Next generation treatments for metastatic breast cancer

Despite the effectiveness observed with endocrine agents and the availability of CDK4/6 inhibitors for metastatic treatment, there is a requirement for studies investigating agents like OP-1250. This necessity arises from the fact that tumors can develop resistance to therapies. Additionally, certain endocrine agents that are used after treatment with CDK4/6 inhibitors do not achieve the desired level of effectiveness.[1]

OP-1250 is a type of medication that can be taken by mouth. It works by completely blocking the estrogen receptor, which is involved in the growth of certain types of breast cancer. It also prevents the receptor from carrying out its normal functions and causes it to break down. Scientists believe that OP-1250 may be more effective than other medications that only partially block the receptor. In lab studies, OP-1250 has shown to be effective against both mutated and non-mutated forms of breast cancer. These findings have led to ongoing clinical trials to test the effectiveness of OP-1250 in patients with advanced breast cancer who have not responded to other treatments. Early results from a phase I trial showed that a small percentage of patients had a positive response to the medication, with some experiencing tumor shrinkage or stabilization.

Other mechanisms of different drug classes:

Adopted by Lloyd MR et al.

Ongoing clinical trials of next-generation endocrine therapies in the metastatic, adjuvant, and neoadjuvant setting. [1]

Adopted by Lloyd MR et al.

[1] Alison D Parisian, Leslie Hodges-Gallagher, Richard Sun, Susanna Barratt, Gopinath S Palanisamy, Julia Lawrence, Pamela Klein, David C Myles, Cyrus L Harmon, Peter J Kushner. The complete estrogen receptor antagonist OP-1250 can combine with HER2 inhibition to inhibit estrogen receptor-driven cellular proliferation and shrink xenograft tumors in ER+/HER2+ breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-07.

[2]Lloyd MR, Wander SA, Hamilton E, Razavi P, Bardia A. Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role. Ther Adv Med Oncol. 2022 Jul 30;14:17588359221113694. doi: 10.1177/17588359221113694. PMID: 35923930; PMCID: PMC9340905.

KRAS mutation of Non-Small Cell Lung Cancer (NSCLC) - An Emerging Promisingly Treatable Subgroup

Lung cancer, which has the highest mortality rate among all cancer types, can primarily be classified based on the genetic mutations responsible for its development. KRAS represents a specific mutation occurring in a cluster of genes that play a crucial role in controlling cell growth and division. Over 80% of KRAS mutations occur in codon 12, and the most common mutations are KRAS G12C (mutation of glycine to cysteine; approximately 40%), KRAS G12V (mutation of glycine to valine; approximately 18–21%), and KRAS G12D (mutation of glycine to aspartic acid; approximately 17–18%), amongst others. Patients diagnosed with non-small cell lung cancer (NSCLC) that carries KRAS mutations generally exhibit poor response to chemotherapy and have an unfavorable overall prognosis. The emergence of immunotherapy has provided a ray of hope for these patients, as it has shown to enhance clinical outcomes in individuals with KRAS-mutant NSCLC. Although there are presently no targeted drugs specifically designed for KRAS-mutant NSCLC, encouraging results from clinical trials involving novel small-molecule inhibitors targeting KRAS G12C such as Sotorasib (AMG510) and Adagrasib (MRTX849) have presented at latest international conferences, suggesting their potential in treating this form of NSCLC. Furthermore, numerous other targeted drugs are currently under development. See below the fig to understanding more:

Sotorasib (AMG510):

Sotorasib was administered orally once per day at a dosage of 960 mg. The objective response rate (ORR) was 37.1% with a median response duration of 11.1 months. The median overall survival was 12.5 months with a disease control rate (DCR) of 80.6% in participants. Treatment-related adverse events (TRAEs) were reported in 69.8% of patients, with 19.8% grade 3 events. The majority of side effects related to the gastrointestinal system, such as diarrhea (31.7%), nausea (19%), and slightly elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (15.1%), offering low-grade hepatic toxicity. The U.S. Food and Drug Administration (FDA) recently granted sotorasib designation for the treatment of advanced KRAS-G12C-mutated NSCLC in adult patients[1].

Adagrasib (MRTX849):

Adagrasib (MRTX849) is another direct KRAS G12C inhibitor that acts irreversibly and selectively. A phase I/II study called KRYSTAL-1 (NCT03785249), in patients with a similar profile to that mentioned for sotorasib, evaluated the ORR and DCR of adagrasib and the results showed that in 51 patients with NSCLC, with a dosage of 600 mg twice per day, the ORR and DCR were 45% and 96% respectively. TRAEs of grade 3 or 4 were reported in 30% of patients; those with the highest frequency were fatigue (6%) and increased AST/ALT (5%). In a subgroup of patients with the STK-11 co-mutation the ORR was 64%, which may indicate the beneficial role of this co-mutation in therapeutic progress.

[1] https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug Last assessed date: 4 Oct 2023

[1] https://www.targetedonc.com/view/treatment-of-gist-recent-changes-and-recommendations. Last accessed date: 19 Oct 2023.

[2] Mazzocca A, Minelli A, Paternostro F, Silletta M, Napolitano A, Vincenzi B. New molecularly targeted drugs for gist after imatinib, sunitinib and regorafenib: a narrative review. Gastrointest Stromal Tumor 2022;5:4.

Immunotherapy for Non-Small Cell Lung Cancer (NSCLC)[1]

In the last ten years, there has been a significant paradigm shift in the treatment of lung cancer. Advances in our knowledge of lung cancer biology have resulted in the creation of numerous targeted therapies and immunotherapy treatments. Immune checkpoint inhibitors (ICIs) have demonstrated remarkable effectiveness in treating non-small cell lung cancer (NSCLC). They are currently being utilized as the initial treatment option for metastatic disease, as a consolidation therapy after chemoradiation in unresectable locally advanced disease, and as an adjuvant therapy following surgical resection and chemotherapy in resectable disease.

The initial breakthrough in utilizing ICIs for lung cancer treatment came with the introduction of the PD-1 inhibitor nivolumab. In randomized phase III trials, nivolumab demonstrated a higher objective response rate (ORR) and overall survival (OS) compared to docetaxel in patients with advanced squamous and non-squamous NSCLC who had experienced progression after platinum-based chemotherapy. Subsequently, the US FDA approved another PD-1 inhibitor, pembrolizumab, and a PD-L1 inhibitor, atezolizumab, for the same indication. These approvals were based on the superior efficacy of these agents compared to docetaxel as second-line treatments. The success of ICIs in the second-line setting opened the door for their use as first-line treatments for advanced NSCLC. In the last five years, numerous phase III clinical trials have been conducted, revealing long-lasting responses and remarkable enhancements in overall survival (OS) when using immune checkpoint inhibitors (ICI) alone or in combination with platinum-based chemotherapy, as opposed to chemotherapy alone. These findings have significantly broadened the range of first-line treatment choices available for patients with advanced non-small cell lung cancer (NSCLC) who do not have specific EGFR mutations or ALK translocations. These options include pembrolizumab, atezolizumab, cemiplimab, nivolumab plus CTLA-4 inhibitor ipilimumab, pembrolizumab plus platinum-based chemotherapy, atezolizumab plus platinum-based chemotherapy with or without bevacizumab (for non-squamous histology), and nivolumab plus ipilimumab plus two cycles of platinum-based chemotherapy. The choice of therapy in clinical practice is largely determined by PD-L1 expression, burden of disease, and tumor mutation profile.

[1] Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in Lung Cancer: Current Landscape and Future Directions. Front Immunol. 2022 Feb 9;13:823618. doi: 10.3389/fimmu.2022.823618. PMID: 35222404; PMCID: PMC8864096.

Immunotherapy for hepatocellular carcinoma[1]

Hepatocellular carcinoma (HCC) is a rapidly progressing and highly lethal tumor worldwide, often associated with chronic liver disease. While treatment options such as curative resection, liver transplantation, trans-arterial chemoembolization, radioembolization, radiofrequency ablation, and chemotherapy exist for HCC, their effectiveness is limited and they may worsen the underlying liver condition, offering little benefit to a significant number of patients with advanced HCC.

The treatment landscape for hepatocellular carcinoma (HCC) has been significantly transformed by recent advancements in immunotherapy and combination therapies. Ongoing clinical studies are continuously progressing to further enhance treatment options. Immunotherapy has demonstrated the potential to improve survival rates and achieve long-term cancer control in specific subsets of HCC patients, while also reducing the occurrence of adverse effects. Exploring the combination of immunotherapy with existing treatments for early and intermediate stages of HCC holds promise for a broader range of patients. Continued research into various markers, including programmed cell death-1/programmed cell death ligand 1, tumor mutational burden, circulating tumor DNA, microsatellite stability, DNA mismatch repair, neutrophil/lymphocyte ratio, cytokines, and peripheral immune response, aims to identify the most reliable indicators for selecting and sequencing systemic treatments, ultimately leading to optimal outcomes for HCC patients.

To date, the FDA has granted approval for seven immune checkpoint inhibitors (ICIs) that specifically target programmed cell death protein-1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), or programmed cell death-ligand 1 (PD-L1) proteins. Additionally, there are other promising immunotherapeutic strategies, such as chimeric antigen receptor (CAR) T-cell therapy, adoptive cell treatment utilizing modified immune cells, customized cytokines, and cancer vaccines, which are nearing readiness and offer renewed optimism for patients with hepatocellular carcinoma (HCC).

PD-1 inhibitor

Nivolumab (Opdivo)        

Pembrolizumab (Keytruda)

Tislelizumab (Tevimbra)

PD-L1 inhibitor

Atezolizumab (Tecentriq)

Durvalumab (Imfinzi)

CTLA-4

Ipilimumab (Yervoy)

Tremelimumab (Imjudo)

Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol. 2023 Feb 14;29(6):1054-1075. doi: 10.3748/wjg.v29.i6.1054. PMID: 36844141; PMCID: PMC9950866.

New treatment options for Gastrointestinal stromal tumour (GIST)

The treatment landscape for patients with gastrointestinal stromal tumor (GIST) has undergone significant changes over the past two decades. Currently, there are several FDA-approved agents available for GIST treatment, namely sunitinib (Sutent), regorafenib (Stivarga), ripretinib (Qinlock), and avapritinib (Ayvakit).

Initially, the targeted therapy drug imatinib (Gleevec) is commonly used as the first-line treatment for GIST patients. However, patients with advanced GIST or those who cannot continue using imatinib due to adverse effects require alternative options.

In such cases, sunitinib is currently considered the standard second-line treatment for these patients. Sunitinib works by targeting the KIT gene and inhibiting blood vessel growth in tumors. Another option is regorafenib.

Additionally, other targeted therapies like ripretinib, which has been included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines, may be employed in the treatment of GIST patients when sunitinib is no longer effective.

For patients who do not respond to these therapies, there are additional options available in the form of tyrosine kinase inhibitors, such as pazopanib (Votrient), nilotinib (Tasigna), and dasatinib (Sprycel).

Novel target therapies included in the following table:

[1] https://www.targetedonc.com/view/treatment-of-gist-recent-changes-and-recommendations. Last accessed date: 19 Oct 2023.

[2] Mazzocca A, Minelli A, Paternostro F, Silletta M, Napolitano A, Vincenzi B. New molecularly targeted drugs for gist after imatinib, sunitinib and regorafenib: a narrative review. Gastrointest Stromal Tumor 2022;5:4.