First-Line Treatment Paradigm of NSCLC and the Advent of Immunotherapy

Non-small cell lung cancer begins when abnormal cells develop in the tissue lining the bronchi, bronchioles, and alveoli. NSCLC is considered advanced or metastatic when the cancer is observed to have spread to tissues surrounding the lungs, lymph nodes, or other organs. Emerging data suggest that tumor-infiltrating lymphocyte (TIL) therapy could be a highly effective option for patients with advanced/metastatic NSCLC.

Targeted Oncology™: Can you provide a historical perspective on the treatment of patients with advanced/metastatic NSCLC?

Joshua Sabari, MD: It's imperative to understand if the patient has a driver alteration. If the patient has a driver mutation, it will match the patient to a targeted therapeutic, which has the best possible outcome for that patient. In patients who are driver negative, we then look at histology as well as PDL-1 expression in patients with lung adenocarcinoma or Swami’s histology in PDL-1 expression greater than 50%. You were generally using a single agent PDL-1 inhibitor, in patients with PDL-1 expression less than 50% or negative, we were using a combination of a platinum doublet in combination with a PD-1 inhibitor. The shortcoming of these older therapies is that there are subsets of patients who did not seem to benefit from immunotherapy, regardless of whether their PDL-1 expression was high.

Targeted Oncology™: Please briefly explain the rationale for PD-1/PD-L1 and CTLA-4 blockade in NSCLC.

Joshua Sabari, MD: I remember the early days of the studies in 2013 and 14, where patients were being treated in the second and later line setting post progression on the platinum doublet, and irrespective of PDL-1 expression we were seeing about a 25% response rate. But what was exciting is that in some patients we were achieving durable or long-term responses. It was not until Keynote 024 a randomized phase three trial looking at Pembrolizumab a PD-1 inhibitor versus chemotherapy in the PDL-1 high patient population greater than 50%. That led to the first FDA approval in 2016 of a PD-1 inhibitor in the frontline setting. And this changed the landscape of non-small cell lung cancer; about a third of patients have a high PDL-1 expression, and to this day, we still give patients a single agent PD-1 inhibitor, if their PDL-1 expression is high. Later on, we saw the utilization of chemotherapy in combination with a PD-1 inhibitor, particularly in patients who had a low PDL-1 expression or negative PDL-1 expression, more recently around 2018. We saw the utilization of CTLA4 inhibitors, particularly ipilimumab, with Checkmate-227 and Checkmate-9LA entering the first-line landscape. And again, there's increased toxicity due to a CTLA4 inhibitor but in the right patient, this regimen may be a more effective strategy for our patients.

Targeted Oncology™: Please summarize recent first-line immunotherapy approvals in the field, including single-agent IO in combination with platinum chemotherapy and chemo-sparing combination IO.

Joshua Sabari, MD: There are seven FDA-approved regimens now. The initial regimen FDA approved in the frontline setting was pembrolizumab as a single agent back in 2016. And that was in patients who have PDL-1 expression greater than 50%. More recently, we saw the FDA approval of cemiplimab in patients who are smokers who had a PDL-1 expression greater than 50%. And then some of the combinations that we've seen over time, the Keynote 189 regimen of carboplatin pemetrexed said plus pembrolizumab, as well as the Keynote 407 of carboplatin, Paclitaxel, and pembrolizumab in the Swain population, have now been approved in both of those regimens are commonly used in clinical practice. More recently, we saw the approval of the IM Power150 regimen, which includes carboplatin, Paclitaxel, Bevacizumab, and atezolizumab, and even more recently, the FDA approval of CTLA4 inhibitors in the Checkmate-9LA and Checkmate-227 regimens which include ipilimumab, nivolumab, as well as chemotherapy. The 227 regimen is chemotherapy-sparing and a very interesting and exciting opportunity for patients in a setting.

Targeted Oncology™: What are some benefits and drawbacks of combining single-agent IO with platinum-based chemotherapy for first-line treatment of patients with advanced/metastatic NSCLC?

Joshua Sabari, MD: If you go back historically, the first PD-1 inhibitor approved pembrolizumab back in 2016, really selected for patients who are PDL-1 high, but what about that patient population who was PDL-1 low or less than 50? It's there where we added chemotherapy to a platinum-based doublet with Keynote-189. And now the question is, but what about patients who are PDL-1 negative or zero? Can we do more for our patients, or in patients who don't respond well to the Keynote-189 regimen the carboplatin pemetrexed and pembrolizumab, how can we treat that patient population and a very unique patient population are those with coalterations and STK-11 And KETE-1, predominantly those who have KRAS STK-11 And KETE-1 coalterations, is this patient population who does not seem to benefit as much from single agent PD-1 inhibitor or even PD-1 inhibitor in combination with chemotherapy. That's a real big advance in my opinion, in the sense of utilizing a CTLA4 inhibitor in combination with a PD-1 inhibitor. For example, the CheckMate9LA and the Checkmate-227 regimens have been common for me to use in this patient population who were very difficult to treat. So in general, PDL-1 negative zero, as well as STK-11 and KETE-1 alterations, are alterations that actually drive immunotherapy resistance.

Targeted Oncology™: Briefly outline the ongoing trials and investigational regimen looking at first-line combination immunotherapy and chemotherapy.

Joshua Sabari, MD: There are many CTLA4 inhibitors that are now being investigated in clinical practice. Ipilimumab a CTLA4 inhibitor plus a PD-1 inhibitor nivolumab is now approved in the frontline setting in the CheckMate9LA as well as the 227 regimen, which is chemotherapy-sparing. And more recently, we saw exciting data from the Poseidon trial, looking at a combination of durvalumab A PDL-1 inhibitor, tremelimumab a CTLA4 inhibitor, as well as a platinum-based doublet. This was a positive study both for progression-free survival as well as overall survival. And the real question is Who benefits from the addition of a CTLA4 inhibitor, we looked at subset analysis in this patient population presented recently at ESMO 2022. And it was really exciting to see that in patients who had KRAS alterations, this regimen seemed to benefit patients over the historical control of chemotherapy. And more important in that very difficult-to-treat population, patients who had KRAS as well as STK-11, and KETE-1 coalterations. These are often synonymous with resistance to immunotherapy, patients seem to perform better with the addition of tremelimumab, a CTLA4 inhibitor, this data has also been recapitulated in the 9LA and 227 data sets. So it's really important now if you have a patient in your office, who has a KETE-1 or STK 11 coalteration. This is a patient who may not benefit from standard PD-1 inhibitor if they're PDL-1 high, or PD-1 inhibitor plus chemotherapy if they're PDL-1 negative or low, they may need the potential addition of a CTLA4 inhibitor and ongoing trials now we're underway to elucidate the signal in patients with these co alterations.

Targeted Oncology™: Are there any data from these trials that you are particularly excited about seeing?

Joshua Sabari, MD: The data that I'm most excited about in these prospective trials are the subset analyses from some of these driver alterations and coalterations. Again, these are not prospective. These are subset analyses, and particularly the STK-11, and KETE-1 subset is one that is very exciting to me because it really seems to show a benefit for the addition of a CTLA4 inhibitor. What we do need moving forward though are prospectively designed studies to address this question. Does the addition of a CTLA4 inhibitor actually benefit patients with these hard-to-treat non-small cell lung cancer, in particular those with STK-11 And KETE-1 coalterations or maybe even more broadly, KRAS alterations in the frontline setting.