Chemotherapy was once the only treatment option for metastatic non-small cell lung cancer (NSCLC). But five years ago, immunotherapy—treatment that boosts a patient’s own immune system to fight cancer—came on the scene. In 2015, the U.S. Food and Drug Administration (FDA) approved the drug nivolumab (brand name Opdivo) as next-line treatment for NSCLC after chemotherapy. Today, new immunotherapy options continue to alter the NSCLC treatment landscape.
New Approaches for NSCLC Without “Druggable” Mutations
While some NSCLC tumors have key molecular features—such as mutations in the EGFR or ALK genes—that drive tumor formation and can be targeted with specific drugs, many do not. Immunotherapy provides a potentially powerful tool against NSCLC tumors without “druggable” mutations.
The first FDA-approved immunotherapy for non-small cell lung cancer, nivolumab, is an immune checkpoint inhibitor (ICI)—a drug that activates the immune system’s T cells to attack cancer cells. Now, the FDA has approved a total of four ICI drugs for NSCLC. These include two “anti-PD-1” drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo), which work by targeting an immune system protein called PD-1, one “anti-PD-L1” drug, atezolizumab (Tecentriq), which targets the protein PD-L1. A fourth ICI, the “anti-CTLA4” drug ipilimumab (Yervoy), has just been FDA-approved for NSCLC, in combination with nivolumab.
In 2016, pembrolizumab became an FDA-approved option for first-line treatment. However, pembrolizumab as a single drug is now recommended only for patients with high levels of PD-L1 protein in their tumors. In the Keynote-024 clinical trial, patients who tested positive for PD-L1 in over 50% of their tumor cells had an overall survival time of 30 months if treated with pembrolizumab, while patients who received only chemotherapy lived an average of 14 months. Patients with low or absent PD-L1 do not respond nearly as well to pembrolizumab. Now, a specific, FDA-approved test (PD-L1 IHC 22C3 pharmDx) can measure PD-L1 levels to help inform the decision of whether pembrolizumab is an appropriate first-line treatment. Atezolizumab was approved on May 18, 2020, only for patients with PD-L1 expression in over 50% of their tumor cells. Overall survival seen with this drug in a clinical trial was 20 months, versus 14 months with chemotherapy.
However, the response rate (percentage of patients who experience a benefit) for ICI drugs on their own is not high, so treatments combining ICIs with other drugs have been tested in numerous trials. Now, in less than two years, preferred first-line treatment for NSCLC has largely shifted from a single ICI to the combination of ICIs with chemotherapy. In March of this year, The American Society of Clinical Oncology and Ontario Health released new guidelines for first-line NSCLC treatment that practically mandate combining chemotherapy with ICIs (with some exceptions, such as for patients with high PD-L1 levels or poor ability to perform everyday activities).
ICI Plus Chemo: A Superior Combination
Multiple clinical trials have now confirmed the superiority of combined chemotherapy and immunotherapy with ICIs for patients with newly diagnosed NSCLC. Here is a brief summary of the most pivotal trials and their results:
|Trial Name and NSCLC type (squamous or non-squamous):||Treatments tested:||Median Overall Survival (months) with/without ICIs:||Response rate (%) with/without ICIs:||Status:|
|Pembrolizumab + carboplatin + pemetrexed versus chemotherapy alone
|Accelerated approval in 2017; Full approval in August 2018|
|Atezolizumab + carboplatin + paclitaxel + bevacizumab versus chemotherapy + bevacizumab||19/15
|Approved in December 2018|
|Atezolizumab + carboplatin + nab-paclitaxel versus chemotherapy alone
|19/14||49/32||Approved in December 2019|
|Pembrolizumab + carboplatin + paclitaxel versus chemotherapy alone||16/11||58/38
|Approved in October 2018|
Both squamous and non-squamous
|Nivolumab + ipilimumab
versus chemotherapy alone
|Approved May 15, 2020
Both squamous and non-squamous
|Nivolumab + ipilimumab (low dose) and short course of chemotherapy (two cycles only) versus chemotherapy alone||Not published yet||Not published yet||Under review|
Clearly, combinations of ICIs and chemotherapy are more efficacious, both in terms of response rate and overall survival time, especially in non-squamous NSCLC. Moreover, the results of several trials mentioned above show that the presence of PD-L1 in patients’ tumors does not significantly influence responses to combined chemo- and immunotherapy (unlike for ICIs alone). Results for the Checkpoint 9-LA trial (a very short course of treatment with chemotherapy and two ICI drugs) have not been reported yet, but trial is included above because an application for approval has been submitted to the FDA, hopefully signifying that results were favorable.
The side effects of combined chemo- and immunotherapy for non-small cell lung cancer tend to be largely similar to those of chemotherapy alone, but are more serious than with ICIs alone. However, the clearly superior efficacy largely outweighs those effects.
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Now, the pressing question is what treatments could be offered to patients who either 1) do not respond to combined chemotherapy and ICI treatment, or 2) experience disease progression after an initially good response.
Many NSCLC tumors without key mutations like EGFR or ALK do have mutations in the gene KRAS. KRAS mutations are major drivers of tumor formation across many cancer types and are found in around 30% of NSCLC tumors. There has been a proliferation of drugs in trials targeting KRAS mutations, which was previously thought to be “undruggable.” What started with a single promising drug for a specific KRAS G12C mutation is now at least 10 KRAS-targeting drugs currently being tested in clinical trials. These drugs could be promising for patients with KRAS mutations who do not respond to ICIs.
In addition, there are many trials specifically for patients who have already received immunotherapy with ICIs but have grown resistant to them and need new treatment. These trials are exploring immunotherapy drugs that target other immune-system-regulating proteins beyond PD-1 or CTLA-4 (e.g., the proteins LAG-3, OX40, TIM3, TIGIT, and more). But so far, combining these drugs in different ways to overcome resistance to anti-PD/PD-L1 drugs has failed. The search is still ongoing.
Other types of combination treatments are currently in trials, such as ICIs combined with targeted drugs, personalized cancer vaccines, CAR T-cell therapy, and cytokine drugs. Time will tell which combinations will be better than “simply” adding chemotherapy to immunotherapy with ICIs.
The important message is that combined chemo- and immunotherapy—called a “paradigm shift” by some—is now the preferred treatment for newly diagnosed NSCLC patients.
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To learn more about specific terms used in this piece, visit the NCI Dictionary of Cancer Terms
The European Society for Medical Oncology (ESMO): FDA Expands Approved Use of Nivolumab in Advanced Lung Cancer
The U.S. Food and Drug Administration (FDA) approved drugs: Pembrolizumab (KEYTRUDA) Checkpoint Inhibitor
Journal of Clinical Oncology: Treating KRAS-mutant NSCLC: latest evidence and clinical consequences
Targeted Oncology: FDA Approves Pembrolizumab Companion Diagnostic for Frontline PD-L1+ NSCLC