Readers of this blog will already know a thing or two about immunotherapy (immune system-activating drugs) and targeted therapy in lung cancer. Both approaches have benefited many patients in recent years. Now, research is being done to combine immunotherapies with other types of drugs. Of particular interest are immunotherapies that target PD-1, PD-L1, and CTLA4. These drugs, also known as immune checkpoint antibodies, are being tested in combination with other drugs in patients participating in the clinical trials below.
There are fundamental differences between the effects of targeted and immunotherapy drugs on cancer. In general, targeted drugs (like Tarceva or Xalkori) produce relatively high rates of good responses in patients whose tumors have relevant gene alterations. These responses, however, tend to fade over time. Most patients whose tumors shrink after targeted treatment experience a relapse and must seek other treatments. In contrast, immunotherapies, or more precisely, immune checkpoint antibodies, generally induce tumor shrinkage in a lower percentage of patients, but these responses tend to be long lasting.
The relatively low response rates to immune checkpoint antibodies present a major challenge. The immune system is governed by a very intricate system of checkpoints, which can be tweaked by immunotherapies in order to direct immune cells to attack tumor cells. Unlike with targeted drugs, for which the presence of a particular mutation signals a high likelihood of response to a relevant drug, there is currently no way to predict who will respond to immunotherapy, with one notable exception: Certain immune checkpoint antibodies (like nivolumab, made by Novartis, and Keytruda, also known as MK3475, from Merck) work by disabling the ‘brake’ or ‘checkpoint’ protein PD-1 on immune system cells called T cells. This frees up T cells to attack tumor cells. Recent data strongly suggest that these drugs work better when used in patients whose tumor cells express a protein called PD-L1. PD-L1 is a ploy by tumors to escape immune system attack because it engages PD-1 and thwarts T cells’ killing power.
In addition to nivolumab and Keytruda, two companies have developed immune checkpoint antibodies to disable PD-L1 itself: MEDI4736 from MedImmune and MPDL3280A from Genentech. These drugs have shown promising activity in several cancers, including non-small cell lung cancer (NSCLC). An older antibody drug called ipilimumab (brand name Yervoy) targets another checkpoint protein, called CTLA4, which keeps T cells from attacking tumors. Tremelimumab is another CTLA4-targeting antibody that is currently being tested in volunteer patients in some of the clinical trials listed below.
Even considering the lack of understanding of the mechanisms that underlie patient response (or lack of it) to immune checkpoint antibodies, it is prudent to explore combining them with targeted drugs. In the best of worlds, a combo approach just might result in a happy pairing of the higher response rate of targeted drugs with the longer-lasting response of immunotherapies. There are several hypotheses that support a scientific rationale for combining immunotherapies and targeted or other therapies, including chemotherapy and radiotherapy. In addition, preliminary results are in for clinical trials testing the combination of two different checkpoint antibodies, and they are promising.
Below, I showcase some of the clinical trials that are exploring various combinations of immunotherapies and other therapies. These trials are in early phase, so their initial goal is to test the safety of giving patients a drug combination. This is always an important part of clinical testing, but the safety concerns in this case are well-informed by the results of a trial in which melanoma patients were given ipilimumab and the targeted drug vemurafenib at the same time. The few patients enrolled developed liver problems, and though the side effects were reversed when the drugs were stopped, the trial was stopped as well. Many of the trials below start with cohorts of patients who will receive different dosages of drugs to determine the maximum tolerable dose (MTD) that is safe, and most of the trials will administer the drugs sequentially, rather than at the same time.
The hope is that these drug combinations will achieve the ultimate goal of providing a high rate of long-lasting responses in lung cancer patients without serious side effects. Explore these trials if your treatment options are dwindling:
|NCT number and phase||Immunotherapy drug||Second drug or treatment||Condition and notes|
|NCT01454102, Phase I||Nivolumab (anti-PD-1)||Several options based on tumor characteristics: chemotherapy drugs ipilimumab (anti-CTLA4), erlotinib, or placebo||NSCLC stage IIIB-IV. Patients will receive nivolumab and one of several relevant drugs including ipilimumab, another checkpoint antibody|
|NCT02039674, Phase I, II||MK-3475/Keytruda (anti-PD-1)||Several options based on tumor characteristics: chemotherapy drugs, ipilimumab (anti-CTLA4), erlotinib, or placebo||NSCLC, stage IIIB-IV. Patients will receive nivolumab and one of several relevant drugs including ipilimumab, another checkpoint antibody|
|NCT01928576, Phase II||Nivolumab (anti-PD-1)||Oral azacitidine or azacitidine + entinostat, given BEFORE nivolumab||NSCLC, stage IIIB-IV. The drugs given before nivolumab may ‘prime’ tumors to become sensitive to destruction by T cells activated by nivolumab|
|NCT01928394, Phase I, II||Nivolumab (anti-PD-1)||Ipilimumab (anti-CTLA4), or placebo||Preliminary results from this trial are already available|
|NCT01840579||MK-3475/Keytruda (anti-PD-1)||Chemotherapy drugs||NSCLC, stage IIIB-IV|
|NCT01998126, Phase I||Ipilimumab (anti-CTLA4)||Targeted drugs erlotinib or crizotinib||Stage IV NSCLC with alterations in EGFR or ALK|
|NCT02239900, Phase I, II||Ipilimumab (anti-CTLA4)||SBRT (precision radiation treatment)||Lung cancer, condition not specified|
|NCT02000947, Phase Ib||MEDI4736 (anti-PD-L1)||Ipilimumab (anti-CTLA4), immune||Advanced NSCLC|
|NCT02088112, Phase I||MEDI4736 (anti-PD-L1)||Gefitinib (targeted to EGFR)||NSCLC, stage IIIB-IV|
|NCT02179671, Phase II||MEDI4736 (anti-PD-L1)||Several options based on tumor characteristics: gefitinib, AZD9291 (targeted to EGFR), selumetinib + docetaxel (targeted therapy + chemotherapy), or tremelimumab (anti-CTLA4, immunotherapy)||Stage IIIB-IV NSCLC. Drugs will be given sequentially, with MEDI4736 given as the second drug|
|NCT02143466, Phase I||MEDI4736 (anti-PD-L1)||AZD9291 (targeted to EGFR)||Stage IIIB-IV NSCLC; enrolling patients who progressed on EGFR inhibitors. Several drugs, including MEDI4736, will be combined with the EGFR-inhibitor AZD9291|
|NCT02013219, Phase I||MPDL3280A (anti-PD-L1)||Erlotinib||Stage IIIB-IV NSCLC; enrolling patients with mutations in EGFR|