At the beginning of August, a press roundtable on the specialist field of oncology was held in Zurich. Insight was provided into “targeted therapy” in breast carcinoma, acute lymphoblastic leukemia (ALL), and non-small cell lung cancer (NSCLC), and two new approvals in the Swiss healthcare market and one indication extension were discussed.
Targeted therapy” is a relatively new way of treating cancer. It exploits specific biological characteristics or processes in cancer cells to target toxic therapies to the desired site of action. Optimally, these specific features/processes do not occur or occur only to a small extent in healthy cells. The goal is to make malignancy therapy safer and more effective. In most cases, these new approaches are combined with already established therapeutic standards.
Breast Cancer
Breast cancer is the most common malignant tumor in women. Approximately 20-30% of patients develop metastases during the course of the disease. The median survival after this diagnosis is usually a few years. At the beginning of March 2017, Ibrance (active ingredient palbociclib), a new drug in the field of “targeted therapy”, was approved in Switzerland for some of the patients affected by metastatic breast cancer. In the USA and Europe, this step was already taken in 02/2015 and 11/2016 respectively. The indication is HR-positive, HER2-negative advanced or metastatic breast carcinoma that has already undergone endocrine pretreatment. Ibrance was approved in combination with Fulvestran (estrogen receptor antagonist). The pivotal PALOMA-3 clinical trial [1] demonstrated a significant prolongation of progression-free survival in patients receiving a combination of palbociclib and fulvestrant compared to those taking fulvestrant combined with placebo (9.5 months vs. 4.6 months, p<0.0001). This superiority was seen in both premenopausal and postmenopausal women whose breast cancer had progressed on prior endocrine therapy. Among patients who had measurable disease at baseline, about 25% showed partial or complete remission, which the authors equate with previous data on response rates to chemotherapy. The median follow-up of the study was 8.9 months. The mechanism of action is based on influencing cell cycle control by inhibiting the cyclin-dependent kinases CDK 4 and 6, a signaling pathway that is also partially inhibited by anti-hormonal therapy. Reactivation of these kinases is associated with resistance to endocrine therapy. A synergistic effect of endocrine therapy in combination with inhibition of CDK4/6 was demonstrated. This combination enhances the reactivation of retinoblastoma (Rb) protein by inhibiting Rb phosphorylation, leading to growth arrest [2].
Ibrance had a comparatively quite favorable side effect profile in the study.
Non-small cell lung cancer
Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers. This form of lung cancer can be further divided into subtypes. Approximately 1% of NSCLCs have chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase, and 3-7% have ALK (anaplastic lymphoma kinase) rearrangements, providing an opportunity for “targeted therapy.” After crizotinib was approved as an ALK inhibitor back in 2011 and received approval from Swissemdic in 2015 as a first-line therapy for ALK-positive advanced NSCLC, the indication was expanded to include ROS1-positive advanced NSCLC in March 2017. This decision is based on the investigation of a single-arm expansion cohort of the PROFILE 1001 study [3]. In this, 50 patients with ROS1 rearrangement were studied. It showed a median progression-free survival of 19.2 months. The objective response rate was 72%, with 3 patients showing complete remission (6%) and 33 showing partial remission (66%). According to the authors, the dual inhibition of ALK and ROS1 is most likely due to the structural similarity of the tyrosine kinases. ROS1 rearrangements are found more frequently in patients who have either never smoked or smoked little. Toxic side effects were rated as grade 2 or less.
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is more commonly known from pediatrics. The greatest incidence is seen between the ages of 2 and 5. It also has the best chance of cure in childhood. Most deaths caused by ALL occur in adults, approximately 80%. A distinction is made in ALL between T and B cells. Approximately 85% are B-cell ALL. Previous therapies show a good response rate, but many of the adult patients suffer a relapse during the course, with a median survival of a few months. As a form of “targeted therapy” in this field, Bespona (inotuzumab ozogamicin) has been approved by Swissmedic since July 2017. Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 is a cell surface antigen that is expressed by B cells, including the majority of blasts in B-cell ALL. After inotuzumab binds orgamicin to CD22, it is taken up into the cell and calicheamicin is released. The effect of the antibiotic unfolds via DNA double-strand breaks, which eventually leads to apoptosis. Approval was based on the phase III study by Kantarjian et al [4]. This compared adult patients with relapsed or refractory, CD22-positive B-precursor cell ALL who received either inotuzumab ozogamicin or standard chemotherapy. There was a significantly higher rate of remission in the arm taking the monoclonal antibody compared to chemotherapy (80.7% vs. approximately 30%, p<0.001). Similarly, more patients in the former arm received stem cell transplantation following therapy, which is understood to be the only curative treatment option, according to the study authors. Median progression-free survival was 5 months in the inotuzumab ozogamicin arm, compared with 1.8 months in the standard group (p<0.001). The most frequent hematological side effects were cytopenias, the most severe “veno-occlusive disease”, mostly associated with transplantation. Patients with Philadelphia chromosome positive ALL should have demonstrated treatment failure with at least one tyrosine kinase inhibitor prior to initiation of treatment with inotuzumab ozogamicin.
Source: Pfizer Media Roundtable Oncology, August 11, 2017, Zurich
Literature:
- Cristofanilli M, et al: Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17(4): 425-439.
- Finn RS, et al: PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11(5): R77.
- Shaw AT, et al: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 2014; 371: 1963-1971.
- Kantarjian HM, et al: Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med 2016; 375(8): 740-753.
