Clinical Challenge: Finding the Right Regimen in EGFR-Positive NSCLC

The phase III PACIFIC trial was a game-changer for patients with unresectable stage III non-small cell lung cancer (NSCLC) without disease progression after concurrent chemoradiotherapy. The results showed that patients continued to see durable survival outcomes with the immune checkpoint inhibitor (ICI) durvalumab (Imfinzi), with the first pass at estimated median overall survival (OS) based on the trial data coming in at 47.5 months.

The updated OS findings prompted one expert to call them “Impressive Data!!!” and “Definitely a practice-changing landmark trial.” But that high praise from Martin Sebastian, MD, of University Hospital Frankfurt in Germany, aside, there remains a key unanswered question from PACIFIC, according to Sebastian himself: “Is the [regimen] effective in patients with driver mutations?”

In the trial, about half of the patients were positive for EGFR mutations. Overall, there was OS and progression-free survival (PFS) in prespecified subgroups, with the exception of patients with EGFR mutations, reported Corinne Faivre-Finn, MD, of the University of Manchester in England, at the 2020 European Society for Medical Oncology (ESMO) virtual meeting. “However, the small size of this subgroup, only 43 [patients], and also exploratory nature of this analysis preclude definitive conclusions,” she added.

Therein lies one of the major challenges in NSCLC care: How can chemotherapy plus radiotherapy with ICIs be deployed most effectively in patients with EGFR mutations? Researchers have tackled this question from multiple angles, including more work in the PACIFIC population.

PACIFIC Progress

Marina Garassino, MD, of the University of Chicago, reported results from the PACIFIC-6 trial at the 2021 virtual European Lung Cancer Congress, explaining that “in the big PACIFIC [trial], the patients had to receive concurrent chemoradiation, and then were randomized to receive either durvalumab for 1 year, or placebo after 42 days, after their completion of concurrent chemoradiation.”

“However, as we know from our daily practice, there are several problems about the volume of the tumor; the access to the radiation oncology … And so not all the patients are eligible from the beginning for concurrent chemoradiation,” she said in a VJOncology video. “And it is also quite frequent to have patients that … need the sequential chemoradiation.”

For PACIFIC-6, most patients received a median of four chemoradiation cycles, with 68% receiving a total radiotherapy dose of 54-60 Gy and 32% receiving >60 to 66 Gy; chemotherapy and radiotherapy did not overlap in 84% of the cases. Based on the early assessment, Garassino’s group reported good results with durvalumab after sequential chemoradiotherapy, with a safety profile similar to that of the original PACIFIC cohort.

“The results I presented … suggested that the safety profile is very similar to what was observed in the PACIFIC after the concurrent chemoradiation, and they are mainly represented by the pneumonitis,” Garassino said.

An ancillary expanded-access study, PACIFIC-R, offered insight into the use of the trial regimen in a real-world setting, and those researchers reported that for the patients who received concurrent chemoradiotherapy, time to durvalumab start from the end of chemoradiotherapy was longer in the clinic than it was in the trial in most instances.

Ross Soo, MBBS, PhD, of the National University Cancer Institute in Singapore, said “the findings from PACIFIC-R actually reflect clinical reality and the challenges of initiating consolidation therapy post-concurrent chemoradiation as many patients have yet to recover from the toxicities of concurrent chemoradiation.”

But Soo also inquired of PACIFIC-R: “is it real enough?” and like Sebastian, stressed that more data were needed on the impact of EGFR mutations, as “we know that EGFR-positive lung cancer has a tumor-suppressive microenvironment.”

Whether ongoing or upcoming trials will offer any clarity is uncertain, as many studies, such as AFT-16 (chemoradiotherapy as part of an induction regimen), and NIRVANA-LUNG (concurrent chemoradiotherapy) exclude patients with known EGFR mutations. However, the ongoing phase III PACIFIC-2 (concurrent chemoradiotherapy) does not exclude patients with EGFR-mutated NSCLC.

‘More Complex Treatments’

The principal investigator for PACIFIC-2 is Jeffrey D. Bradley, MD, of Emory University School of Medicine/Winship Cancer Institute in Atlanta, who also led the RTOG 0617 trial. The latter confirmed the current standard-of-care radiation dose for the treatment of unresectable stage III NSCLC at 60 Gy given in daily fractions of 2 Gy to a target volume directed at the tumor plus a margin on the basis of CT and PET/CT, excluding elective nodal irradiation.

While definitive word may be lacking or pending for patients with EGFR-mutated NSCLC, there are data on how to get the most out of the radiation therapy protocol.

“The radiotherapy technologies that we have, the intensity-modulated radiotherapy [IMRT] … using arc therapies, VMAT [volumetric modulated arc therapy], or similar allow us to deliver much better doses of radiation without other organ damage, and allows bigger or more complex treatments … so that’s really good,” noted David Gilligan, MB BChir, of Cambridge University Hospitals NHS Foundation Trust in England, in a VJOncology webinar from the 2021 British Thoracic Oncology Group virtual meeting.

Bradley told MedPage Today in an earlier interview that the RTOG trial “taught us to keep heart dose constraints in mind during treatment planning. Heart dose was a major factor on multivariate analysis of overall survival.”

Another revelation of the RTOG 0617 trial was that IMRT resulted in less toxicity, although there was no OS difference seen between IMRT and 3D-conformal radiation therapy (CRT).

“I use IMRT in every case of locally advanced lung cancer,” Bradley explained. “It spares normal tissues better, resulting in fewer side effects. Frankly, it’s easier today with new techniques for a radiation oncologist and team to plan and deliver IMRT compared to 3D-CRT. It results in shorter treatment times for the patient as well,” although Bradley cautioned that RTOG 0617 did not demonstrate that IMRT led to better OS, only to less toxicity.

Back in 2018, Daniel Gomez, MD, then of the University of Texas MD Anderson Cancer Center in Houston, and colleagues reported results from a multicenter trial in patients with oligometastatic stage IV NSCLC (12% had EGFR mutations) that had spread to no more than three sites.

Patients received either standard platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors. Patients with non-progressing cancers after first-line treatment were randomized to either an investigational arm of surgery or radiation therapy (specific treatment regimens can be found here) at the tumor site, or to standard systemic maintenance therapy and observation.

Outcomes were dramatic: In the experimental arm, PFS came in at 14.2 months versus 4.4 months in patients who received standard treatment and observation, while OS was 41.2 months versus 17.0 months, respectively.

Because the number of patients with mutated disease was small, the authors went with a multivariable model with the two clinical covariables that demonstrated the strongest association with OS: number of metastases and EGFR/EML4-ALK alterations. In that model, the local consolidative therapy arm remained tied to improved OS.

More recent research from Taiwan demonstrated that radiotherapy only for primary lung tumor (RTPLT) after EGFR tyrosine kinase inhibitor (TKI) therapy improved survival in patients with treatment-naive advanced EGFR-mutated lung adenocarcinoma patients, whether there was polymetastasis or not.

The investigators also found no significant differences for PFS based on radiotherapy methods — specifically conventional or stereotactic ablative radiotherapy (SABR, also known as stereotactic body radiation therapy or SBRT), although conventional treatment carried more grade ≥2 pneumonitis (47.1%) versus 20.7% with SABR. But there was no difference in radiation pneumonitis between the first- and second-generation EGFR TKIs.

“The decision for using either SABR or conventional radiotherapy depended upon the location and size of the primary tumor,” explained Gee-Chen Chang, MD, PhD, of Chung Shan Medical University Hospital in Taichung, Taiwan, and colleagues. “In our practice, we used the definition of central lesion for tumors within 2 cm in all directions of any mediastinal critical structure, including the bronchial tree, esophagus, heart, brachial plexus, major vessels, spinal cord, phrenic nerve, and recurrent laryngeal nerve.”

While data came from a single-center study in a small population (138 patients), the authors suggested that “RTPLT within 24 weeks after EGFR-TKI initiation appeared to be more beneficial with tolerable radiation pneumonitis.”

Researchers led by Heather Wakelee, MD, of Stanford Healthcare in California, conducted a retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who had completed concurrent chemoradiotherapy, either with or without durvalumab. Of the 24 patients who completed chemoradiotherapy without durvalumab, eight completed the former with induction or consolidation EGFR TKIs.

The team concluded that patients with EGFR-mutated NSCLC did not benefit from consolidation durvalumab, mostly because of a high frequency of immune-related adverse events (irAEs), and that “patients who initiate osimertinib [Tagrisso] after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.”

Finally, the West Japan Oncology Group evaluated if gefitinib plus concurrent thoracic radiotherapy would be effective in chemotherapy-naive, locally advanced NSCLC patients with EGFR mutation (mostly exon 21 L858R). About 30% of PACIFIC participants had EGFR mutations and “they seemed to be less likely to benefit from consolidation durvalumab,” noted Junichi Shimizu, MD, PhD, of Aichi Cancer Center Hospital, in a presentation at the 2020 ESMO Virtual Congress.

In that 27-patient study, oral gefitinib was delivered at 250 mg/day for 2 years, along with concurrent thoracic radiotherapy at 64 Gy (32 fractions). The primary endpoint was 2-year PFS based on the hypothesis that the regimen would improve 2-year PFS rate at 2 years from 20% to 40%.

Shimizu’s group found that the 2-year PFS rate was 29.6%, with a median PFS of 28.6 months, and median OS of 61.1 months. While pneumonitis was seen frequently, they were all considered mild events, according to the researchers. But initial relapse was an issue, with two cases within the radiation field (one lymph node; one at primary site), and 23 cases outside the radiation field (nine at intrathoracic sites; 14 extrathoracic, mainly brain only).

“Among unresectable, locally advanced NSCLC patients with EGFR mutation, gefitinib with concurrent thoracic radiotherapy showed favorable efficacy with manageable safety, although this study did not meet the primary endpoint,” Shimizu stated.

Sebastian pointed out that “the radiotherapy regimen was really good,” with manageable pulmonary toxicity. But the study still had some loose ends, such as why patients with ECOG performance status of 0-1 received no chemotherapy — would that constitute “undertreatment?” he noted — and why the gefitinib regimen was for 2 years. And with only 27 patients, the study population was simply too small to draw any “robust conclusions.”

Once again, the bigger issue is that most trials that have looked at immunotherapy plus chemoradiotherapy have been single-arm trials that did not break out findings in patients with and without EGFR mutations, Sebastian stressed. “We need a randomized trial with backbone radiotherapy comparing TKI versus chemotherapy plus TKI versus chemotherapy alone.”