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Progression After New ICI Options
New Immunotherapy Paradigms Earlier in NSCLC: What Comes After Progression?

Released: July 26, 2018

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New and exciting phase III trial data on the use of immune checkpoint inhibitors (ICIs) in the first-line setting are changing practice for our patients with newly diagnosed metastatic NSCLC. Pembrolizumab is now standard-of-care first-line therapy for patients with metastatic NSCLC and high tumor PD-L1 expression (TPS ≥ 50%) based on results from the KEYNOTE-024 trial that showed improved efficacy with less toxicity compared with platinum-based chemotherapy (CT) in this group. More recently, the international KEYNOTE-042 study reported an OS benefit with first-line pembrolizumab vs CT in patients with PD-L1 expression ≥ 1% (24-month OS: 39.3% vs 28.0%, respectively; HR: 0.81; P = .0018). However, almost one half of the patients enrolled in KEYNOTE-042 had TPS ≥ 50%; this group was the major driver of the survival benefit reported for the overall patient population.

Other recent data show benefit with first-line CT plus ICI combination therapy vs CT alone. In nonsquamous disease, survival was significantly prolonged in the KEYNOTE-189 trial with the addition of pembrolizumab to 4 cycles of platinum/pemetrexed followed by maintenance therapy (median OS: not reached vs 11.3 months; HR: 0.49; P < .001). Similarly, in the IMpower150 trial, the addition of atezolizumab to 4-6 cycles of carboplatin/paclitaxel/bevacizumab followed by maintenance therapy significantly improved survival in patients with newly diagnosed nonsquamous NSCLC (median OS: 19.2 vs 14.7 months; HR: 0.78; P = .0164). Some positive data have also emerged on combination therapy in the setting of squamous disease. The KEYNOTE-407 trial showed an OS benefit with the addition of pembrolizumab to first-line carboplatin/paclitaxel or albumin-bound paclitaxel for 4 cycles followed by single-agent pembrolizumab (median OS: 15.9 vs 11.3 months; HR: 0.64; P = .0008). Furthermore, in the IMpower131 trial, the addition of atezolizumab to 4-6 cycles of carboplatin/nab-paclitaxel followed by maintenance atezolizumab significantly improved PFS in patients with newly diagnosed squamous NSCLC (median OS: 6.3 vs 5.6 months with CT; HR: 0.71; P = .0001). However, an interim analysis of OS found no significant difference (median OS: 14.0 vs 13.9 months; HR: 0.96; P = .6931).

Currently, the only FDA-approved, first-line combination regimen is carboplatin/pemetrexed plus pembrolizumab for patients with advanced nonsquamous NSCLC. However, given the generally supportive data described above, we can anticipate the approval of additional combination regimens and more patients with metastatic NSCLC being treated with first-line CT plus ICIs. This of course raises a very important question: Which treatment options can we offer our patients at the time of progression following first-line CT plus ICIs?

Treatment Options After Progression on First-line CT Plus ICIs
There are currently 3 options for patients who progress following treatment with first-line CT plus ICIs. The first option is docetaxel with or without ramucirumab; we used docetaxel-based therapies before immunotherapy was available, and I would still consider this to be a reasonable, established treatment option for these patients. Although docetaxel plus ramucirumab was shown to prolong median survival vs docetaxel alone in the phase III REVEL trial, the benefit was limited to approximately 1.5 months.

The second option is other single-agent chemotherapies, such as gemcitabine. In patients with metastatic nonsquamous NSCLC who did not receive pemetrexed as part of their initial treatment regimen, pemetrexed is another second-line option.

The third option—which would be the first choice at my institution and other academic centers—is a clinical trial. An active area of interest in advanced NSCLC is combining a PD-1/PD-L1 inhibitor with a CTLA-4 inhibitor; however, in previously treated patients who had received single-agent PD-1/PD-L1 therapy, the combination of durvalumab plus tremelimumab showed limited activity (ORR of approximately 5%). Various other therapies proposed to potentially increase the efficacy of PD-1/PD-L1 inhibitors are being evaluated.

Treatment Options for Patients Progressing Following Durvalumab for Unresectable Stage III NSCLC
In addition to these new first-line developments in metastatic NSCLC, there are many studies investigating moving immunotherapy earlier in the treatment paradigm. At this time, the sole nonmetastatic NSCLC setting with an FDA-approved immunotherapy is for durvalumab in unresectable stage III disease that has not progressed following concurrent platinum-based CT and radiation. That approval was based on the phase III PACIFIC trial, which showed a significantly prolonged PFS with durvalumab vs placebo in this group of patients (median PFS: 16.8 vs 5.6 months; HR: 0.52; P < .001).

A big question is what to do for patients who progress after this regimen. In my practice, I approach patients with unresectable stage III NSCLC who progress after ICIs differently based on the timing of progression. For instance, if a patient progresses 6 weeks after completing durvalumab therapy, I think it would not make sense to go back to an ICI-based regimen. But if a patient progresses to metastatic disease 18 months after completing durvalumab therapy, it may be reasonable to consider a first-line regimen with another ICI, particularly if the patient had biomarkers suggesting likely benefit from ICIs. In between these extremes is a large gap of uncertainty in which individual patient and disease characteristics and clinical judgment will play a big role until we have data informing how to best manage our patients who experience progression in this clinical scenario.

Your Thoughts
How do you anticipate managing your patients with either unresectable stage III NSCLC or newly diagnosed metastatic NSCLC who progress on or after a regimen using an immune checkpoint inhibitor? Please share your thoughts by joining the conversation in the comments box below and responding to the polling question at the right of your screen.