Joshua K. Sabari, MD

Videos

Two experts discuss the evolving treatment landscape for patients with non-small cell lung cancer (NSCLC) and reviews the role of molecular testing and discusses some of the challenges faced.

Importance of Biomarker Testing in Patients with NSCLC

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?

 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.

 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.

 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?

 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.

 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?

 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.

Articles

Joshua Sabari, MD, a thoracic medical oncologist at NYU Langone Health Perlmutter Cancer Center in New York, NY reviews clinical trial data and explains the rationale of using tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC) treatment.

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

In the first installment of this series, Joshua Sabari, MD, provides an overview on the use of chemotherapy for first-line treatment of NSCLC, and discusses how the more recent availability of PD-1/PD-L1– and CTLA-4–targeted immunotherapy is changing the field. 

A Historical Perspective on First-Line Treatment of NSCLC and Recent Advances in Immunotherapy

Joshua K. Sabari, MD, assistant professor of the department of medicine at NYU Grossman School of Medicine and medical director at NYU Langone Health, discusses the significance of 

 exon 20 insertion mutations in patients with non–small cell lung cancer.

 mutation that does not respond well to the standard treatment of osimertinib (Tagrisso) for 

 exon 19 and 21 mutations, though Sabari says that a higher dose of osimertinib does have a 20% to 25% response rate for patients with exon 20 insertions.

The standard of care in the first line is platinum-based doublet therapy with pemetrexed plus either cisplatin or carboplatin. Immunotherapy has been investigated, but according to Sabari, the median progression-free survival (PFS) for patients receiving pembrolizumab (Keytruda) is only about 2 to 2.5 months. In addition, immune-related adverse events (irAEs) associated with immunotherapy when combined or followed by EGFR tyrosine kinase inhibitors (TKIs) can be especially dangerous.

Two targeted therapies have been approved in the second line specifically for patients with an 

 exon 20 insertion. Amivantamab (Rybrevant) is an intravenous EGFR/cMET bispecific antibody. Mobocertinib (Exkivity) is an oral therapy with a different mechanism of action, and is an EGFR HER2 exon 20 TKI. 

 exon 20 insertion mutations is that patients do not respond to standard therapies. So osimertinib at 80 mg, which is a standard FDA-approved dose, is ineffective in this population. We've looked at 160-mg dosage, and we see about a 20% [to] 25% response rate in the population. So it's important that in the 

 exon 20 insertion population, we're using agents that have activity in that specific setting. The standard of care in the frontline setting remains chemotherapy with a platinum doublet, carboplatin and pemetrexed or cisplatin and pemetrexed.

The utilization of immunotherapy remains controversial. The median PFS for single-agent immunotherapy in this setting—pembrolizumab—is about 2 to 2 and a half months. So not only is it not effective, but we know that there's increased risk of irAEs or toxicities when we then think about using 

-directed therapy subsequently. So in my clinical practice, I'm using chemotherapy alone in the frontline setting.

In the second line setting, we now have 2 FDA-approved therapies for patients so if you identify an 

 exon 20 insertion mutation, you can match your patient to either amivantamab, an EGFR/cMET bispecific antibody, or mobocertinib, an EGFR/HER2 exon 20 TKI, a tyrosine kinase inhibitor.

Joshua K. Sabari, MD, discusses the significance of EGFR exon 20 insertion mutations in patients with non–small cell lung cancer. 

EGFR Therapies Fail to Benefit Patients With NSCLC and Exon 20 Insertions

Joshua K. Sabari, MD, medical director of Kimmel Pavilion 12 at NYU Langone Health’s Perlmutter Cancer Center and assistant professor of medicine at NYU Grossman School of Medicine, discusses the trials that showed efficacy for durvalumab (Imfinzi) and atezolizumab (Tencentriq) in patients with extensive-stage small cell lung cancer (ES-SCLC).

The phase 3 CASPIAN trial (NCT03043872) investigated whether durvalumab with or without tremelimumab given alongside carboplatin or cisplatin and etoposide would improve overall survival (OS) and progression-free survival (PFS) in patients with ES-SCLC versus carboplatin or cisplatin and etoposide alone. The phase 3 IMpower133 trial (NCT02763579) investigated the OS and PFS benefit of atezolizumab with carboplatin and etoposide versus carboplatin and etoposide alone.

According to Sabari, the study designs were similar, though in the CASPIAN trial, up to 6 cycles of platinum-based chemotherapy could be used compared with 4 cycles in the IMpower133 trial. The IMpower133 trial also did not allow enrollment of patients who had received prophylactic cranial irradiation (PCI). Both studies did not allow patients with untreated brain metastases due to the high rate of recurrence and death in patients with central nervous system (CNS) involvement.

The studies had similar positive results, with durvalumab showing an objective response rate (ORR) of 68% in the CASPIAN trial, while atezolizumab had an ORR of 60% in the IMpower133 trial. The hazard ratio for death was nearly identical according to Sabari.

Both trials met their primary end point of OS and PFS, leading to approval by the FDA for use in this setting.

 I think both of these studies were very similar to each other in their design. The major differences here being that the CASPIAN study using durvalumab allowed for 6 cycles of cisplatin [or carboplatin] use. The ORR in the CASPIAN study appeared to be slightly higher at 68% than in the IMpower133 study, [which was] about 60%. And when you look across both of these studies, though, the rate of CNS recurrence and the rate of mortality in patients who had CNS disease upfront was quite high. So both of these studies did not allow any untreated patients with brain metastases, but did allow for patients with treated metastasis.

 One other thing that you need to consider is in the CASPIAN study, it did allow for PCI, whereas the IMpower133 study did not. Again, that being said, when you look at the hazard ratio of both of these studies, it’s…0.76 [in IMpower133] and 0.75 [in CASPIAN], being very similar. It's really hard to distinguish. I think one thing that will be interesting in the future is looking at the tail of the [Kaplan-Meier] curve. Are there a substantial number of patients alive and doing well on 1 agent versus the other? That might differentiate these 2 combinations, but in 2022, I don't think there's any major difference between the 2 regimens.

Joshua K. Sabari, MD, discusses the trials that showed efficacy for durvalumab and atezolizumab in patients with extensive-stage small cell lung cancer. 

Joshua K. Sabari, MD | Authors

Articles

Importance of Biomarker Testing in Patients with NSCLC

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

A Historical Perspective on First-Line Treatment of NSCLC and Recent Advances in Immunotherapy

EGFR Therapies Fail to Benefit Patients With NSCLC and Exon 20 Insertions

Atezolizumab and Durvalumab Show Similar Benefit for ES-SCLC