There is no single “best” immunotherapy for lung cancer. The right choice depends on the type of lung cancer you have, how much of a specific protein (PD-L1) your tumor produces, whether the cancer has spread, and whether you’re a candidate for surgery. That said, pembrolizumab is the most widely recommended immunotherapy across the broadest range of situations, and it forms the backbone of current treatment guidelines for advanced non-small cell lung cancer (NSCLC), the most common form of the disease.
Why PD-L1 Levels Drive the Decision
Before choosing an immunotherapy, oncologists test a tumor sample to measure how much PD-L1 protein sits on the surface of cancer cells. This protein acts like a shield, telling your immune system to leave the cancer alone. Immunotherapy drugs called checkpoint inhibitors strip that shield away, letting immune cells recognize and attack the tumor. The more PD-L1 a tumor produces, the more likely it is to respond to immunotherapy on its own, without chemotherapy added in.
The key cutoff is 50%. When half or more of tumor cells express PD-L1, three checkpoint inhibitors are approved as standalone first-line treatments: pembrolizumab, cemiplimab, and atezolizumab. All three have shown better outcomes than chemotherapy alone in this group. For tumors with PD-L1 between 1% and 49%, pembrolizumab is approved as monotherapy, though many oncologists still prefer combining it with chemotherapy for a stronger response. Below 1%, immunotherapy alone is rarely sufficient, and combination regimens become the standard approach.
Combination Regimens for Advanced NSCLC
Most people with metastatic NSCLC don’t have PD-L1 levels high enough for immunotherapy alone, or their oncologist may prefer the added punch of a combination. Current NCCN guidelines designate pembrolizumab plus platinum-based chemotherapy as the primary recommended combination for both squamous and nonsquamous NSCLC. This pairing has become the default first-line approach in many treatment centers.
A second major option pairs two immunotherapy drugs together: nivolumab plus ipilimumab, with or without a short course of chemotherapy. These two drugs work through different mechanisms. Nivolumab blocks PD-1 (the receptor PD-L1 binds to), while ipilimumab targets a separate checkpoint called CTLA-4. Five-year data from the CheckMate 227 trial showed that this dual-immunotherapy combination kept 24% of patients with PD-L1 of 1% or higher alive at five years, compared to 14% with chemotherapy alone. Even among patients whose tumors had less than 1% PD-L1, the combination produced a 19% five-year survival rate versus 7% with chemotherapy. That advantage in low-PD-L1 tumors makes the nivolumab-ipilimumab combination a particularly important option for patients who might not respond well to other immunotherapy regimens.
Other approved first-line combinations include durvalumab paired with tremelimumab and platinum chemotherapy (approved in late 2022), cemiplimab with platinum chemotherapy, and a four-drug regimen of atezolizumab, bevacizumab, and two chemotherapy agents for nonsquamous NSCLC.
Small Cell Lung Cancer Has Fewer Options
Small cell lung cancer (SCLC) accounts for about 15% of lung cancers and is treated differently. For extensive-stage SCLC, the standard first-line approach combines chemotherapy (a platinum drug plus etoposide) with either atezolizumab or durvalumab. After the initial treatment cycles, the immunotherapy drug continues alone as maintenance therapy. This combination appears to help some patients live longer than chemotherapy alone, though the benefit is more modest than what’s seen in NSCLC. For patients whose SCLC has progressed after chemotherapy, a newer drug called tarlatamab is available as a later-line option.
Immunotherapy Before and After Surgery
Immunotherapy isn’t limited to advanced cancer. For patients with earlier-stage NSCLC who are candidates for surgery, checkpoint inhibitors are increasingly used before the operation (neoadjuvant therapy) to shrink tumors and destroy microscopic cancer cells that might have spread. Nivolumab combined with chemotherapy before surgery has been shown to produce pathologic complete responses, meaning no viable tumor is found in the tissue removed during surgery, in a meaningful percentage of patients. That complete elimination of visible cancer correlates with longer disease-free survival. Studies are also evaluating atezolizumab, durvalumab, and other checkpoint inhibitors in this pre-surgical setting.
Side Effects Across Different Drugs
Immunotherapy side effects are fundamentally different from chemotherapy side effects. Because these drugs rev up the immune system, they can cause the immune system to attack healthy tissues. The organs most commonly affected are the skin, gut, liver, thyroid, and lungs. About 30% of NSCLC patients on checkpoint inhibitors develop immune-related side effects of some kind, while a systematic analysis across 23 studies found that roughly 64 to 66% experienced side effects of any severity.
Most of these are mild. Serious side effects (grade 3 or higher) occur in about 14% of patients on PD-1 inhibitors and 21% on PD-L1 inhibitors. The risk rises significantly when two immunotherapy drugs are combined: CTLA-4 inhibitors like ipilimumab carry a 31% rate of serious side effects compared to 10% for PD-1 inhibitors alone. Gut inflammation (colitis) is the most common concern with combination therapy, affecting 20 to 32% of patients. Liver inflammation occurs in 2 to 8% of patients on single-agent PD-1 or PD-L1 inhibitors, usually at a manageable severity.
Pembrolizumab tends to produce slightly more immune-related side effects than nivolumab, though both are generally well tolerated. The dual combination of nivolumab plus ipilimumab carries higher toxicity but also offers survival advantages in certain patient groups, which is the core tradeoff oncologists weigh.
How the Choice Gets Made
The “best” immunotherapy ultimately comes down to a handful of patient-specific factors. Tumor PD-L1 expression is the single biggest determinant: high expressors have the most options, including monotherapy. Tumor type matters too, as squamous and nonsquamous NSCLC have different approved regimens, and SCLC has its own limited set. Genetic mutations in the tumor (EGFR, ALK, ROS1) can disqualify a patient from front-line immunotherapy entirely, steering treatment toward targeted therapies instead. And overall health plays a role: a patient who can tolerate combination therapy may benefit from a more aggressive regimen, while someone with autoimmune conditions or frailty may do best with a single agent.
For the largest group of patients, those with metastatic NSCLC and no targetable mutations, pembrolizumab-based regimens remain the most broadly recommended option. When PD-L1 is low or absent, nivolumab plus ipilimumab offers a proven survival benefit that no other regimen has matched in that specific population.