Lung Cancer Survival: how targeted immunotherapy has changed the treatment landscape
- REDUCED THE RISK OF DISEASE PROGRESSION BY 42%
- HELPED PATIENTS LIVE LONGER
- MORE PATIENTS HAD TUMORS SHRINK
- Pembrolizumab reduced the risk of non-small cell lung cancer patients dying by 37 percent
- 1 in 5 patients treated with atezolizumab was alive at 3 years. This places atezolizumab among the drugs with the highest landmark overall survival [OS] in previously treated lung cancer patients.
Lung cancer is the leading cause of cancer-related deaths among men and women in the United States, despite being the second most commonly diagnosed cancer. Based on Surveillance, Epidemiology, and End Results (SEER) Program data from 2009 to 2013, cancers of the lung and bronchus account for 57.3 new cases of cancer per 100,000 individuals and 46.0 deaths per 100,000 individuals in the United States each year, and the risk of developing some form of lung or bronchus cancer over the course of a lifetime is about 6.5%. Further, in 2016, it was estimated that more than a quarter of all cancer-related deaths (26.5%; 158,000) will be attributed to lung and bronchus cancer. Overall, according to SEER data, an estimated 224,390 new cases of lung and bronchus cancer will occur in 2016 in the United States, which represents 13.3% of all new cancer diagnoses.
Lung cancer is divided into 2 major classes: non–small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC is the most common form of lung cancer (83%). The estimated 5-year survival rate is 21%.
In recent years, Immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking the programmed cell death receptor-1 (PD-1) and its ligand the programmed cell death ligand-1 (PD-L1) have emerged as novel treatment strategies in NSCLC, demonstrating undoubted superiority over chemotherapy in terms of efficacy. Cancer cells often express PD-L1 protein on their surface — a cancer cell biomarker that can bind to its receptor PD-1 that is expressed by immune T-cells. When this happens, the immune cells are blocked and can’t attack the cancer cells.
Several of these immune checkpoint modulators have recently gained regulatory approval for the treatment of advanced NSCLC, such as nivolumab, atezolizumab and pembrolizumab in first-line (only the latter) and second-line settings, and more recently, durvalumab as maintenance after chemoradiotherapy in locally advanced disease. There is a consensus that PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors in several tumor types. Hence PD-L1 expression evaluated by immunohistochemistry (IHC) is currently used as a clinical decision-making tool to support the use of checkpoint inhibitors in NSCLC patients. However, the value of PD-L1 as the ‘definitive’ biomarker is controversial as its testing is puzzled by multiple unsolved issues such as the use of different staining platforms and antibodies, the type of cells in which PD-L1 is assessed (tumor versus immune cells), thresholds used for PD-L1-positivity, or the source and timing for sample collection. Therefore, newer biomarkers such as tumor mutation burden and neoantigens as well as biomarkers reflecting host environment (microbiome) or tumor inflamed microenvironment (gene expression signatures) are being explored as more reliable and accurate alternatives to IHC for guiding treatment selection with checkpoint inhibitors in NSCLC.
Common PD-1 and PD-L1 Inhibitors used
One cancer immunotherapy approach is to interfere with checkpoint mechanisms, such as PD-L1/PD-1 signaling, an interaction that inactivates T cells and spares cancer cells (A). When PD-L1 or PD-1 is bound by a checkpoint inhibitor, such as a monoclonal antibody, T cells stay activated, boosting the antitumor response
Selective Immune-mediated tumor destruction is fascinating for science and tantalizing for oncologic doctors and patients, and in the last six years, researchers have found ways to point and manipulate the immune system’s destructive power in the direction of cancerous cells that have previously dodged detection. Clinical use of currently approved immunotherapeutics has demonstrated the power and durability of these therapies in a variety of cancer types, yet much work remains to be done before science can realize the potential that exists to modulate the immune system. Some of the common features and treatments so far observe during immunotherapy include:
- Referring to trials with so-called ‘immune checkpoint inhibitors’. These drugs bring the tumor out from where it is hiding from the defense system.
- Tumor cells, by producing and presenting large quantities of PD–L1 proteins on its surface, engage the PD1 protein on lymphocytes and as a result cancer cells evade the tumor-destroying cells known as T lymphocytes.
- The antibody’s mission, used in immunotherapy, is to prevent this harmful union, which enables the defenses to release their safety brake, recognize the tumor as foreign once more and attack it
- Much personalized targeted medicine is based on therapies that block a particular aspect of each tumor molecular signatures.
- Immunotherapy could be administered in conjunction with those already existing or with others currently being studied, including chemotherapy, radiotherapy, targeted therapies or even vaccines, which would require several further studies.
- In 2015, nivolumab (Opdivo®) was the first PD-1 inhibitor approved for lung cancer. This treatment is used for patients with Non-small cell lung cancer(NSCLC) who no longer respond after chemotherapy and EGFR or ALK-targeted therapy (if their tumor has those genetic mutations). It is also approved for bladder cancer, melanoma, kidney cancer, and head and neck cancer.
- Pembrozulimab (Keytruda®) is approved for patients with NSCLC and high levels (at least 50%) of the PD- L1 marker, and negative for EGFR and ALK. It is approved with chemotherapy to treat nonsquamous NSCLC, even with no sign of the PD-L1 marker. This therapy is also approved for any tumors with MSI-H or dMMR biomarkers, head and neck cancer, Hodgkin lymphoma, and melanoma.
- Atezolizumab (Tencentriq ®) is used for patients with NSCLC whose disease progressed after chemotherapy and EGFR or ALK-targeted therapy (if their tumor has those genetic mutations). It is also approved to treat bladder cancer.
- Avelumab (Bavencia®) was approved in 2017 to treat Merkel cell carcinoma and bladder cancer. It is being studied as a treatment for NSCLC.
- Durvalumab (Imfinzi™) was approved in 2017 to treat bladder cancer. It is also being studied as a treatment for NSCLC.
Some of this checkpoint inhibitor such as Pembrulizumab may also be used alone for advanced NSCLC if you have tried chemotherapy that contains platinum and it did not work or is no longer working and your lung cancer tests positive for PD-L1 and, if your tumor has an abnormal “EGFR” or “ALK” gene, you have also received an “EGFR” or “ALK” inhibitor medicine that did not work or is no longer working.
Pembrulizumab may also be used with the chemotherapy medicines pemetrexed and carboplatin as your first treatment for advanced NSCLC when it is a type of lung cancer called “nonsquamous.”
Nivolumab (Opdivo®) was the first PD-1 inhibitor approved for lung cancer
Cancer cells often express PD-L1 protein on their surface — a cancer cell biomarker that can bind to its receptor PD-1 that is expressed by immune T-cells. When this happens, the immune cells are blocked and can’t attack the cancer cells. taking advantage of immunotherapy drugs like Opdivo, which was designed to inhibit the PD-1 receptor and prevent it from binding to PD-L1, it becomes possible to boost the activity of immune cells to recognize malignancies and attack cancer cells.
The Phase 3 CheckMate 026 trial (NCT02041533) compared the effectiveness of Bristol-Myers Squibb’s anti-PD-1 antibody Opdivo with standard-of-care chemotherapy regimens for treatment of patients with advanced untreated or recurrent NSCLC positive for PD-L1 expression. A total of 541 patients were included in the trial, of whom 418 had more than 5 percent of tumor cells expressing PD-L1, and 214 patients had more than 50 percent of their tumor cells expressing PD-L1. The patients were randomized to receive either Opdivo or physician’s choice of chemotherapy — Gemzar (gemcitabine); Platinol (cisplatin); Taxol (paraplatin); or Alimta (paclitaxel).
About 60 percent of the patients treated with chemotherapy ended up being treated with Opdivo due to disease progression.
Interestingly, a detailed analysis of treatment response in the subgroup of patients who had tumors with higher levels of PD-L1 (more than 50 percent) and high tumor mutation burden showed a greater benefit with Opdivo therapy.
“The good news is that we discovered that a subset of patients who had both high tumor mutation burden and high PD-L1 positive status did experience a significant benefit from immunotherapy,” David Carbone, MD, PhD, said recently. Carbone is a professor at the Ohio State University Comprehensive Cancer — James Cancer Hospital and Solove Research Institute, and lead author of the study.
Indeed, 75 percent of the patients in this subgroup responded to treatment compared to only 16 percent of the patients who received immunotherapy, but had low mutation burden and low PD-L1. These two subgroups of patients presented the same response rate when treated with standard chemotherapies. These results highlight the importance of these biomarkers in immunotherapy efficacy.
“This study is an important step toward understanding the impact of tumor mutation burden and PD-L1 in immunotherapy response. This data shows we should evaluate these two factors independently to most accurately define who will benefit from immunotherapy,” Carbone said.
Pembrozulimab (Keytruda®) is approved for patients with NSCLC and high levels (at least 50%) of the PD- L1 marker, and negative for EGFR and ALK
The KEYNOTE-024 trial demonstrated Keytruda’s superiority over standard chemo as a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) whose tumors express high levels of the PD-L1 protein. The expression is the process by which information from a gene is used to create a functional product like a protein.
Pembrozulimab (Keytruda®) reduced the risk of non-small cell lung cancer patients dying by 37 percent, compared with standard chemotherapy, according to updated information from a Phase 3 clinical trial. Sixty-one percent of the patients who received Keytruda were still alive after 18 months, versus 43 percent in the standard chemo group. The therapy also halved the risk that the disease would progress after a patient started a second line of treatment, the update indicated.
The trial covered 305 patients with squamous and non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. Patients were randomized to receive either Keytruda or a standard of care platinum-based chemotherapy. Keytruda reduced the risk of a patient dying by 37 percent, compared with chemo. It also lowered by 52 percent the risk of the disease progressing after a patient started a second line of treatment — again, compared with standard chemotherapy. Sixty-one percent of the patients who received Keytruda were alive after 18 months, versus 43 percent in the chemotherapy group.
The follow-up results, including improved overall survival, give us further confidence in Keytruda as a first-line treatment for patients with non-small cell lung cancer whose tumors express high levels of PD-L1.
Atezolizumab (Tencentriq ®) is used for patients with NSCLC
According to 3-year survival findings from the phase II POPLAR study, anti-PD-L1 immunotherapy with atezolizumab (Tecentriq) demonstrated strong superiority to docetaxel in locally advanced or metastatic non–small cell lung cancer (NSCLC).
For those with low-to-high PD-L1 expression, the 3-year OS rate for atezolizumab was 18.0% versus 11.0% for docetaxel (P = .1759). For those with no PD-L1 expression, the 3-year OS rate was 20.5% versus 6.8% (P = .0693), respectively.
The 3-year findings from POPLAR represented the longest follow-up reported to date with anti-PD-L1 immunotherapy in patients with previously treated, advanced NSCLC. Patients (n = 287) were recruited from 61 sites across 13 countries and randomly assigned to 1200 mg of atezolizumab or 75 mg/m2 of docetaxel every 3 weeks.
The overall response rate was 15% in the intent-to-treat populations of both treatment groups, but median duration of response 3 times longer with atezolizumab (22.3 vs 7.2 months).
The European Commission (EC) granted marketing authorization for Tecentriq (atezolizumab) as a monotherapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior treatment with chemotherapy.
Tecentriq can be administered regardless of PD-L1 status, and patients that have EGFR-activating mutations or ALK-positive tumor mutations must have received targeted therapy prior to administration of Tecentriq . This approval is based on the positive results obtained from a large randomized Phase III OAK study, which demonstrated that treatment with Tecentriq can help patients survive to a median of 13.8 months, which is 4.2 months longer than patients on docetaxel chemotherapy (9.6 months).
Durvalumab (Imfinzi™) was approved in 2017
IMFINZI was studied in 713 patients with unresectable Stage 3 NSCLC who completed at least 2 cycles of chemotherapy that contained platinum given at the same time (concurrent) as radiation before starting the trial. Patients in the study had good Performance status (WHO 0 or 1). IMFINZI was tested against a placebo (no medication). The main goal of the study was to measure the length of time people remained progression-free (without cancer growing or spreading) and overall survival. At the time of analysis, overall survival comparison was not yet available. This trial is still ongoing.
People receiving IMFINZI had a 48% lower chance of lung cancer growing or spreading than people receiving placebo. It was proven to give people 3x more time without their cancer growing or spreading compared with placebo. The median time that tumors did not grow or spread was 16.8 months for the 476 patients receiving IMFINZI compared with 5.6 months for the 237 patients receiving placebo.
Durvalumab antibody blocks PD-1 and PD-L1 interaction, which prevents a SHP2-mediated co-inhibitory signal, allowing the neoepitope expressed by MHC-i to act as signal in stimulating an immune response, leading to the release of perforins and granzymes, theoretically leading to the destruction of the tumor cell. Abbreviations: PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase; MHC, major histocompatibility complex; TCR, T-cell receptor. Durvalumab, is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80.
The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease.
- American Cancer Society
- The National Cancer Institute
- National Comprehensive Cancer Network
- American Academy of Gastroenterology
- National Institute of Health
- MD Anderson Cancer Center
- Memorial Sloan Kettering Cancer Center