Nivolumab Investigator Discusses Expanded Approval, Compares With Pembrolizumab

Ben Creelan, MD

Following the recent FDA approval of nivolumab (Opdivo) for non-squamous non—small cell lung cancer (NSCLC), the PD-1 inhibitor is now approved across all NSCLC histologies and is poised to make a significant impact in the treatment of lung cancer.

The nonsquamous approval was based on data from the phase III CheckMate-057 trial, in which second-line nivolumab reduced the risk of death by 27% versus docetaxel. This included a 60% risk reduction among patients with the highest levels of PD-L1 expression.

A diagnostic for PD-L1, the IHC 28-8 pharmDx test, was approved along with the expanded indication, to help guide treatment decisions for patients with both histologies of NSCLC. However, the test is a "complementary," not a "companion," diagnostic, meaning its use is not mandated prior to administering nivolumab.

Nivolumab was previously approved in March 2015 for patients with squamous cell NSCLC who have progressed on or after platinum-based chemotherapy. This initial approval was based on the phase III Check-Mate-017 trial, in which nivolumab improved overall survival (OS) by 3.2 months versus docetaxel in previously treated patients with advanced or metastatic squamous cell NSCLC. The estimated 1-year survival rate was 41% and the median OS was 8.2 months.

The PD-1 inhibitor pembrolizumab (Keytruda) was also recently approved by the FDA for patients with pretreated advanced non—small cell lung cancer (NSCLC) across all histologies. Unlike nivolumab, pembrolizumab was only approved for patients with PD-L1–positive tumors, as determined by the PD-L1 IHC 22C3 pharmDx companion diagnostic, which was simultaneously approved with the drug.

OncLive: What impact will the expanded approval of nivolumab have on clinical practice?

Can you discuss the trial that lead to the approval of nivolumab in nonsquamous NSCLC? What questions still remain regarding the use of the drug in this patient population?

For additional insight on the impact of the expanded approval of nivolumab in NSCLC and how the drug compares with pembrolizumab, OncLive spoke with the Ben Creelan, MD, a clinical investigator on both the Check-Mate-057 and -017 trials, and a medical oncologist at the Moffitt Cancer Center.Creelan: I think it will have a broad and sustained impact in community practice nationwide. It is the first trial to show an OS benefit of immunotherapy compared to chemotherapy for this nonsquamous NSCLC population.The CheckMate-057 design was quite simple, almost identical to the CheckMate-017 trial for squamous NSCLC. It randomized almost 600 patients to our gold standard of docetaxel versus nivolumab. Patients were required to have progressive or refractory measurable cancer after prior platinum-doublet chemotherapy. All patients were required to have tumor tissue for PD-L1 determination by immunohistochemistry using Dako’s antibody, 28-8 epitope, with automated scoring, but this was a secondary endpoint. Since docetaxel was adopted as our standard in 1999, no monotherapy has beat docetaxel for OS benefit. Therefore, this trial was not simply an incremental addition to our arsenal of drugs, but a big leap forward. All our trials should aim for these kind of gains.

Like the 017 trial, this trial hit it out of the park. At a planned interim analysis after 86% of events, it crossed the boundary for superiority and the trial was reported early. The HR was 0.73 with P = .0015, which equates to almost a 30% higher probability of surviving with nivolumab during the course of the study. The response rate was 19% compared to 12% for docetaxel, with an odds ratio of 1.7, P = .02, which equates to a 1.7 times higher odds of achieving a partial or complete response with nivolumab compared with docetaxel. Also, the median duration of response was roughly 17 months, which was over twice as long as the chemotherapy, which was 5.6 months. Over half of these nivolumab responses were ongoing at the time of analysis.

It is true the survival difference was greatest in the higher PD-L1 expressing tumors. However, even in the <1% PD-L1 expression subgroup, the survival curve was essentially identical compared to docetaxel. So nivolumab, may still offer less toxicity than docetaxel for these patients. Most patients who have progressed after platinum chemotherapy want to try something new. Also, the <1% PD-L1 expression subgroup had a 10% overall response rate, which is still better than docetaxel.

What questions still remain?

Is there any difference in efficacy or toxicity with nivolumab in the squamous versus nonsquamous populations?

Nivolumab is not approved with a companion diagnostic. Without a biomarker test required, how is it determined which patients will most benefit from the drug?

Are there any toxicities oncologists should be aware of when using this drug?

Is there any potential to use nivolumab in combination with other drugs in this patient population?

How does nivolumab compare with pembrolizumab?

Could they be used in sequence?

What challenges still remain with these anti—PD-1 agents in NSCLC?

In my personal experience, we have several patients from 057 at our center who remain in remission several years after starting nivolumab.The main question at this point is when to stop nivolumab, if ever. The phase III 057 and 017 trials have continued nivolumab indefinitely for subjects until progression, but we don’t know if that is essential. The phase III/IV 153 trial has randomized subjects to 1 year of dosing versus continuous dosing until progression. However, this 153 analysis is a secondary endpoint and will inevitably be underpowered. Also, often subjects do not want to stop treatment. So this is still an outstanding question that we may not be able to resolve completely.No differences in toxicity were seen in the squamous versus nonsquamous populations. Regarding efficacy, the response rates were similar. The hazard ratios were more dramatic in the squamous population, 0.59 squamous versus 0.73 non-squamous, but that is likely because there are fewer effective subsequent therapies in the squamous population. The squamous tumors may also be enriched for the higher burden of passenger mutations.Patients with substantial smoking histories tend to have a higher burden of passenger mutations in their tumor, which seems to result in a more inflamed tumor phenotype. These passenger mutations can create neoepitopes which make the tumor cell easier for the immune system to recognize as non-self. Smoking history is simply a surrogate though, and we need better tests.There are rare but important toxicities, especially if not recognized promptly. Autoimmune thyroiditis, nephritis, hepatitis, and pneumonitis are particularly important to look out for.There are hundreds of exciting PD-1 combinations under study. Right now, I cannot advocate using nivolumab in combination with chemotherapy outside of a trial, because preliminary results have not suggested this approach is superior. At high doses, most chemotherapy depletes the effector CD8-positve T-cell compartment. So I can’t advocate combining nivolumab with chemotherapy until the proper chemotherapy dose and schedule is determined.Pembrolizumab is humanized, whereas nivolumab is fully human, so theoretically there could be higher rate of infusion reactions with pembrolizumab but that hasn’t borne out, to date. On the other hand, pembrolizumab can be dosed every 3 weeks, which could be an advantage for patients with transportation problems. Right now, nivolumab has been under study for a longer period with a bigger study population, and so the side effect profile is slightly more defined. In the future, cost may also become an important deciding factor.Both drugs are IgG4 monoclonal antibodies to a specific epitope of the PD-1 receptor. Both drugs have the same stabilizing S228P amino acid sequence alteration at the antibody hinge region. This alteration prevents half-molecule exchange, and decreases toxicity to lymphocytes. Given these similarities, there is little theoretical reason to think that pembrolizumab would be active in nivolumab failures, or vice versa. The one situation in which switching drugs would make sense would be if a patient suffered a severe allergy to the drug. For example, formation of host anti-drug antibodies is a rare phenomenon seen with almost all therapeutic monoclonal antibodies. For this type of allergic reaction, it would be reasonable to try switching.We are still searching for the best test to predict durable remission with nivolumab / pembrolizumab monotherapy. The PD-L1 immunohistochemistry tests are helpful, but far from perfect.