Chemoimmunotherapy Transforms Treatment in Nonsquamous NSCLC

Edward S. Kim, MD, discusses how the use of immunotherapy has resulted in a paradigm shift in advanced nonsquamous non–small cell lung cancer and the steps that are being taken to broaden its use in clinical practice.

Edward S. Kim, MD

The combination of immunotherapy and chemotherapy has shown unprecedented survival in patients with newly diagnosed advanced nonsquamous non—small cell lung cancer (NSCLC), said Edward S. Kim, MD.

In the phase III KEYNOTE-189 trial, patients who received the combination of pembrolizumab (Keytruda) and standard platinum-based therapy experienced a 48% reduction in the risk of progression or death versus those who received chemotherapy alone (HR, 0.52; 95% CI, 0.43-0.64; P <.001). The primary overall survival (OS) analysis showed that the median OS was not reached was not reached with the pembrolizumab regimen compared with 11.3 months in the chemotherapy-alone arm.1 Based on these data, the regimen received a full approval from the FDA for the treatment of patients with metastatic nonsquamous NSCLC.

Additionally, updated data shared at the 2019 ASCO Annual Meeting showed that treatment with the combination led to a longer median OS versus chemotherapy alone at 22.0 months versus 10.7 months, respectively (HR, 0.56; 95% CI, 0.45-0.70).2

An OS benefit was also reported with the addition of atezolizumab (Tecentriq) to chemotherapy and bevacizumab (Avastin) versus chemotherapy and bevacizumab alone in patients enrolled in the phase III IMpower150 trial (HR, 0.78; 95% CI, 0.64-0.96; P = .0164).3 The regimen is approved by the FDA for the first-line treatment of patients with metastatic nonsquamous NSCLC, excluding patients with EGFR/ALK aberrations.

“Frontline therapy for patients with nonsquamous NSCLC has completely changed,” said Kim. “When I was a fellow, we used [chemotherapy] doublets. [Treatment] has changed dramatically with the addition of immuno-oncology drugs.”

What hasn’t changed, added Kim, are the eligibility criteria for clinical trials, which tend to be more exclusionary than they are inclusive. Careful reevaluation of those criteria is needed, said Kim, so that investigators can build a better body of evidence regarding novel combinations that is more representative of real-world populations.

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Kim, chair of the Department of Solid Tumor Oncology at Levine Cancer Institute, discussed how the use of immunotherapy has resulted in a paradigm shift in advanced nonsquamous NSCLC and the steps that are being taken to broaden its use in clinical practice.

OncLive®: How has the addition of immunotherapy altered the treatment of patients with advanced nonsquamous disease?

Kim: The KEYNOTE-189 trial has changed the entire treatment paradigm. In the trial, investigators evaluated the combination of carboplatin, pemetrexed, and pembrolizumab. The combination led to outstanding responses and OS and has become the de-facto first-line treatment for patients with advanced nonsquamous NSCLC. A patient doesn’t need to have high PD-L1 status to be eligible for this regimen. Single-agent pembrolizumab [can be used in patients] with higher PD-L1 expression.

I used the triplet regimen the other day and told the patient that they will be able to tolerate it. Patients are always anxious about the first cycle when they receive chemotherapy. However, after a couple cycles, the patient told me that it wasn’t as bad as she thought it would be. It's really gratifying to see that, because some of us older oncologists had to deal with the fatigue [from the drugs we would use]—that we knew didn’t work too well. We knew [those agents] would continue to beat up our patients, and there was no guarantee that we could say they would feel better after 6 to 10 months [of treatment].

Drugs such as pemetrexed are so easy to take; they don't affect blood levels. Also, carboplatin has not been an issue to give in combination. With the immunotherapy, you can continue it as maintenance therapy in patients who are doing well. Everyone's immune system works differently, but sometimes you can get a long-lasting effect after stopping treatment. In the patient I mentioned, she was off treatment for 1.5 years before her cancer started growing again. It's amazing what we can [do].

There are also data from the IMpower150 trial, which evaluated the combination of carboplatin and paclitaxel, bevacizumab, and atezolizumab. Bevacizumab was one of the agents with which we built off of platinum-based regimens in the early 2000s. [That agent] finally gave us the ability to push out the survival curve by a little over 2 months, which was a big deal back then.

There are some interesting subsets in the trial who [seemed to benefit from the quadruplet therapy], such as patients with liver metastases and those with EGFR or ALK alterations. This is one of the few trials that allowed patients with EGFR or ALK alterations to enroll. Normally, if a patient has a driver mutation, especially an EGFR mutation, you don't want to treat them with immunotherapy.

However, IMpower150 is one of the studies that enrolled about 100 patients [with these alterations] and showed a benefit. Perhaps we can use the combination in patients who have progressed on targeted therapy instead of giving them a chemotherapy doublet. It's not our standard frontline treatment, but it is there for that specific population.

Could you discuss the eligibility criteria for these regimens?

I always talk about the importance of eligibility criteria; it’s something that's easy to forget. The number of eligibility criteria in clinical trials is out of control. I led a task force about 5 years ago to see if we could make any recommendations for changing eligibility criteria. We looked at and pharmaceutical company [requirements] to see how quickly they could get trials done based on the number of eligibility criteria they had in place. We found that if you had less than 27 eligibility criteria, your trials had a statistically significant likelihood of enrolling faster.

Then, ASCO teamed up with Friends of Cancer Research; I was honored to lead the effort. We went through an analysis of about 7 eligibility criteria, which included minimum age. Why is 18 [years of age] the exclusion barrier? What does that matter? HIV [is another exclusion criterion] that drives me crazy. The truth is, patients with HIV live as long as the general population, so there’s no reason to exclude them [from these trials]. We also looked at brain metastases and organ function , such as creatinine clearance and liver enzymes. We want to allow patients to enroll on trials and then find scientifically rational reasons why, based on a particular drug, this population should be excluded. We don’t want to just cut and paste from previous protocols.

In October 2017, we published our results in the Journal of Clinical Oncology. [Subsequently], CTEP changed their protocol templates in the summer of 2018, and the FDA issued guidance documents in the spring of 2019. Now, we’re just waiting for our industry partners to pick it up, but all the cooperative groups have already adopted this. I sit on a central institutional review board where we see these changes coming through that are allowing patients aged 12 years and older [to enroll on trials] instead of 18. We have another version coming [soon].

I hate wash-out periods. There's no reason why you should wait 4 weeks for wash-out periods, radiation, or concomitant medication, so we're [recommending eliminating] another 5 eligibility criteria. We won't stop until the majority of our patients with cancer are eligible for these clinical trials. [This work] resonates with patients, investigators, and clinical trial groups alike.

As a clinician, I feel that I should be able to enroll my patients on clinical trials. Patients who are facing their mortality seek out these opportunities. It’s difficult to see that only 5% to 8% of our oncology population is able to enroll on clinical trials. The solution in the past has been to open more clinical trials. That may increase the number [of trials], but it’s not going to improve the percentage [of eligible patients].

Moreover, we would just be burdening the trial sites with extra work. That's not a good route. I believe there should be less than 10 eligibility criteria. When a drug is approved, do we use those same criteria [from the trial] to decide who is going to get treated? Or, does anyone with that disease in that setting get that drug? We have to consider whether we’re enrolling a real-world population into our trials. We have to make sure patients are safe, but their risk-benefit profile is much different from the outside looking in.

Are there any emerging combinations that you are excited about?

It seems like anything paired with immunotherapy is an intriguing combination right now. In the past, anything combined with pemetrexed or docetaxel was exciting. I hope we have more scientific rationale [for combinations moving forward]. Frankly, who would've thought that immuno-oncology would work in lung cancer? I'm always open to exploration; it’s what phase I trials are for.

Many trials are investigating TKIs with immunotherapy and combined IO approaches. However, these combinations will have to show an obvious benefit. We're not looking for subtle benefits anymore. The field of immunotherapy resistance is a very big area because everyone is getting treated with immunotherapy. We have to figure out what we’re going to do when patients progress and need another therapy.

What is your take-home message to your colleagues working in the space?

The most important point is to do no harm. In order to do that, you have to measure mutations or biomarkers upfront. If patients have an EGFR mutation, they should not be receiving immunotherapy. It’s the biggest mistake you can make, but it’s something I see being done out there. Some clinicians are anxious to start treatment and don't want to wait the extra couple weeks [for genetic testing]. Therefore, they start with chemotherapy, and if the mutations come back [negative], then they add the immunotherapy. I would rather wait a couple weeks.

Chemotherapy is not that magical; it won't turn someone around that quickly. [Lung cancer] is not prostate cancer or leukemia, so it's better to wait. Do your due diligence, so you can start the patient on the right therapy upfront. If you're having trouble with pathology or turnaround times, that needs to be marched to a higher level because the standard of care is to [test for] these markers along with [getting] a pathology diagnosis, so that we can use the appropriate drug upfront in these patients.


  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
  2. Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(suppl; abstr 9013). doi: 10.1200/JCO.2019.37.15_suppl.9013.
  3. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.