Gandara Reviews Chemotherapy and Immunotherapy for NSCLC Based on Stage

David R. Gandara, MD

During a Targeted Oncology™ Case-Based Roundtable event, David R. Gandara, MD, professor of Medicine Emeritus Director og Thoracic Oncology and senior adviser to the director at UC Davis Comprehensive Cancer Center, discusses chemotherapy and immunotherapy in non-small cell lung cancer.

Targeted Oncology^TM: What is the evidence for platinum chemotherapy on the various stages of non–small cell lung cancer (NSCLC)?

GANDARA: A lot of the clinical trials that we will talk about were done using either the [American Joint Commission on Cancer TNM staging system] sixth or seventh staging edition. The eighth edition has been in clinical use since late 2016 or early 2017, but a lot of the trials were designed before that, and they still use the seventh system.

[In 2008, the Lung Adjuvant Cisplatin Evaluation Collaborative Group did a pooled analysis of the available] phase 3 adjuvant chemotherapy trials and provided data on the efficacy by stage.¹ [The trials, including ALPI,²IALT (NCT00002823),³ NCIC (NCT00002583),⁴ CALGB (NCT00002852)^,5 and ANITA⁶, were done during] the sixth or seventh edition of the staging. Of the trials that tested for stage IA or IB, platinum chemotherapy did not improve survival over just observation after surgery in any case in stage I. The positive trials were really in stage II and stage IIIA.

The patient that we described would have been stage IB according to the seventh system. But the eighth system defined tumor stage probably more accurately than any others, [as it emphasized] that if you have a bigger tumor, it really makes a difference in prognosis. [The tumor in] our case was even bigger; it was larger than 5 cm, so that’s not a good analogy. But 4 to 5 cm is T2b in the eighth system. This would have been a stage IB in the seventh system, but it’s a stage IIA in the eighth system. In the survival curves from this most recent analysis, over 100,000 cases, overall survival [OS] for this patient at stage IIA at 5 years is only about 60%.⁷ So clearly, even early-stage patients [progress] quite often.

What do you think of these poll results?

These are good results, because there is subtlety here. Some patients may not be candidates for platinum adjuvant chemotherapy; some patients may not recover in a sufficient amount of time. I tend to give up to 4 months afterward, and that’s what some of our clinical trials have done. But obviously, the sooner the better, as long as the patient has recovered. I saw a patient recently who was 6 months out. They came to me for a second opinion, saying, “I was against it, and now they think maybe I should have it, and what do you think?” I said, “I think maybe the window has closed at 6 months.

In your opinion, if one chooses to treat with a platinum doublet, should it be with cisplatin?

In my book, the answer is yes. The CALGB trial, which was done [on what was classified as] stage IB at the time, is the only randomized trial ever done with carboplatin. The event-free survival was positive for chemotherapy vs just surgery. The OS benefit went away after 2 or 3 years.⁸ So if the patient can take cisplatin—if they have good kidneys, hearing, and so forth—then that’s my preference. If it’s stage IV, carboplatin is what I use the great majority of time. But if it’s a curative setting, I think there is some benefit to cisplatin, and I think the data support that.

Can you discuss the most recent National Comprehensive Cancer Network (NCCN) guidelines for NSCLC?

The latest version of the guidelines has been updated for the eighth staging system. For stage IA, there’s not much question; unless the margins are positive, the patients are going to get observation, because chemotherapy hasn’t been shown to be beneficial. In terms of stage IB and IIA, there is the option for chemotherapy in what are called high-risk patients. Then there is the new option of osimertinib [Tagrisso] if the patient has a cancer with an EGFR-activating mutation. If margins are positive, there is some rationale for radiation.⁹

The NCCN high-risk features [for use of chemotherapy in stage IB or IIA include the following: tumors greater than 4 cm, vascular invasion, poorly differentiated tumors, visceral pleural involvement, wedge resection, and unknown lymph node status].⁹ Our thoracic surgeons say that these things don’t make sense to them, and they don’t make sense to me, either. Some of them are maybe not bad—for instance, tumors greater than 4 cm, or vascular invasion—but wedge resection and unknown lymph node status make no sense. In other words, if they have a lobectomy for a certain stage, you’re not going to give chemotherapy; but if they have a wedge resection, you’re going to give chemotherapy? Or, if the surgeon didn’t take out any lymph nodes, and you don’t know what the stage is, you’re going to give chemotherapy? None of these are predictive of benefit. Even visceral pleural involvement is not predictive of benefit from chemotherapy. It is prognostic. Same thing for vascular invasion. We need to do better in terms of predicting benefit from adjuvant chemotherapy.

Is there a molecular profiling tool for selection of adjuvant platinum chemotherapy?

There is 1 test that is now commercially available, called DetermaRx, which is a gene molecular profiling tool developed by our colleague David Jablons, MD, and his group at University of California, San Francisco [UCSF]. It has been extensively validated and published multiple times. It has [also] been transformed into a polymerase chain reaction assay. [It includes] the cancer-related genes and 3 reference genes. They don’t tell you the proprietary weighting that are put behind these. When they developed this some time ago, [they used a score to put patients into] high-risk, intermediate-risk, and low-risk [categories]. They had a training set at UCSF; they had a validation set at Kaiser Permanente, with stage I; and then, they had a huge validation set with the China Cancer Genome Consortium of 1000 patients.^10-12

All these [studies] showed there was an association with outcome, dependent on high, intermediate, or low risk, even in the very small cancers. The issue was whether this was just prognostic or whether it was predictive. So they did subsequent studies, and the largest of them was at UCSF, where they did the assay on all their patients. The patients weren’t randomized, but the medical oncologist was given the information and the majority of participants used it; but for whatever reason, some didn’t get adjuvant chemotherapy, even though they were high risk. The molecular low-risk patients did not get chemotherapy. Even with these stages we talked about, though you expect up to a 40% rate of relapse and death [in the high-risk category], they did equally well [compared with the low-risk patients] if they were high risk and got adjuvant chemotherapy [P = .004].¹²

Most recently, the group has analyzed this database for EGFR mutation. They’ve shown that this assay is equally predictive for chemotherapy benefit regardless of the EGFR mutation.¹³ It’s now undergoing a randomized prospective trial for the high-risk patients. But it is a commercially available test. We use it at UC Davis when we have difficult cases.

Can you discuss the data on adjuvant EGFR tyrosine kinase inhibitor (TKI) therapy in NSCLC?

There have been several trials in the past that tried to look at EGFR TKIs postoperatively. The largest up until now was the RADIANT trial [NCT00373425], which was chaired by my colleague at UC Davis, Karen Kelly, MD. It was giving adjuvant erlotinib [Tarceva] across the board to patients after surgery, EGFR wild type and EGFR mutated. It turned out that for those who had EGFR mutation in their cancer, there was some benefit to disease-free survival [DFS]; no benefit, though, for OS.¹⁴

The CTONG trial, also called ADJUVANT [NCT01405079], from China, was a little different, because it was comparing the EGFR TKI gefitinib [Iressa] with vinorelbine [Navelbine] and cisplatin. Again, compared with chemotherapy in patients with an EGFR-mutated lung cancer, there was improvement in DFS [HR, 0.60; 95% CI, 0.42-0.87; P = .005], but there was no improvement in OS [HR, 0.92; 95% CI, 0.62-1.36; P = .67]. Up until now, in most people’s minds, giving an EGFR TKI post-operatively in an early-stage patient after surgery—and after adjuvant chemotherapy—would still be considered investigational.^15,16

At the American Society of Clinical Oncology [ASCO] annual meeting last year and in the New England Journal of Medicine [NEJM], we heard about the ADAURA trial [NCT02511106]. It was a large, randomized trial where patients got adjuvant chemotherapy postoperatively, if the investigator felt it was needed. They were then randomized to osimertinib or placebo. This was done using the seventh staging system; it had stages IB, II, and IIIA. It only included the 2 major mutations: exon 19 deletion and L858R. The difference in this [study's results], compared with the earlier trials, is that it gave 3 years of the TKI, not just 2 years.^17,18

It was stopped early because the data safety monitoring committee [found] the DFS improvement so impressive, they didn’t feel it was ethical to continue. So, although it’s still a big study—about 340 patients in both arms—it’s not as big as it would have been, and it also was less mature when it was presented and published. We don’t see hazard ratios of 0.17 in oncology; at least, we don’t see them in lung cancer [95% CI, 0.12-0.23; P < .001]. So, this is quite impressive. Essentially all the groups benefited from adjuvant osimertinib in terms of DFS. [Even] in stage IB, you can still see benefit. The hazard ratio is 0.5.^17,18

Looking at DFS by stage, as you might expect, stage IIIA had the best benefit [HR, 0.12; 95% CI, 0.07-0.20]; stage II, intermediate [HR, 0.17; 95% CI, 0.08-0.31]; and stage IB, the least [HR, 0.39; 95% CI, 0.18-0.76], but still a good hazard ratio for potential benefit. And remember, this is the seventh system.¹⁸

The investigator got to choose whether the patient got adjuvant chemotherapy. As you might expect, it was mainly the patients with stage IB who did not get adjuvant chemotherapy—because it’s controversial, at least using the seventh system—whereas 70% to 80% of the patients with stage II and IIIA did get adjuvant chemotherapy. Osimertinib improved DFS regardless of whether the patient got adjuvant chemotherapy. [With chemotherapy, the hazard ratio was 0.16 (95% CI, 0.10-0.26); without chemotherapy, the hazard ratio was 0.23 (95% CI, 0.13-0.40)]. This wasn’t in the original presentation; this was updated at the International Association for the Study of Lung Cancer [IASLC] World Conference on Lung Cancer in January 2021. This answers 1 of the criticisms, [that] regardless of whether you got adjuvant chemotherapy, you still benefited.¹⁹

The other big thing for EGFR-mutated lung cancer is that it loves to go to the brain. This is a classic place of failure, either in surgically resected or in metastatic cases. Osimertinib delayed the onset of recurrence in the brain substantially [HR, 0.18; 95% CI, 0.10-0.33].¹⁸ To me, that’s an additional plus for this study.

But the downside is there was no difference in OS at the time it was evaluated, and these are preliminary data. I probably would not have included those data. I would have probably said they’re immature, but for a variety of reasons, they thought they should [include them]. I wouldn’t make anything out of this particular hazard ratio [of 0.40]; the study’s only 5% mature [95% CI, 0.18-0.90]. Some physicians use OS as the gold standard, and after surgery, of course, we don’t do that in some other cancers. We think progression-free, or disease-free, or event-free survival isn’t enough. Osimertinib is a safe drug, and [for adverse events] there’s really nothing that stands out, including pneumonitis.¹⁷

Can you discuss the adjuvant immunotherapy trials?

There are 4 large, randomized trials with all your favorite drugs: pembrolizumab [Keytruda], durvalumab [Imfinzi], nivolumab [Opdivo], atezolizumab [Tecentriq]. [DFS was an end point in each of these studies.] Only 2 of the trials were in patients with positive PD-L1 expression; in other words, you had to be positive to get in the trial—or, I should say, to get in the primary end point.

What were the design and efficacy of the IMpower010 trial?

This trial [NCT02486718] with atezolizumab was just presented by Heather Wakelee, MD, at ASCO. The bottom line for this is trial is that it’s a very similar design to that of the ADAURA trial, in that all patients got adjuvant chemotherapy. Although it was in stage IB to IIIA by the seventh system, the primary end point [was DFS] in stage II and IIIA who were positive for PD-L1. So again, this is a subset, but it’s predefined; this is their primary end point [HR, 0.66; 95% CI, 0.50-0.88; P = .004]. The data didn’t look as fantastic as the osimertinib data did, but for immunotherapy, they impressed me. I think these are good data. Of course, the same thing is true; we don’t have the survival. The FDA hasn’t approved this, it hasn’t even been fully published, just presented at ASCO.²⁰

Can you comment about neoadjuvant studies?

The neoadjuvant trials are moving along rapidly. In other words, this is getting neoadjuvant immunotherapy prior to surgery, or neoadjuvant immunotherapy plus chemotherapy prior to surgery. The initial nivolumab data, 2 doses of nivolumab, [published in] NEJM by Patrick Forde, MD, MBBCh, and his group, included 21 patients [NCT02259621]. They looked fantastic, but it was just pathologic response. In other words, no outcome.²¹

Then, the ones using immunotherapy after that raised some concerns because 10% to 20% of the early-stage patients couldn’t get to surgery. They died of immunotherapy, or they progressed, or they had some adverse event. So, you’re losing patients who could have been possibly cured with surgery.

The CheckMate 816 trial [NCT02998528] was geared to get pathologic complete response—that was the primary end point. [Neoadjuvant therapy] has never been shown to associate with survival for lung cancer, so I don’t think that will get FDA approval; that’s my opinion.

In IMpower010, they specified they will analyze 1 group. If it meets its end point, then they’ll analyze the next and then analyze the OS. Can you explain this method of investigation?

That’s called hierarchical, and it’s being done very commonly now. It’s like you’re in Las Vegas and you’re playing roulette. What you’re doing is you’re making your bets on what you think would be your best end point for your study. Then you say, “We will only analyze for this second one if the first one is positive; and then we’ll only analyze for the third one if the first and second are positive.”

If you have an incredibly positive trial, you analyze for all of them, and you might get a broader indication. If you have a trial that’s mildly positive, then you may not get to the third one. In the case of IMpower010 with atezolizumab, they got [over] the first 2 hurdles, which was PD-L1–positive stage II and III, and then they got all-comers, including PD-L1–negative stage II and III. But they just missed on the stage IB, all-comers. So how will the FDA act on that? I don’t know. It’s a great question.

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