An ongoing phase 2 trial of the novel immunotherapy M7824 with concomitant chemoradiation has investigators hopeful that it will show equivalency, if not superiority, to the PACIFIC regimen in patients with unresectable stage III non–small cell lung cancer (NSCLC).

In the international, double-blind, phase 2 study (NCT03840902), which is expected to enroll 350 patients, investigators are evaluating the efficacy and safety of concomitant chemoradiation plus M7824 followed by M7824 compared with chemoradiation plus placebo followed by durvalumab (Imfinzi) in this patient population. The primary end point is progression-free survival as assessed by an independent review committee. 

“It's so important to all of these studies that are addressing [this patient population]; they are going to be big difference makers,” said Dan Costin, MD. “We are treating so much stage IV lung cancer; we would love to be able to get these therapies for the [patients with] stage II and III lung cancer, so we never have to get to stage IV lung cancer.

, Costin, who is co-medical director of the White Plains Hospital Center for Cancer Care, and director of Cancer and Blood Specialists of New York, discussed his strategies for patients with early-stage lung cancer and ongoing trials that could improve outcomes even further.

: Let's say you have a patient who comes in with early-stage lung cancer. How do you determine local therapy? What is your approach with this type of patient?

: If they are candidates for up-front surgery, we want them to have an appropriate surgical procedure. Then, depending on the pathologic staging, we'll decide on the need for adjuvant therapy. For patients who are not candidates for surgery, they generally would be considered for stereotactic body radiation [SBRT]. Here, at our center, those patients would be referred to the KEYNOTE-867 trial, which is a study that's looking at patients with stage I or stage IIA disease and would be randomized to SBRT alone or SBRT with 1 year of pembrolizumab. 

We think that this a very important study. Even in patients who have stage I disease, we're still finding that 40% of patients may still be at risk at about 5 years for recurrence. We are really interested to see if immunotherapy may be an important game changer in terms of the management of those patients. We hope that study will accrue quickly. Hopefully, in the next 3 to 5 years, we'll have some good answers that may hopefully change the way we approach the management of those patients.

Patients with clinical stage I and IIA disease will go on and have pathologic staging. Then, depending on the pathologic findings, we would decide on the need for adjuvant-driven therapy. Now the recent compelling data in terms of early-stage lung cancer with the presence of an 

 mutation has been an important breakthrough. At the present time, we will go ahead and do molecular analysis to look for an 

 mutation. In the patients who do have an 

 mutation, we will be considering them for adjuvant osimertinib [Tagrisso] if they have potentially a poor prognosis, and they have stage I, II, or resectable stage III NSCLC.

In all of those patients, the issue of adjuvant chemotherapy may still be in play. Generally, we'll reserve the adjuvant chemotherapy for patients with stage II NSCLC or resected stage III NSCLC. However, there may be some patients with higher-risk stage I disease that we may also consider [adjuvant chemotherapy for], but the data are not strong for stage I disease.

How do you approach molecular testing in these patients with earlier-stage disease? Has the ADAURA trial impacted that?

Molecular analysis is important, even in the early-stage setting. If we find that the patient has stage IIB, or resectable stage IIIA NSCLC, this is also an important point of reference where we're still looking for better therapies. For those patients, we will encourage participation in CheckMate-617, and this is an important neoadjuvant protocol that is addressing the use of neoadjuvant chemotherapy in combination with nivolumab [Opdivo] followed by definitive surgery, followed by additional immunotherapy, if they were randomized to the immunotherapy arm. That is a very important study because in patients with stage IIB and stage III resected disease, too many of them are recurring, relapsing, and dying from lung cancer. Therefore, we need to have better therapy.

Even with the use of surgery and chemotherapy, we're happy with the results, but we're not nearly where we need to be. The preliminary results from immunotherapy as neoadjuvant therapy look terrific. If this randomized study is able to confirm that, it could be a major game changer in terms of how we approach our patients.

Now, those patients on the study will not be offered the possibility of osimertinib if they have an 

 mutation. Patients will probably be screened for 

 before being considered for the clinical study, and I suspect that most of the patients who have an 

 mutation will not be considered for this immunotherapy study. For patients who don't go on study, they will get surgery, and then we'll give them standard chemotherapy. In rare instances, [they will get] adjuvant radiation therapy, depending on the pathologic findings.

They will get trimodality therapy: surgery, chemotherapy, and osimertinib if they're 

-positive, and depending on pathologic findings, they may need adjuvant radiation therapy.

What treatment decisions shift for you when the patient has unresectable stage III disease?

If they do meet the criteria for unresectable disease, then we're dealing with a space where our standard of care is up-front chemoradiation with 1 of 3 platforms of chemotherapy that can be considered: weekly paclitaxel with weekly carboplatin in combination with radiation therapy, radiation in combination with cisplatin and etoposide, and radiation in combination with cisplatin and pemetrexed would all be reasonable. 

In the community here, we tend to use a little bit more of the weekly paclitaxel/carboplatin for the ease on the patients. Once completing that, we will then offer them 1 year of immunotherapy with durvalumab, which is a PD-L1 immunotherapy, and try to get them through 1 year of therapy. An unanswered question, which is a little bit of a dilemma, is: What happens in these unresectable stage III patients who have an 

 mutation? We don't know the answer to that. 

Because the data are very, very strong in terms of the benefit of osimertinib in 

-positive patients, there are probably some of those patients who are going to be leaning toward avoiding immunotherapy and just getting osimertinib based on [ADAURA], but again, those data are a different space that we haven't studied [in unresectable stage III NSCLC].

The data for osimertinib is resected patients—not patients who were not resected and got radiation and chemotherapy. Whether you might still see that benefit in patients who get chemoradiation and have 

 positivity, and then get osimertinib, we just don't know.

However, the other concern we have is that we do have data in advanced lung cancer that patients with advanced NSCLC with 

 mutations do not tend to respond well to immunotherapy. The idea that you have somebody with stage III unresectable NSCLC with an 

 mutation and you give them 1 year of immunotherapy is a little counterintuitive to some. 

If we look at the PACIFIC data, they did have some patients with 

 mutations; however, the numbers were small, and I'm not sure we can make any conclusions [from that]. 

We have to individualize it. A good question would be: Would you bother doing the molecular assay if you don't have those data? That's a fair question, but in medicine and cancer, patients have this one opportunity for us to do the right things. We're always better trying to have a little bit more information rather than putting our hands over our eyes and blinding ourselves, even though the decisions may be difficult. It's better having that information in hand so we can make the right decisions for our patients. 

In stage III resectable disease, we are thrilled with PACIFIC and with the results, but unfortunately, the percentage of people who relapse and die from lung cancer is still very high. We actually opened up a study here at our cancer center that is addressing a novel PD-L1 immunotherapy, as an alternative to durvalumab, and giving it in combination with chemoradiation, and then continuing this novel immunotherapy drug for 1 year. We would be randomizing the patients to that versus the standard approach of chemoradiation followed by durvalumab. The thinking is that this isn't going to be a compromise; it's still an immunotherapy. The preliminary data indicated that [the novel immunotherapy] may be better than durvalumab and may be an opportunity to work off of the positive results of PACIFIC and do something even better.

Everyone is excited about PACIFIC, but it would be a huge mistake to think, "OK, we're done. There is no more space to move to do better." There is a huge amount of open space to even do better. Patients with stage III disease who are eligible should be placed on novel clinical studies that are addressing ways to make those treatments even better. This is a great study, because half of the patients get our standard of care and the other half are going to get what looks to be potentially equivalent or better than standard of care. We are excited about that. We think that this international study will accrue quickly and projections are that it may be done with accrual by the end of this year. Imagine building on the benefits of PACIFIC and getting something even better than that?

It's a multicenter, double-blind, randomized, controlled study. The immunotherapy drug is M7824 with concurrent chemoradiation, followed by M7824 versus concurrent chemoradiation plus placebo followed by durvalumab for unresectable stage III NSCLC.

The first patient went on study in October 2020; our site is expected to open [study this] month. They're expecting accrual by October or November.

What other ongoing efforts are tackling this population?

The other thing I would encourage is the KEYNOTE-671 trial. That is so important because, again with stage IIB and stage IIIA disease, when we're just dealing with surgery and chemotherapy, we get good results but not great results. We had 1 patient who went on a double-blinded study and they had a 6 cm primary tumor. He had a complete pathologic response to neoadjuvant therapy; he underwent surgery and there was no residual disease. We don't know [what treatment they received]. They got chemotherapy, right? Did they also get immunotherapy? We don't know. However, I've never seen that type of response from chemotherapy alone. 

The early studies that went into the phase 2 studies were all showing, for neoadjuvant therapy, that 80% to 90% of patients had either near complete responses [CRs] or CRs—incredible numbers. Immunotherapy can be something very magical in lung cancer, and we're seeing that potentially 20% of our patients with stage IV lung cancer are being cured, which are patients with significant tumor burdens. We could only imagine if you're treating [patients with a] bad prognosis, and have stage II and stage III disease, what you could potentially expectance in terms of improving cure rates, or giving that immunotherapy early on before stage IV disease. 

Articles

Dan Costin, MD, discusses his strategies for patients with early-stage lung cancer and ongoing trials that could improve outcomes even further. 

Ongoing Novel Immunotherapy Trial Builds on PACIFIC Benefits in Stage III NSCLC

David R. Gandara, MD, director of the Thoracic Oncology Program, professor, and senior advisor to the director of University of California Davis Comprehensive Cancer Center, as well as a 2017 Giant of Cancer Care® in Lung Cancer, discusses the benefit of nivolumab (Opdivo) and ipilimumab (Yervoy) in combination with chemotherapy in metastatic non–small cell lung cancer (NSCLC).

The phase 3 CheckMate-9LA trial is examined the potential benefit of adding a short course of chemotherapy to nivolumab and ipilimumab, according to Gandara. The regimen demonstrated substantial benefit in this patient population. However, the main issue is that the study was published with a relatively short follow-up, adds Gandara.

Although the long-term impact of the combination on overall survival is not yet clear, there is a potential benefit of receiving at least 2 cycles of chemotherapy with the immunotherapy combination, says Gandara. With this regimen, it is possible to stop early disease progression from immunotherapy approaches such as nivolumab/ipilimumab or nivolumab monotherapy. It is also possible to prevent hyperprogressive disease, Gandara concludes.

Videos

David R. Gandara, MD, discusses the benefit of nivolumab and ipilimumab in combination with chemotherapy in metastatic non–small cell lung cancer.



Dr. Gandara on the Benefit of Nivolumab/Ipilimumab Plus Chemo in Metastatic NSCLC

Howard (Jack) West, MD, executive director of Employer Strategy and associate clinical professor of the Department of Medical Oncology & Therapeutics Research, discusses the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) in metastatic non–small cell lung cancer (NSCLC).

The combination has been utilized in this disease for several years; however, within the past 18 months, nivolumab/ipilimumab has demonstrated an overall survival benefit in this patient population, according to West. This benefit extends to patients who have PD-L1 positivity and those who do not, as well as in those with squamous or nonsquamous histology, West adds.

The phase 3 CheckMate-227 trial led to the May 2020 

 in the treatment of patients with metastatic NSCLC without 

 genomic tumor aberrations, and whose tumors express a PD-L1 level of 1% or greater. In this trial, the comparator was single-agent chemotherapy, an older standard of care that has since been replaced, says West. In some ways, this is a lateral progression due to pembrolizumab (Keytruda) having shown superiority to single-agent chemotherapy in the phase 3 KEYNOTE-024 and KEYNOTE-042 trials, in which the agent showed benefit in the PD-L1–high population, West concludes.

Howard (Jack) West, MD, discusses the use of nivolumab in combination with ipilimumab in metastatic non–small cell lung cancer.

Frontline Immunotherapy Updates in Advanced NSCLC | Supplements and Featured Publications

Ongoing Novel Immunotherapy Trial Builds on PACIFIC Benefits in Stage III NSCLC

Dr. Gandara on the Benefit of Nivolumab/Ipilimumab Plus Chemo in Metastatic NSCLC

Dr. West on the Use of Nivolumab/Ipilimumab in Metastatic NSCLC