Research Signal – Source date 2021-03-23
A gene change can make a lung cancer vulnerable to drugs designed to block that change, yet leave it difficult to treat with immune checkpoint drugs. In a review published in 2021, the authors describe this split in cancers with an ALK rearrangement: ALK-targeted medicines can produce substantial responses, while retrospective patient studies found little response to checkpoint treatment given alone.
An ALK rearrangement is a change in a cell’s genetic material that can help drive cancer. It occurs in roughly 5–6% of non-small cell lung cancers. Blocking ALK can slow or shrink these tumors, but resistance to ALK inhibitors usually develops over time. The review asks whether immune-based treatments might help, and why the presence of an apparent immune target has not translated into reliable benefit for patients.
The immune marker does not tell the whole story
One candidate target is PD-L1, a protein that can bind to PD-1 on immune cells and dampen their attack on a tumor. Blocking this interaction can release one brake on immune activity. In laboratory studies discussed by the review, ALK activity increased PD-L1 in lung cancer cells. Some experiments also found that an ALK inhibitor lowered PD-L1, while adding a PD-1-targeting drug further reduced cancer-cell viability in the lab.
Those experiments suggest a possible interaction between ALK and the PD-1/PD-L1 checkpoint. But a marker on cancer cells is only one part of the setting in which an immune treatment must work. In patient-tumor analyses reviewed by the authors, ALK-rearranged tumors often had few CD8-positive T cells—the immune cells that can directly attack cancer—and more features associated with immune suppression. Regulatory T cells can restrain other immune cells, while tumor-associated macrophages can also contribute to the local immune environment.
The result is a mismatch: cell studies linked ALK activity to more PD-L1, but the patient tumors described in the review did not show that this marker reliably identified people likely to benefit from checkpoint treatment. If too few tumor-fighting T cells reach or remain active in a tumor, blocking one checkpoint may not be enough to create an effective attack. The review also notes that ALK-rearranged cancers tend to have fewer mutations than smoking-associated lung cancers, which may mean fewer tumor changes for the immune system to recognize.
Patient studies found few responses, with important gaps
Retrospective studies—the kind that look back at treatments patients already received—reported weak results for checkpoint drugs used alone in ALK-rearranged lung cancer. In one single-center analysis, no ALK-positive patient had an objective response, meaning measurable tumor shrinkage, while 23.3% of ALK-negative patients did. In a separate multicenter analysis, none of 23 patients with ALK-rearranged disease had confirmed tumor shrinkage on scans; 21% had stable disease and 78% had progression. A global registry analysis of 83 patients found a median of 2.1 months before checkpoint treatment stopped and a median of 2.3 months before cancer progression or death.
These figures point to limited activity in the groups studied, but they do not combine into one definitive estimate. The studies were retrospective, and their patient groups and treatment circumstances differed. They also cannot answer whether a particular person might respond.
Randomized lung-cancer trials offer a stronger way to compare treatments overall, but the trials cited in the review could not settle the ALK-specific question. Some excluded patients with ALK rearrangements; others included only a handful, or did not report outcomes for that subgroup because there were too few participants. In the POPLAR and OAK trials, ALK-rearranged patients appeared only in the chemotherapy groups. Results for a broad lung-cancer population therefore cannot be read as a meaningful test of checkpoint treatment specifically for ALK-rearranged disease.
Combining treatments brought a serious safety concern
Pairing an ALK inhibitor with a checkpoint drug seems like one way to address both the cancer-driving change and the immune brake. Early trials explored that idea, but the experience described in the review shows why a stronger treatment effect cannot be considered separately from harm.
In CheckMate 370, a phase I/II study of nivolumab plus crizotinib for previously untreated advanced ALK-rearranged lung cancer, five of the first 13 participants developed severe liver toxicity. Two participants died from treatment-related adverse effects, and enrollment was stopped. These outcomes made safety a central concern for this combination.
Another small trial combined nivolumab with ceritinib. Among patients who had not previously received an ALK inhibitor, reported response rates were 83% in one dose group and 70% in another. However, severe side effects—including increased liver enzymes, rash, and diarrhea—led to changes in the study and ultimately its discontinuation. A separate early trial reported a higher response rate with avelumab plus lorlatinib than with avelumab plus crizotinib, but these preliminary results also do not establish that either combination offers an acceptable balance of benefit and harm.
The trials were small and early, and their results do not establish a durable advantage. For immune combinations to become useful, they would need to show lasting benefit while avoiding the serious toxicity seen in some of these studies.
Vaccines and engineered cells aim to recruit an attack
A checkpoint drug tries to release a brake on immune cells that are already present and able to respond. An ALK-directed vaccine aims at a different problem: getting immune cells to recognize ALK and enter the tumor in the first place. That approach has a clear laboratory rationale because the review describes ALK as a potential tumor target that is normally limited in its expression outside the nervous system.
In a mouse model of ALK-rearranged lung cancer, researchers tested a vaccine made from a DNA plasmid encoding part of ALK. At week 20, the control mice had an average of 58 tumors, compared with 16 in vaccinated mice. Survival was extended by 18 weeks in the vaccinated mice, and their tumors contained more T cells, including a higher ratio of tumor-fighting CD8-positive cells to suppressive regulatory cells. In mice with high PD-L1, the vaccine was less effective; adding a PD-1-blocking antibody overcame that limitation in the model.
These findings offer a concrete example of an approach that may recruit an immune response as well as address a checkpoint. They remain results in mice, however, and do not show that vaccination benefits people with ALK-rearranged lung cancer.
Engineered T cells, including CAR-T cells, are another attempt to direct immune cells toward cancer. The review describes substantial hurdles for solid tumors: researchers need a suitable target on the cancer cells, enough target for the engineered cells to recognize, and a way for those cells to work within a suppressive tumor environment. The CAR-T examples cited include other ALK-positive tumors and studies in broader lung-cancer groups. They do not demonstrate benefit in people with ALK-rearranged lung cancer.
What a safer immune treatment could offer after ALK drugs fail
When an ALK inhibitor stops controlling a tumor, a lasting immune-based option could give some patients another treatment path after targeted drugs. That possibility depends on finding an approach that can bring an effective immune attack into ALK-rearranged lung cancer and sustain it without the unacceptable toxicity reported in some early drug combinations. The 2021 review presents vaccines and other immune strategies as avenues to investigate, not as established treatments; its central challenge remains turning promising biological ideas into safe, durable benefit for patients.
Key Sources
- Primary source: Immunotherapy for <i>ALK</i>-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches.
DOI or Journal Page · Review or Meta-Analysis · 2021-03-23
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