The evolution of non-small cell lung cancer metastases in TRACERx
Studies Supporting The Use Of PD-L1 Therapy Plus Chemo In ES-SCLC
Federico Albrecht, MD, comments on clinical trials supporting the use of PD-L1 inhibitor therapy in combination with standard chemotherapy for the treatment of patients with extensive-stage small cell lung cancer.
Federico Albrecht, MD, an oncologist/hematologist at Miami Cancer Institute, discusses evidence-based treatment of extensive-stage small cell lung cancer (ES-SCLC).
Albrecht says that ES-SCLC is aggressive and progresses quickly. Therefore, after initial treatment patients with ES-SCLC experience disease recurrence. There were 2 important clinical trials that provide guidance on how to approach treatment of these patients.
First, adding PD-L1 to standard chemotherapy was shown to improve survival in patients with ES-SCLC in the IMpower133 study (NCT02763579), which evaluated the use of atezolizumab (Tecentriq) in combination with the chemotherapy doublet, carboplatin plus etoposide. Initial findings published in the New England Journal of Medicine showed a median overall survival (OS) of 12.3 months with the addition of atezolizumab vs 10.3 months with chemotherapy alone. The median progression-free survival shown was 5.2 months with atezolizumab and chemotherapy compared with 4.3 months with chemotherapy alone. Updated findings published in the Journal of Clinical Oncology confirmed that chemotherapy plus atezolizumab is a standard of care.
In another study, CASPIAN (NCT03043872), the addition of durvalumab (Imfinzi) to platinum-etoposide or of tremelimumab (Imjudo) to platinum-etoposide led to significant improvements in OS in patients with ES-SCLC. Primary results showed a median OS of 13.0 months with added durvalumab vs 10.3 months with platinum-etoposide alone. Three-year OS analysis results from CASPIAN were presented at the European Society of Medical Oncology Congress in 2022, further demonstrating the durvalumab added to platinum-etoposide if a standard of care therapy for ES-SCLC.
0:09As you know, small cell lung cancer is an aggressive and rapidly progressing malignancy. So, while typically respond to initial chemotherapy, the orphans recur and in in a matter of months resulting in a poor prognosis. So, 2 crucial phase three trials have been conducted in recent years. The first one is called the IMpower133, which was initially published in the New England Journal of Medicine in2018 and subsequently updated and published in the Journal of Clinical Oncology. This study demonstrated that adding a PD-L1 monoclonal antibody to the standard treatment of carboplatin and etoposide improved survival. Furthermore, patients were able to continue receiving this immunotherapy as maintenance treatment until this is progression.
1:08The second study, known as the CASPIAN trial, [which] investigated the use of durvalumab and other PD-L1 monoclonal antibody, in combination with carboplatin or cisplatin and etoposide. It was first published in The Lancet into 2019, and it also received recent updates.
1:43So, once again, both trials showed an improvement in survival rates for the first time in more than 20 years. So, both of these agents have now been approved by the FDA and have become the standard of care for patients with extensive disease small cell lung cancer. Currently, research is underway to determine whether similar benefits can be achieved in patients with limited-stage disease small cell lung cancer.
Changes To The SCLC Treatment Landscape Stirs Up Hope For Oncologists
In an interview with Targeted Oncology, Sagun Shrestha, MD, evaluated new developments and clinical trials for patients with extensive-stage small cell lung cancer.
This article was originally published on Targeted Oncology. It had been lightly edited.
After several decades of limited options, patients with small cell lung cancer (SCLC) now have multiple treatment options, including the immune checkpoint inhibitors (ICIs) atezolizumab (Tecentriq), and durvalumab (Imfinzi).
Prior to the FDA approvals of atezolizumab and durvalumab, chemotherapy made up the standard of care for patients with SCLC. The backbone of treatment for these patients was platinum-etoposide chemotherapy.
However, the FDA approved these 2 ICIs in 2019 and 2020, respectively, in combination for patients with extensive-stage SCLC based on findings from the IMpower133 trial (NCT02763579) and CASPIAN study (NCT03043872).
Now, these options have filled this patient population with hope after years of limited options.
"All the drugs equally have a competitive response rate, especially in terms of using them as a maintenance drug. I think that changes how we are or how we have been treating extensive-stage small cell lung cancer," Sagun Shrestha, MD, told Targeted OncologyTM, in an interview.
In the interview, Shrestha, medical director of medical oncology at City of Hope Phoenix, evaluated new developments and clinical trials for patients with extensive-stage SCLC.
Targeted Oncology: Can you discuss some of the recent advances in the small cell lung cancer space?
Shrestha: In small cell lung cancer over the last several decades, the treatment of choice has been the same with the platinum-etoposide backbone. Over the last few years, the main change we have had, and the exciting thing is about adding immune checkpoint inhibitors. One of the main drugs we use is atezolizumab [Tecentriq] or durvalumab [Imfinzi], and that has really given more of an improvement in overall survival and decreased the chance of recurrence over time. That has changed the landscape of how we treat extensive-stage small cell lung cancer.
Can you discuss some of the newer studies that are being explored on anti PD-1 therapy in the first-line setting?
There have been several studies going on, but none of them have been FDA-approved yet for early-stage small cell lung cancer. There is the CASPIAN trial with immunotherapy, and the addition of pembrolizumab [Keytruda]. Even now, we can add pembrolizumab as 1 of the other immune checkpoint inhibitors, but we still prefer the atezolizumab and durvalumab at the present time. All of them are showing improvements in overall survival, and a decrease in disease-free progression has been improved by adding immunotherapy.
What are some recent trials that you can highlight in this space?
The CASPIAN trial is 1 which is promising, but all the drugs equally have a competitive response rate, especially in terms of using them as a maintenance drug. I think that changes how we are or how we have been treating extensive-stage small cell lung cancer.
What are some challenges that community oncologists are facing in the space?
Just because of how small cell lung cancer is, they have a very rapid doubling time with a high growth fraction, how most of them present at a late stage, [and] the development of early metastasis, the main thing we face that by the time we see patients is that the majority of are in the late stage of disease. When we are faced with a late-stage disease, even for limited-stage, the median survival is around 15 to 30 months, and the 5-year survival is around 10% to 13%. For extensive-stage, this goes down to a median survival of around 8 to 13 months, and the 5-year survival is just 1% to 2%. Overall, the prognosis is so poor.
At the same time, the small cell lung cancers are very sensitive to chemotherapy and sensitive to radiation. The initial responses we get quickly, a couple even in the first 2 rounds of chemotherapy, and they get a great response. But the problem here is being able to hold the disease-free progression for a longer period. That period is very short. Now, by adding the checkpoint inhibitors, we have been able to improve not just the overall survival, but the disease-free progression.
How do you envision the treatment landscape evolving over the next 5 to 10 years?
We are doing a lot of screening for smokers. For people who are chronic smokers, we are doing the low-dose CAT scans. [This is] like for breast cancer where we do mammograms, that's the standard of care. Now, we are promoting more and saying we need to do low-dose CT scans for patients who are chronic smokers. We can catch them at an earlier stage. That makes a whole lot of difference. In the next 5 to 10 years, we should be able to diagnose small cell lung cancer earlier in these patients, because it is a disease for smokers. If we can have all these patients who are smokers able to do the CAT scan and get them diagnosed early, I think the overall prognosis is going to change. I'm hoping that in the next couple of years we can add the checkpoint inhibitors earlier for the earliest stage, even for stage II. I think that that will change our perspective of how we treat small cells, how their prognosis will be, and how their prognosis will improve.
What advice do you have for community oncologists when treating patients with small cell lung cancer?
Having a team approach is very important. Sometimes we think that for small cell, there is no role for the surgeon or the radiation. That's not the case. I feel that the team approach, having all patients being seen by a medical oncologist, a thoracic surgeon, and a radiation oncologist, makes a whole lot of difference. For instance, most of the time for small cell, we say that surgery is not an option. But if it is stage I or small nodule, still having the surgeon involved and having it removed, I think, gives a better prognosis. Then, the role of radiation. Most of the time, the treatment of choice, especially for extensive-stage disease, is chemotherapy with immunotherapy. For instance, if there is disease which is improved after chemotherapy, adding radiation because they are radiosensitive is an important part. The other is for the earliest stage. If the disease is improved and there is no disease, that response is great. Then adding prophylactic cranial radiation or radiation to the brain to prevent recurrence in the brain is important. The team approach, as we have in like a cancer hospital setting, should be the case in any community practice too.
Apart from that, the support system, like counseling for smoking, is important. I think for every patient who is still a smoker, helping them with smoking cessation is an important part of it. For all our patients who are smokers, we let them have smoke counseling, have the pulmonary rehab, the pulmonologist involved, and have the team approach. I didn't mention the pulmonologist, but they're a big part of it in our hospital. Every patient that comes sees the pulmonologist and the whole team. Seeing the pulmonologist, seeing the rehab, smoking cessation counseling, and the psychological aspect of it, we have a psychologist who sees the patient so that emotional support is there, is another important part of it for when patients are going through it. Whenever [a patient] gets a diagnosis of small cell lung cancer, most of them talk about saying that dense kind of thing, but when they get the support system from everyone, it's not just a medical oncologist treating the patient, but a whole team of people.
FDA Awards Orphan Drug Designation To Quratusugene Ozeplasmid In SCLC
A phase 1/2 study marks the beginning of Genprex, Inc's clinical development of quratusugene ozeplasmid in small cell lung cancer.
The FDA has granted orphan drug designation to quratusugene ozeplasmid (Reqorsa) for the treatment of SCLC, according Genprex, Inc, the developer of the drug.1
"We are excited to receive orphan drug designation from the FDA for Reqorsa for patients with SCLC," said Rodney Varner, president, chairman, and chief executive officer of Genprex, Inc, in a press release.
Quratusugene ozeplasmid (Reqorsa) functions by targeting the TUSC2 gene. The drug is intended to be injected intravenously into tumor cells to interfere with cell signaling pathways and recreate pathways for cancer cell death. The agent also modulates the immune response against cancer cells and blocks the development of drug resistance.
Treatment with quratusugene ozeplasmid in patients with ES-SCLC will be investigated in the phase 1/2 ACCLAIM-3 study. Following a 3 + 3 dose-escalation design during the phase 1 portion, patients will be administered IV quratusugene ozeplasmid once every 21 days in combination with IV atezolizumab (Tecentriq) 1200 mg given once every 21 days. Treatment during phase 1 will continued until disease progression or unacceptable toxicity occurs. The primary end point during phase 1 is to determine the maximum-tolerated dose of quratusugene ozeplasmid.2
During the second phase, patients will be treated with IV quratusugene ozeplasmid at the recommended phase 2 dose, once every 21 days in combination with IV atezolizumab 1200 mg, which is given once every 21 days until patients experience disease progression or unacceptable toxicity. The primary end point to be explored during phase 2 is progression-free survival (PFS) rate at 18 weeks according to RECIST v1.1.
Secondary end points to be explored during both phases of the study include safety determined by adverse events, PFS per RECIST v1.1, pharmacokinetics, and overall survival.
Small cell carinoma of lungImage Credit: © MdBabul - www.Stock.Adobe.Com
Patients are eligible to enroll given they have documented history of histologically or cytologically confirmed ES-SCLC before receiving atezolizumab, carboplatin, and etoposide, and achieved a response following at least 3 cycles of prior therapy. Patients are required to have an ECOG performance status of 0 or1, as well as adequate organ function and laboratory tests at baseline. The study permits patients with asymptomatic brain metastases with additional criteria. Also, patients with stable cardiac condition may enroll with a left ventricular ejection fraction ≥40% within ≤21 days of starting the study. Female patients must produce a negative pregnancy test before beginning study treatment, and all patients must agree to the use of contraception during the study and for 4 months following the end of study treatment. Male patients must also agree to these terms relating to sperm donation.
ACCLAIM-3 excludes patients who cannot tolerate atezolizumab, as well as those previously treated with a gene therapy, or prophylactic cranial irradiation or consolidation thoracic radiation.
"This FDA orphan drug designation in combination with our recently received FDA fast track designation underscores the great need for better treatment options for patients with SCLC, ES-SCLC, and non–small cell lung cancer [NSCLC]," Varner said, in the press release.1
Specifically, the FDA previously granted 3 fast track designations to quratusugene ozeplasmid in combination with other agents. The indications include quratusugene ozeplasmid in combination with osimertinib (Tagrisso) for the treatment of patients with late-stage non–small cell lung cancer (NSCLC) whose disease progressed after treatment with osimertinib (Tagrisso); quratusugene ozeplasmid in combination with pembrolizumab (Keytruda) for the treatment of patients with late-stage NSCLC whose disease progressed after treatment with pembrolizumab; and qaratusugene ozeplasmid in combination with atezolizumab for the treatment of patients with extensive-stage SCLC who did not develop tumor progression after receiving atezolizumab and chemotherapy as initial standard treatment.
"We look forward to initiating the Acclaim-3 clinical trial expected in the fourth quarter of 2023 in order to bring hope of an effective new therapy to patients suffering with this life-limiting cancer," Varner added.
REFERENCES:
1. Genprex granted FDA orphan drug designation (odd) for Reqorsa® immunogene therapy for the treatment of small cell lung cancer. News release. August 10, 2023. Accessed August 11, 2023. Https://tinyurl.Com/mpfk5mns
2. Quaratusugene ozeplasmid (Reqorsa) and atezolizumab maintenance therapy in ES-SCLC patients (Acclaim-3). ClinicalTrials.Gov. Updated March 24, 2023. Accessed August 11, 2023. Https://tinyurl.Com/4x39d96m
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