- Immunotherapy combined with chemotherapy has better efficacy and mildly increased side effects, but is tolerated by most patients.
- Combination of immunotherapy with chemotherapy + anti-vascular therapy resulted in higher disease remission rates and longer progression-free survival.
- Radiotherapy combined with immunotherapy further enhances the tumor-specific immune effect and patient survival is longer.
- The combination of two immune checkpoint inhibitors with different targets theoretically enhances the immune response against the tumor, but also has increased toxicities and remains to be studied more.
In immunotherapy for lung cancer, there is a large class of drugs called “immune checkpoint inhibitors,” as listed below. Two drugs are already available in China.
| Drug name | Type | Application |
| Ipilimumab (eprilimumab, also known as epilimumab) | CTLA-4 inhibitors | Melanoma |
| Tremelimumab | CTLA-4 inhibitor | Malignant mesothelioma (orphan drug only) |
| Nivolumab (nabumab, launched in China in 2018, trade name nabulizumab) | PD-1 inhibitor | melanoma, kidney cancer, lung cancer, and more |
| Pembrolizumab (pembrolizumab, launched in China in 2018, trade name pablizumab) | PD-1 inhibitors | melanoma, lung cancer, uroepithelial cancer, and others |
| Atezolizumab (atezolizumab) | PD-L1 inhibitor | Lung cancer, uroepithelial cancer, and others |
| Durvalumab | PD-L1 inhibitor | Bladder cancer, lung cancer, and more |
| Avelumab | PD-L1 inhibitor | Merkel cell carcinoma, uroepithelial carcinoma |
There are many questions that remain to be explored about this new class of drugs. One of them is who it can be used in combination with to make a “golden pair” that works best.
There are four potentially effective combination regimens: combination chemotherapy or radiotherapy, combination anti-angiogenic drugs, combination radiotherapy, and combination of two immune checkpoint inhibitors, and the advantages and disadvantages of each of these “partners” are described below.
Immunotherapy in combination with chemotherapy
In a Keynote-021 study, chemotherapy (pemetrexed+carboplatin) combined with pembrolizumab nearly doubled the objective remission rate compared with chemotherapy alone in patients with advanced non-squamous non-small cell lung cancer (NSCLC) without targeted therapy (55% vs 29%); median progression-free The median progression-free survival was also considerably longer (13.9 vs. 8.9 months). Side effects were mildly increased in the combination therapy group but were tolerated by most patients.
The FDA therefore approved this regimen for first-line treatment of advanced NSCLC. There are similar trials of nabolutumab (Nivolumab) and atezolizumab (Atezolizumab), suggesting that immunotherapy + chemotherapy may be the standard of care for patients with advanced lung cancer without driver genes.
Immunotherapy combined with chemotherapy + antivascular therapy
Preliminary results from an IMPower150 study suggest that initial treatment of patients with advanced nonsquamous NSCLC with a triple combination of atezolizumab (immunotherapy) + chemotherapy (carboplatin + paclitaxel) + bevacizumab (Bevacizumab, an antiangiogenic agent) is associated with higher rates of disease remission and longer progression-free survival than a double combination of chemotherapy + bevacizumab.
Theoretically, chemotherapy can enhance the effects of immunotherapy by killing tumor cells while promoting antigen release, enhancing the ability of tumor cells to bind to antibodies or lymphocytes, enhancing the sensitivity of immune effects, and blocking the immunosuppressive effects of tumors.
Immunotherapy combined with radiotherapy
Radiotherapy works by causing cancer cell necrosis, releasing large amounts of neoantigens, and attracting immune cells to move to the tumor site to kill the tumor. Radiotherapy combined with immunotherapy can further enhance the tumor-specific immune effect.
A Keynote-001 study found that progression-free survival (4.4 months vs 2.1 months) and overall survival (10.7 months vs 5.3 months) were significantly longer in patients treated with pablizumab compared to patients who had not been treated with radiation.
Two immune checkpoint inhibitors in combination
The combination of two immune checkpoint inhibitors with different targets theoretically enhances the immune response of patients’ T cells to the tumor and enhances the effectiveness of killing tumor cells.
There are also a number of potentially effective combination regimens available, such as nabolutumab (Nivolumab) + eprilimumab (also known as Ipilimumab, Ipilimumab).
CheckMate-012 was the first study to show a benefit from combination therapy. The results showed that the efficiency of the combination therapy increased as PD-L1 expression increased. Patients in the combination group with PD-L1 expression ≥1% had an objective remission rate of 57%; patients with PD-L1 expression ≥50% had an objective remission rate of 92% .
However, the results of another study, MYSTIC, were disappointing: for patients with stage IV NSCLC with PD-L1 expression >25%, Durvalumab in combination with Tremelimumab failed to deliver better outcomes compared with chemotherapy.
While dual immunotherapy enhances efficacy, it also has relatively increased toxicities. Therefore, it is important to have a strong combination and not ignore the toxicities.
Therefore, dual immune combination therapies are still being explored and more data are needed to confirm the best regimen.
Co-reviewed by: Guangdong Provincial People’s Hospital Guangdong Lung Cancer Institute Dr. Xue-Tao Li, Associate Chief Physician, Wang Zhen