GRACE :: Lung Cancer



Dr. Goldman

Why Carboplatin, Pemetrexed and Pembrolizumab Have Become My New Go-to Regimen for First-Line Non-Squamous NSCLC Treatment


Why carboplatin, pemetrexed and pembrolizumab have become my new go-to regimen for first-line non-squamous NSCLC treatment.

By Jonathan W. Goldman, MD

Metastatic non-small cell lung cancer (NSCLC) treatment has generally improved by optimizing care for “slices of the pie”—pieces of a pie chart representing all of lung cancer patients. Initially, mutation-based treatment led the way; 10% of lung cancers were identified as EGFR-mutant and treated with appropriate tyrosine kinase inhibitors. Subsequently, thinner and thinner slices of the population, each 1-7% of NSCLC patients, have been described and their cancers targeted. More recently, immunotherapy entered the picture, but again the greatest benefit of this therapy was limited to the 20-25% of patients that were PD-L1 positive. Despite all of these advances, we still had at least half of patients receiving more than 10-year-old chemotherapy as their initial treatment.

We now have preliminary evidence that this may be changing. Langer, et al reported in November 2016 (Lancet Oncology) the phase 2 KEYNOTE-021-G1 cohort of non-squamous NSCLC patients treated with the standard, carboplatin and Alimta (pemetrexed), alone or with the PD-1 inhibitor, Keytruda (pembrolizumab). Previous attempts to add to a platinum-doublet had generally provided marginal benefits at best (for example, with Avastin [bevacizumab] or Erbitux [cetuximab]). In contrast, the 021G trial suggested massive benefits, at least as far as response rate (RR) and progression free survival (PFS).

The 021G trial was a moderate-sized phase 2 trial with 123 patients split between the two arms. With Keytruda added to chemotherapy, the response rate increased from 29 to 55%, and importantly this benefit was irrespective of PD-L1 status (above or below a 1% PD-L1 cutoff). PFS was also significantly improved from 8.9 to 13.0 months with a hazard ratio of 0.53, which represents a decrease in the risk of cancer progression by almost half. Many of the trials leading to new drug approvals especially in an unselected cohort report hazard ratios of 0.75 or 0.80, so the benefit in 021G is staggering. The overall survival curves were overlapping at the time of the initial report, and if they suggested a possible survival benefit when updated at the 2017 ASCO Annual Meeting, there was still no statistically significant difference. This lack of a clear survival benefit is certainly at least in part due to crossover at the time of progression from the chemotherapy alone arm to get Keytruda or another immunotherapy (32% within the study and 74% if you count receiving an immunotherapy agent at any point, on or off the trial).

Furthermore, the toxicity associated with the addition of Keytruda was generally manageable, although moderate to severe toxicity (grade 3 or higher) was increased from 28 to 41%. Primarily, these were hematologic toxicities, including anemia and low blood counts, which oncologists are very comfortable managing. Stereotypical immunotherapy toxicities (such as pneumonitis, colitis or hepatitis) were reported at rates similar to previous experience with single-agent PD1 or PDL1 inhibitor therapy. Nevertheless, Keytruda was discontinued due to toxicities in 10% of patients, including in 1 patient with grade 3 pneumonitis, and doctors and patients will need to be on the lookout for such complications.

Many investigators and thought leaders were surprised when the FDA granted priority review for the front-line Keytruda-chemotherapy combination in January 2017. While lung cancer drug approvals had come from phase 2 or even phase 1 data before, that had consistently been for targeted therapy in areas of unmet need. However, just a few months later, on May 10, 2017 the FDA provided accelerated approval based on the RR and PFS benefits reported from KEYNOTE-021-G1. This does require verification in confirmatory trials including the KEYNOTE-189 trial, which mirrors the 021G trial but in a larger, phase 3 format.

This approval further shocked the lung cancer community. It certainly put standard treatment pathways and clinical trials, both open and in planning, in to disarray. However, from the FDA standpoint, how could you say no to a doubling in the response rate and a 50% decrease in the risk of progression? From the patient standpoint, there is now a novel treatment option that applies to the majority of patients. This is an event to celebrate.

There have been several lines of criticism of this combined treatment modality. The clearest is that if the overall survival curves remain overlapping, it may be advantageous to use chemotherapy and immunotherapy sequentially instead of concurrently. However, it seems likely that if the impressive RR and PFS advantages of concurrent therapy are real, they will translate into a survival advantage. It is also important to remember that patients can worsen rapidly during front-line therapy and never have the opportunity to benefit from a second-line treatment. If a survival advantage is not seen in the small phase 2 trial, it seems likely to be demonstrated in the larger phase 3 trial.

Another criticism of the concurrent approach is the associated medical and financial toxicity. Some presume that most patients will be benefiting from either the chemotherapy or the immunotherapy, and that by giving everything together, we are exposing patients to needless drug toxicity and society to unsustainable costs. One could respond, firstly, we do not know exactly how chemotherapy and immunotherapy may be interacting and there may be synergism beyond the efficacy of the individual parts. (Some hypothesize that tumor cell death via chemotherapy releases antigens that prime an immune response, which is then amplified into an immune effector response by immunotherapy.) Secondly, the toxicity profile as seen in the 021G trial shows that concurrent administration of chemotherapy and PD-1 blockade is tolerable for most patients. Thirdly, we have used expensive triplet regimens before (the best example being carboplatin, Alimta and Avastin) but at least with the 021G triplet there is evidence for major benefit.

In the end, we are all awaiting the confirmatory phase 3 trials of chemoimmunotherapy across many of the PD1 and PDL1 inhibitor drug-development pipelines. In the meantime, I applaud the FDA’s provisional approval and I am happy to be able to provide this as an option for my patients. I have heard some doctors state that they will reserve the triplet for patients that “need a response.” I have never met a patient who did not feel that he or she needed a response, and therefore the 021G triplet is my new go-to first-line regimen for non-squamous NSCLC patients without targetable mutations.

Dr. Goldman joins GRACE from UCLA Medical Center in Santa Monica, where he specializes in Hematology and Oncology.  He serves as Assistant Professor of UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology.  






What is the Role of Bevacizumab in Stage IV NSCLC?

GRACE Cancer Video Library - Lung



Dr. Jack West, Swedish Cancer Institute, discusses the anti-angiogenic agent bevacizumab (Avastin) and the trial evidence of its efficacy for non-squamous NSCLC.

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In addition to standard chemotherapy, usually a two drug combination, we sometimes add a third drug called Avastin, also known as bevacizumab. Now this is not a standard chemotherapy agent — instead Avastin acts as an anti-angiogenic therapy, that is, it blocks the tumor’s blood supply, and it is sometimes included in the treatment regimen really only for the patients who have a non-squamous cancer.

Why is that? Well, years ago when Avastin was first being studied in many different kinds of patients with lung cancer — non-small cell lung cancer, either squamous or non-squamous, we found that a significant minority of patients had problems with bleeding complications, specifically coughing up blood that reached a potentially life-threatening or fatal level. That was found to be almost always limited to the patients with squamous histology. So obviously we decided that was not the way to go, and studies after that really limited treatment with Avastin to patients with non-squamous lung cancer. After that we found that even though you could have bleeding complications in a small minority of patients, it was much less of a concern when Avastin is limited to patients with non-squamous lung cancer.

Now, it is FDA approved in combination with two-drug chemotherapy, specifically the combination of carboplatin and Taxol, also known as paclitaxel. That’s because a key trial known as ECOG 4599, which was done across many different centers in North America, compared standard chemotherapy with carboplatin and paclitaxel or Taxol, to the same chemotherapy with Avastin added to it. The study found that patients tended to live longer by an average of about two months. Because of that, and the tolerable side effect profile, it became standard of care to at least consider adding Avastin to the two-drug chemotherapy combination for patients with non-squamous histology.

Now importantly, a couple of other studies have been done since that time, also using Avastin, that didn’t clearly show a survival benefit, and because of that, Avastin is really considered an option but not an absolute mandate, and many oncologists do not routinely use it for most or all of their patients. It’s something to discuss with a patient perhaps, but for patients who have a history of brain metastases or any potential bleeding complications, it may not be advisable because the safety may be enough of a concern to minimize that, and it has not consistently shown a survival benefit after that ECOG trial that I mentioned. But, for some patients it is reasonable to do a two-drug combination of chemotherapy, whether that is carboplatin and Taxol, or perhaps a different one such as carboplatin and Alimta, also known as pemetrexed, while adding Avastin to that.


Trends in Lung Cancer Demographics and Changes in Histology

GRACE Cancer Video Library - Lung



Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, details the trends in lung cancer demographics and changes in histology by race and gender.

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I will speak to you today about trends in lung cancer demographics. So the incidence is probably the most important trend that we’ve had over the years, and this is somewhat different by men and women.


Amongst men you can see that we’ve had a nice decline in cancers of the lung, perhaps not as great as we would like but a very real decline. In contrast, amongst women we had an increase in incidence over the years that has finally leveled off and is beginning to hopefully decline.


There have been some trends in decreased incidence and [improved] survival — these are usually looked at by five year survival rates and unfortunately because of the high morbidity, high mortality, of lung cancer, these rates have not improved as much as some of the other cancers here, but you can see there has been a real, if small decline. This effect has been more pronounced among whites than amongst other minority groups.


We have had a change in histology over time — histology is the type of lung cancer. When we’ve spoken in other podcasts about differences in efficacy of drugs by squamous or non-squamous, that’s the histology we’re talking about, the subtype of lung cancer. What we’ve seen over time is that there is a decline in incidence of squamous lung cancer and an increased incidence of adenocarcinoma. People have talked a lot about why this may be true — I think the dominant hypothesis is the advent of filters. Filters have not reduced lung cancer incidence but what they have done is bring the particulate matter further out to the periphery of the lung instead of larger particles that tend to settle more centrally in the lung. I think that’s probably what’s driving this change in incidence of squamous versus non-squamous histology.


There are some marked racial differences in presentation overall of lung cancer and by histology. The gist of this is that in terms of incidence there is increased incidence amongst black patients as compared to caucasian patients.


Presentation is also worse in black patients — there is a higher incidence of presentation at advanced stage, of course driving inferior outcomes and this is an important target for intervention.

Finally regardless of race, age and histology, I want to talk briefly about the thing that I hope will most change demographics in the years to come, and that’s screening.


Screening has the potential to catch lung cancer at an earlier stage and hopefully improve our cure rates regardless of any of the other factors we’ve talked about: histology, stage — well hopefully it’ll migrate the stage — race or gender. I think that when we talk about this in five or ten years, we’re going to be talking about much more favorable changes based on the results of screening, and so I would encourage screening for appropriate populations. We’ve done a number of other presentations on screening on, and I refer you to those for more information.

Thank you.

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