#LCSM Chat Topic 6/4 8pm ET:  Moving Ahead with Immunotherapy for Lung Cancer–Biomarkers, Timing, Duration, and Combinations

by H. Jack West, MD

The hot subject at ASCO this year was immunotherapy for many cancers, and developments in lung cancer led the charge. The specific findings of greatest interest were that the PD-1 inhibitor Opdivo (nivolumab) was found to have a far superior survival, higher response rate, and overall better side effect profile than Taxotere (docetaxel) as second line treatment after initial chemotherapy. The US FDA approved Opdivo for squamous NSCLC, and we anticipate an approval for non-squamous NSCLC soon. 

But there are still several open questions as we integrate immunotherapy into routine treatment of lung cancer. These questions are what we’ll focus on in our Thursday June 4th #LCSM chat at 8 PM ET (5 PM PT).

The first question is about using biomarkers to predict which patients are more or less likely to benefit. These drugs are extremely expensive, at about $13,000 per month, which is arguably reasonable if patients are benefiting greatly, but not for patients who are destined to show early progression. The trial of nivolumab in squamous NSCLC showed no clear association with the biomarker PD-L1, a protein that interacts with PD-1. Several studies have shown that these immunotherapies are most consistently effective in patients who have tumors and/or immune cells that have a lot of the PD-L1 protein on them. But not all. The trial of Opdivo in squamous NSCLC showed no association of outcomes with PD-L1 staining, but the trial of Opdivo in non-squamous NSCLC showed the improvement in survival with Opdivo was limited to the approximately 55% of patients with PD-L1 expression. Whether the FDA or insurers will limit Opdivo in patients with non-squamous NSCLC is unclear. 

Another question is timing. While these trials were in second line, for patients who progressed on prior chemotherapy, there is great interest in moving immunotherapy up into first line therapy, along with or instead of chemotherapy. We don’t have enough evidence to say that immunotherapy is superior to first line chemotherapy, either in a broad population or in a selected one, but there are large numbers of trials that are testing PD-L1 expression in first line. Even in the absence of that evidence for another year or two, at least, we should expect that many patients and their oncologists are eager to try immunotherapy before chemotherapy if it is covered by their insurer. But without evidence, is that a wise thing to do?

Then there is duration of therapy. While most clinical trials give immunotherapy on an ongoing basis until a patient demonstrates significant progression or side effects, part of the appeal of treating with immunotherapy is that the immune system can potentially sustain the anti-cancer activity stimulated by the initial treatment. I have a patient responding beautifully to nivolumab, now for over two years, but she is tired of getting infusions every two weeks. Meanwhile, there are many patients who were responding to immunotherapy but discontinued it because of side effects, whether mandated to come off of a clinical trial or opting to stop immunotherapy due to their side effects. Many such patients have continued to do well and demonstrate no progression for months or longer. This begs the question of whether patients can pursue a limited course of immunotherapy and stop after several months or a year rather than be tethered to treatments every few weeks that may not be necessary. But we don’t really know.

Finally, there’s the option of pursuing two different immunotherapy agents, such as the combination of Opdivo and Yervoy (ipilumumab). This combination looks very promising in patients with metastatic melanoma, including in patients who don’t have PD-L1 expression. This raises the question of whether the combination may overcome what would have been a weak response in those without a favorable biomarker. However, the combination now makes treatment TWICE as expensive and considerably more toxic. Is immunotherapy as appealing if it now has more side effects than chemotherapy-based treatment, and is it even feasible to consider treatment regimens that now reach a cost over $250,000/year?

With this background in mind, we’ll ask the following questions:

  • T1: If biomarker predicts benefit but isn’t req’d, would you test to decide to do immunoRx, or just favor immunoRx w/o test?
  • T2: If immunoRx is proven 2nd line, after chemo, would you want to try it instead of 1st line chemo if you could get it covered today?
  • T3: If we don’t know whether longer duration is needed in responders, would you stop immunoRx after 6-12 mo & follow off Rx? Stop ever?
  • T4: Are immunoRx combinations attractive & feasible if side effects worse than chemo & costs are >$250K/yr? What if copay was 20%?

Please remember to include #LCSM in ALL your tweets so the other chat participants can see them. You can read a primer on participating in the chat here.

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