement (present or absent) and the time from inclusion to detection of ESR1 mutation in the peripheral blood (<12 months or 12 months or more). The co-Primary endpoints were Progression Free Survival and Grade 3 or more hematologic adverse events in all patients.

At a median follow up of 26.0 months from randomization, switching patients from an Aromatase Inhibitor to Fulvestrant, upon detection of ESR1 mutation in the peripheral blood was associated with a 39% reduction in the risk of disease progression or death. The median Progression Free Survival was 11.9 months in the Fulvestrant and Palbociclib group versus 5.7 months in the Aromatase Inhibitor and Palbociclib group (HR=0.61; P=0·004). The co-Primary endpoint of Grade 3 or more hematologic adverse events found no safety signals associated with switching from an Aromatase inhibitor to Fulvestrant. The most frequent Grade 3 or more hematological adverse events were neutropenia. lymphopenia, and thrombocytopenia. Dose reductions were similar in both randomized treatment groups.

The authors concluded that PADA-1 is the first prospective randomized trial to demonstrate that early therapeutic targeting of ESR1 mutation in the peripheral blood results in significant clinical benefit. The researchers added that the original design explored in PADA-1 might help with addressing acquired resistance to new drugs in future trials.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. The Lancet Oncology. Published: September 29, 2022.DOI:https://doi.org/10.1016/S1470-2045(22)00555-1

FDA Grants Accelerated Approval to LYTGOBI® for Cholangiocarcinoma

SUMMARY: The FDA on September 30, 2022, granted accelerated approval to LYTGOBI® (Futibatinib) for adult patients with previously treated, unresectable, locally advanced, or metastatic intrahepatic cholangiocarcinoma harboring Fibroblast Growth Factor Receptor 2 (FGFR2) gene fusions or other rearrangements. Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades.

Approximately 75% of patients are diagnosed with late-stage disease, and are often treated with Gemcitabine plus Cisplatin, based on the findings of the ABC-02 study. Second line treatment options include FOLFOX regimen, which is associated with a Response Rate of about 5%, median Progression Free Survival (PFS) of about 4 months, and median Overall Survival (OS) of about 6 months. There is therefore an unmet need for new effective therapies.

FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration, and angiogenesis. Activating fusions, rearrangements, translocations, and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-20% of patients, and have been identified as oncogenic drivers. Futibatinib is a highly selective, irreversible FGFR1-4 inhibitor, and demonstrated tolerability and preliminary evidence of clinical efficacy in patients with intrahepatic cholangiocarcinoma.

The present FDA approval was based on the results from the pivotal FOENIX-CCA2 trial (NCT02052778), which is a global, multicenter, open-label, single-arm study that enrolled 103 patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma, harboring a FGFR2 gene fusion or other rearrangement. The presence of FGFR2 fusions or other rearrangements was determined using Next Generation Sequencing testing. Patients received Futibatinib 20 mg orally once daily until disease progression or unacceptable toxicity. The median age was 58 years, 53% had an ECOG Performance Status of 1, all patients had prior anticancer therapy, with 27% receiving prior radiotherapy. FGFR2 fusions were observed in 78% of patients and 22% had a rearrangement. The median time from prior anticancer therapy to the first Futibatinib dose was 1.5 months. The Primary endpoint was Objective Response Rate (ORR) by Independent Central Review. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR), Progression Free Survival (PFS), Overall Survival (OS), Safety, and Patient-Reported Outcomes. At the primary analysis of this trial, an Objective Response Rate of 41.7% was observed, with a median Duration of Response of 9.7 months. The researchers herein reported updated efficacy, including mature Overall Survival, and safety data from the final analysis, with an additional 8 months of follow up.

At a median follow up of 25 months, the median number of treatment cycles was 13.0 and the median treatment duration was 9.1 months. The confirmed Objective Response Rate was 41.7%, like what was noted at the time of primary analysis, and this benefit was consistent across patient subgroups. The Disease Control Rate of 82.5% and was similar as well. The median Duration of Response was 9.5 months, and 74% of responses lasted 6 months or more. The median PFS was 8.9 months, with a 12-month PFS rate of 35%. The median Overall Survival was 20 months, with a 12-month Overall Survival rate of 73%. The most common treatment-related adverse events included hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). Approximately 4% of patients discontinued treatment due to adverse events.

The authors concluded that the final analysis of FOENIX-CCA2 study confirmed the results of the primary analysis and reinforced the durable efficacy and continued tolerability of Futibatinib in previously treated patients with advanced/metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusion/rearrangements. They added that the mature Overall Survival far exceeded historical data in this patient population.

Updated results of the FOENIX-CCA2 trial: Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/rearrangements. Goyal L, Meric-Bernstam F, Hollebecque A, et al. J ClinOncol. 2022;40(suppl 16):4009. doi:10.1200/JCO.2022.40.16_suppl.4009

Expansion of Cancer Risk Profile beyond Breast and Ovarian Cancer for BRCA1 and BRCA2 Pathogenic Variants

SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.

The researchers conducted this study to evaluate the association of BRCA1 and BRCA2 pathogenic variants, with additional cancer types and their clinical characteristics associated with pathogenic variant carrier status. For this study, a large-scale registry based sequencing study was performed across 14 common cancer types in 63, 828 patients and 37, 086 controls, whose data were drawn from a Japanese nationwide multi-institutional hospital-based biobank, between 2003 and 2018. In the study group, the median age was 64 years and 42% were female, whereas the median age was 62 years and 47% were female in the control group. Germline pathogenic variants were identified in the BRCA1 and BRCA2 genes by a multiplex Polymerase Chain Reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Compared with the researchers previous publications for breast, colorectal, pancreatic, and prostate cancers, this study included 14,448 additional controls and 8247 additional cancer cases. These data thus provided a broad view of cancer risks associated with pathogenic variants in BRCA1 and BRCA2 genes.

Pathogenic variants in BRCA1 were significantly associated with increased risk for three other types of cancer types, Biliary tract (Odds Ratio–OR=17.4), Gastric (OR=5.2), and Pancreatic cancer (OR=12.6), in addition to female Breast (OR=16.1) and Ovarian cancer (OR=75.6). Pathogenic variants in BRCA2 increased risk for seven cancer types which included female Breast (OR=10.9), male Breast (OR=67.9), Gastric (OR=4.7), Ovarian (OR=11.3), Pancreatic (OR=10.7), Prostate (OR=4.0), and Esophageal cancer (OR=5.6). Further, Biliary tract, female Breast, Ovarian, and Prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.

The results of this large study suggested that pathogenic variants in BRCA1 and/or BRCA2 are associated with increased risk of biliary tract, gastric, and esophageal cancers, higher than for European populations, granted that these cancers are known to have a higher incidence rate in East Asian countries. Conversely in this study, the cumulative risk of prostate cancer for BRCA2 carriers was lower than that estimated in the UK and Ireland, suggesting that the cumulative risk for each cancer type may be associated with the different incidence rate in each country.

The authors concluded that this study suggested that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types and is likely broader than that determined from previous analysis of largely European ancestry cohorts. It would therefore be useful to expand indications for genetic testing of individuals with family history of these cancer types.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants. Momozawa Y, Sasai R, Usui Y, et al. JAMA Oncol. 2022 Apr 14: e220476. doi: 10.1001/jamaoncol.2022.0476 [Epub ahead of print]

FDA Grants Tumor-Agnostic Accelerated Approval to RETEVMO®

SUMMARY: The FDA on September 21, 2022, granted accelerated approval to Selpercatinib (RETEVMO®) for adult patients with locally advanced or metastatic solid tumors with a Rearranged during Transfection (RET) gene fusion that have progressed on or following prior systemic treatment, or who have no satisfactory alternative treatment options. The FDA on the same day also granted Regular approval to Selpercatinib for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with a Rearranged during Transfection (RET) gene fusion, as detected by an FDA-approved test. FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for Selpercatinib.

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

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

Selpercatinib is a highly selective and potent, oral anti-RET Tyrosine Kinase Inhibitor (TKI) designed to inhibit native RET signaling, as well as anticipated acquired resistance mechanisms. Selpercatinib selectively targets wild-type RET as well as various RET mutants and RET-containing fusion products. Additionally, Selpercatinib inhibits Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), VEGFR3, Fibroblast Growth Factor Receptor 1 (FGFR1), FGFR2, and FGFR3. This results in inhibition of cell growth of tumors that exhibit increased RET activity.

The LIBRETTO-001 is the largest open-label, multicenter, Phase I/II trial in patients with advanced solid tumors, including RET fusion-positive solid tumors, RET-mutant Medullary Thyroid Cancers, and other tumors with RET activation, treated with a RET inhibitor. To investigate the efficacy of Selpercatinib, the trial was conducted in 2 parts: Phase 1 (dose escalation) and Phase II (dose expansion). Patients with advanced cancer were eligible, if they have progressed on or were intolerant to available standard therapies, or no standard or available curative therapy existed, or in the opinion of the Investigator, they would be unlikely to tolerate or derive significant clinical benefit from appropriate standard of care therapy, or they declined standard therapy. A dose of 160 mg BID was the recommended Phase II dose. Up to about 850 patients with advanced solid tumors harboring a RET gene alteration in tumor and/or blood were enrolled in 6 different Phase II cohorts, based on tumor type, RET alteration and prior therapy. Identification of RET gene alterations were prospectively determined in local laboratories using either Next Generation Sequencing, Polymerase Chain Reaction, or Fluorescence In Situ Hybridization. The Phase II portion of the trial had a Primary endpoint of Objective Response Rate (ORR) by Blinded Independent Review Committee (BIRC) and Secondary endpoints of Duration of Response, CNS Objective Response Rate, Progression Free Survival (PFS) and safety.

RET Fusion-Positive Solid Tumors

This group included 41 patients and the most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%). Majority of the patients (90%) received 2 prior systemic therapies and 32% had received 3 or more. The median age of patients was 50 years, 54% were female, 68% were White, 24% were Asian, and 95% had metastatic disease. RET fusion-positive status was detected in 98% of patients using NGS and 2% using FISH.

The Objective Response Rate was 44%, with 5% Complete Response and 39% Partial Response. The median Duration of response was 24.5 months and 67% of patients had a Duration of Response of 6 months or more.

The NSCLC Cohort

Selpercatinib was previously granted accelerated approval in May 2020 for patients with metastatic RET fusion-positive NSCLC based on initial Overall Response Rate (ORR) and Duration of Response (DOR) among 144 patients enrolled in the LIBRETTO-001 trial. The conversion to regular and traditional FDA approval was based on data from an additional 172 patients and 18 months of additional follow up, to assess durability of response. Patients received Selpercatinib until disease progression or unacceptable toxicity and efficacy was evaluated in a total of 316 patients with locally advanced or metastatic RET fusion-positive NSCLC. The median age of patients was 61 years, 58% were female, 49% were White, 41% were Asian and 97% had metastatic disease. Previously treated patients received a median of two prior systemic therapies and 58% had received prior anti PD 1/PD-L1 therapy.

Among the 69 treatment-naïve patients, the ORR was 84%, with 6% Complete Response and 78% Partial Response. The median Duration of Response was 20.2 months and 50% of patients had a Duration of Response of 12 months or more. Among the 247 previously treated patients, the ORR was 61%, with 7% Complete Response and 54% Partial Response. The median Duration of Response was 28.6 months and 63% of patients had a Duration of Response of 12 months or more.

It is estimated that up to 50% of RET fusion-positive NSCLC patients can have brain metastases, and in the subset of patients with brain metastases (N=21), treatment with Selpercatinib demonstrated a CNS Objective Response Rate of 85%, and 38% of responders had an intracranial Duration of Response of 12 months or greater. The most common toxicities in patients were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

LIBRETTO-001 is the largest trial ever reported in RET-altered cancer patients and represents an important milestone in the Precision Medicine arena. Selpercatinib is the first and only RET inhibitor to receive both tumor-agnostic accelerated approval and traditional approval in NSCLC, reinforcing its benefits across diverse tumor types.

Selpercatinib in patients with RET fusion–positive non–small-cell lung cancer: updated safety and efficacy from the registrational libretto-001 phase I/II trial.Published September 19, 2022. Drilon A, Subbiah V, Gautschi O, et al. J Clin Oncol. doi:10.1200/JCO.22.00393

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-solid-tumors

FDA Grants Regular Approval to TABRECTA® for Metastatic Non-Small Cell Lung Cancer

SUMMARY: The FDA on August 10, 2022, granted regular approval to TABRECTA® (Capmatinib), for adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have a mutation leading to Mesenchymal-Epithelial Transition (MET) exon 14 skipping, as detected by an FDA-approved test. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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.

MET is a widely expressed Receptor Tyrosine Kinase and plays a pivotal role in cell growth, proliferation, and survival. The MET gene encodes for a protein known as the Hepatocyte Growth Factor (HGF) Receptor. Upon binding by Hepatocyte Growth Factor (HGF), the HGF Receptor is activated, with resulting activation of the downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby serving different important biological functions. Alterations in the MET gene leading to abnormal MET signaling, has been identified in different types of cancers including thyroid, lung, breast, liver, colon, kidney, ovary, and gastric carcinoma.

Two key MET alterations include MET exon 14 skipping mutations and MET amplification. MET exon 14 skipping mutations occur in approximately 5% of NSCLC patients with enrichment in sarcomatoid lung cancers (22%). MET exon 14 skipping mutation is a recognized oncogenic driver and is a molecular genetic abnormality indicating the presence of a splice site mutation that results in a loss of transcription of exon 14 of the MET gene. Most exon 14 mutations occur in never-smokers and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping generally have very high response rates to MET inhibitors and molecular testing for MET exon 14 skipping should therefore be performed on all lung cancers, because this is a targetable alteration. MET amplification has been more commonly seen in smokers, and responses in patients with MET-amplified tumors might be more variable and dependent on level of amplification, with higher responses noted in tumors with more than 5-6- fold amplification. Tumors with MET exon 14 skipping mutations usually do not harbor activating mutations in EGFR, KRAS, or BRAF or concurrent ALK, ROS1 or RET translocations. However, it appears that cMET exon 14 skipping is not mutually exclusive with cMET amplification.

TABRECTA® is a highly potent and selective, reversible inhibitor of MET tyrosine kinase. The FDA in May 2020 granted accelerated approval for the same indication based on the primary findings from the GEOMETRY mono-1 trial, which is a non-randomized, open-label, multi-cohort, Phase II study, conducted to evaluate the efficacy and safety of single-agent TABRECTA® in adult patients with EGFR wild-type, ALK-negative, metastatic NSCLC, whose tumors have a mutation that leads to MET exon 14 skipping (METex14), as detected by an RNA-based RT-PCR. The conversion to regular approval was based on data from an additional 63 patients (Total N=160), as well as an additional 22 months of follow- up time, to assess durability of response and verify clinical benefit.

In this updated analysis, a total of 160 patients (N=160) with metastatic NSCLC and confirmed MET exon 14 skipping mutations were included, of whom 60 patients were treatment naïve and 100 patients were previously treated. The patients received TABRECTA® at 400 mg orally twice daily until disease progression or unacceptable toxicity. The median patient age was 71 years and all NSCLC histologies including sarcomatoid/carcinosarcoma were included. Majority of the patients (77%) were white and 23% were Asian, 61% never smoked, 83% had adenocarcinoma, and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two, and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy. The Primary efficacy outcome was Overall Response Rate (ORR), and additional efficacy outcomes included Duration of Response, Time to Response, Disease Control Rate, Progression Free Survival (PFS) and Safety, as determined by a Blinded Independent Review Committee (BIRC).

Among the treatment-naïve patients (N=60), the ORR was 68% with a median Duration of Response of 12.6 months. Among the previously treated patients (N=100), the ORR was 44%, with a median Duration of Response of 9.7 months. The most common adverse events (occurring in at least 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. TABRECTA® can also cause Interstitial Lung Disease, hepatotoxicity and photosensitivity.

It was concluded that TABRECTA® is a new treatment option for patients with MET exon 14 skipping- mutated advanced NSCLC, regardless of the line of therapy, with deep and durable responses, and with manageable toxicity profile.

Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study. Wolf J, Garon EB, Groen HJM, et al. DOI: 10.1200/JCO.2021.39.15_suppl.9020 Journal of Clinical Oncology – published online before print May 28, 2021.

FDA Grants Accelerated Approval to ENHERTU® for HER2-Mutant Non Small Cell Lung Cancer

SUMMARY: The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki), for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 or HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. FDA also approved Oncomine™ Dx Target Test (tissue) and Guardant360® CDx (plasma) as companion diagnostics for ENHERTU®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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. However, HER2 overexpression and gene amplification are associated with distinct molecular entities and have limited therapeutic value in lung cancer.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC and is therefore an unmet need.

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 or HER2-Low breast cancer and locally advanced or metastatic HER2-positive Gastric or GastroEsophageal Junction adenocarcinoma who have received a prior Trastuzumab based regimen. Translational research demonstrated that HER2-mutant NSCLC may preferentially internalize the HER2 receptor Antibody-Drug Conjugate complex regardless of HER2 protein expression and overcome resistance to other HER2-targeted agents.

In the DESTINY-Lung01 Phase II, open-label, two-cohort trial of heavily pretreated population of patients with HER2-mutated advanced NSCLC, treatment with ENHERTU® 6.4 mg/kg given by IV infusion every 3 weeks resulted in an Objective Response Rate (ORR) of 55%, with a median Duration of Response was 9.3 months. Responses were observed across different HER2 mutation subtypes. The median PFS was 8.2 months, and the median OS was 17.8 months (NEJM 2022;386:241-251).

The present FDA approval was based on DESTINY-Lung02, which is a global, multicenter, multi-cohort, randomized, blinded, dose-optimization, Phase II trial, in which the safety and efficacy of two doses ENHERTU® (5.4mg/kg or 6.4mg/kg) was evaluated, in patients with HER2 mutated metastatic NSCLC, with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. This study enrolled 152 patients (N=152) and patients were selected for treatment with ENHERTU® based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients were randomized to receive ENHERTU® 6.4 mg/kg or 5.4 mg/kg by IV infusion every 3 weeks, until unacceptable toxicity or disease progression. The Primary endpoint of the trial was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. The primary/interim efficacy analysis included a pre-specified cohort of 52 patients (N=52). The median age in this cohort was 58 years, 69% were female; 79% were Asian, 12% were White, and 10% were of other races.

ENHERTU® 5.4mg/kg IV demonstrated a confirmed Objective Response Rate of 57.7%, with a Complete Response Rate of 1.9%, Partial Response Rate of 55.8%, and median Duration of Response of 8.7 months. The most common adverse effects included nausea, alopecia, increased AST and ALT, cytopenias, and was consistent with previous clinical trials, with no new safety concerns identified.

It was concluded that ENHERTU® is the first HER2-directed treatment option for patients with HER2 mutated NSCLC, and fulfills an unmet medical need in this patient population.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung

PREMMplus Hereditary Cancer Risk Assessment Tool May Identify People Likely to Benefit from Multigene Panel Testing

SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, and germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing.

Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. However, these models only provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc., and there is significant need for a risk assessment model tailored toward MultiGene Panel Testing.

The PREMM (PREdiction Model for gene Mutations) model has been rigorously tested, and is widely recognized and recommended by several professional societies, including the National Comprehensive Cancer Network (NCCN), the American College of Gastroenterology, and the U.S. Multi-Society Task Force on Colorectal Cancer. The PREMMplus model is a clinical prediction algorithm (tool) that estimates the cumulative probability of an individual carrying a germline mutation in 19 genes linked to cancer. Individuals are considered to be high risk if they have a risk score greater than 2.5%, and are eligible for genetic evaluation to determine if they indeed harbor germline mutations, and these individuals in turn could benefit from measures to prevent the cancer, or detect cancer early.

This aim of this study was to develop and validate PREMMplus clinical risk assessment tool (clinical prediction model) that could be used to identify individuals who are likely to have Pathogenic Germline Variant and should undergo MultiGene Panel Testing. PREMMplus was designed to identify individuals carrying Pathogenic Germline Variants in 19 cancer susceptibility genes broadly categorized by phenotypic overlap and/or relative penetrance, and they included 11 Category A genes (APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53) and 8 Category B genes (ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D). Assessment of germline variant pathogenicity was based on the most recent classification made by the clinical laboratory, performing MultiGene Panel Testing. This clinical prediction model was designed to achieve both high sensitivity and Negative Predictive Value (NPV) across a diverse spectrum of syndromes, used clinical data only, did not require tumor tissue thus facilitating scalability, and was adaptable to allow for future expansion, as new genes became incorporated into routine MultiGene Panel Testing.

Clinical predictors for this model included demographics (sex, ancestry, and age at testing), as well as personal, and family history of specific cancers in first- and second-degree relatives. EIGHTEEN cancer types were selected for PREMMplus development, including both common malignancies such as breast cancer and colorectal cancer and uncommon malignancies such as sarcoma and adrenocortical carcinoma, associated with inherited risk. Individuals were excluded from analysis if a personal and family history of any of these 18 cancers were not available, and/or if age at MultiGene Panel Testing was missing. Individuals with 2 or more Pathogenic Germline Variants were excluded from the development cohort.

The performance of this clinical model was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MultiGene Panel Testing ascertained from clinic and laboratory-based settings, respectively.

PREMMplus demonstrated high sensitivity and high Negative Predictive Value for identifying individuals with Pathogenic Germline Variants in the 19 different cancer susceptibility genes. PREMMplus demonstrated a sensitivity of 93.9%, 91.7%, and 89.3% and Negative Predictive Value of 98.3%, 97.5%, and 97.8% for identifying Category A gene Pathogenic Germline Variants carriers, in the development and validation cohorts, respectively. PREMMplus demonstrated a sensitivity of 89.9%, 85.6%, and 84.2% and Negative Predictive Value of 95.0%, 93.5%, and 93.5% for identifying Category A/B gene Pathogenic Germline Variants carriers in the development and validation cohorts, respectively. Overall, 9.4%, 10.8%, and 9.2% of the development, clinic-based validation, and laboratory-based validation cohorts, respectively, harbored a Pathogenic Germline Variant in one of the 19 PREMMplus genes.

It was concluded that PREMMplus accurately identifies individuals with Pathogenic Germline Variants in a diverse spectrum of cancer susceptibility genes, with high sensitivity and Negative Predictive Value. PREMMplus represents a new evidence-based approach and can be used to identify individuals who should undergo MultiGene Panel Testing.

Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment. Yurgelun MB, Uno H, Furniss CS, et al. DOI: 10.1200/JCO.22.00120 Journal of Clinical Oncology

LYNPARZA® Superior to Next-Generation Hormonal Drug in CRPC Patients with Homologous Recombination Repair Gene Alterations

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 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 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. The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination Repair (HRR) genes.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes that recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. Mutations in these genes predispose an individual to develop malignant tumors. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death. LYNPARZA® (Olaparib) is a first-in-class PARP inhibitor and blocks DNA damage response in tumors harboring a deficiency in Homologous Recombination Repair, as is noted in those with mutations such as BRCA1 and/or BRCA2. LYNPARZA® showed promising results in a Phase II trial (TOPARP), when given as monotherapy, in patients with BRCA1/2 or ATM gene-mutated mCRPC, who had received a prior Taxane-based chemotherapy, and at least one newer hormonal agent (ZYTIGA® or XTANDI®).

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial in which the efficacy and safety of LYNPARZA® was compared with physician’s choice of either XTANDI® or ZYTIGA® in two groups of patients with mCRPC, who had progressed on prior treatment with new hormonal anticancer treatments, and had a qualifying tumor mutation in one of 15 genes involved in the Homologous Recombination Repair (HRR) pathway. Patients in Cohort A (N=245) had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B (N=142) had alterations in any one of 12 other genes known to be involved in DNA repair which included BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L. Patients were randomized 2:1 within each cohort to receive LYNPARZA® 300 mg orally BID or physician’s choice of XTANDI® 160 mg orally QD or ZYTIGA® 1000 mg orally QD along with Prednisone 5 mg orally BID. Patient characteristics were well-balanced between arms in each treatment group, median patient age was 68 years, approximately 25% of patients had de novo metastatic disease, about 65% of patients received prior Taxane therapy and more than 20% had received two lines of chemotherapy. Patients were allowed to cross over to LYNPARZA® upon progression. The Primary endpoint was radiographic Progression-Free Survival (rPFS) in Cohort A, assessed by Blinded Independent Central Review (BICR).

The authors had previously reported that in Cohort A, the median PFS was 7.4 months with LYNPARZA®, compared to 3.5 months in the control group (HR=0.34, P<0.0001). This represented a 66% greater delay in disease progression compared to hormonal therapy. The interim Overall Survival analysis in Cohort A showed that median OS was 18.5 months with LYNPARZA® compared to 15 months with control drug treatment (HR=0.64, P=0.0173). In Cohort A, the Objective Response Rate (ORR) was 33.3% with LYNPARZA® compared with 2.3% with control drug therapies (P<0.0001).

The authors in this publication reported the results of the prespecified Secondary endpoints, which included pain, Health-Related Quality of Life (HRQOL), symptomatic Skeletal-Related Events, and time to first opiate use for cancer-related pain in Cohort A group of patients. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). Cohort A included 245 patients with alterations in BRCA1, BRCA2, or ATM genes, of whom 162 patients received the investigational agent LYNPARZA®, and 83 patients received control drug. The median duration of follow up at data cutoff was 6.2 months for all LYNPARZA® group patients and 3.5 months for the control group patients. The median time to pain progression was significantly longer with LYNPARZA® and was Not Reached in the LYNPARZA® group versus 9.92 months in the control group (HR=0.44; P=0.019). Pain interference scores were also significantly better in the LYNPARZA® group (difference in overall adjusted mean change from baseline score −0.85; nominal P=0.0004). Median time to progression of pain severity was Not Reached in either group. Among patients who had not used opiates at baseline (113 in the LYNPARZA® group, 58 in the control group), median time to first opiate use for cancer-related pain was 18.0 months in the LYNPARZA® group versus 7.5 months in the control group (HR=0.61; nominal P=0.044).

The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the LYNPARZA® group than the control group (10% versus 1% respectively; odds ratio=8.32; nominal P=0.0065). The median time to first symptomatic Skeletal-Related Event was not reached for either treatment group and the proportions of patients remaining free of symptomatic Skeletal-Related Events were 89.5% versus 77.1% at 6 months and 77.6% versus 53.6% at 12 months, in the LYNPARZA® and control groups respectively.

It was concluded that LYNPARZA® was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs, in patients with metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Repair gene alterations, who had disease progression after a previous next-generation hormonal drug. The authors added that the study findings support the clinical benefit of improved radiographical Progression Free Survival and Overall Survival identified in PROfound trial.

Pain and health-related quality of life with olaparib versus physician’s choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. Thiery-Vuillemin A, de Bono J, Hussain M, et al. The Lancet Oncology March 2022;23:393-405.