Pathology Expert Unpacks the Future Role MPR and pCR in Neoadjuvant NSCLC Treatment

Ignacio I. Wistuba, MD

Clinical efficacy of neoadjuvant treatment regimens for patients with non–small cell lung cancer (NSCLC) is increasingly being determined by major pathological response (MPR) and pathological complete response (pCR). However, these may be better leveraged as surrogate end points, according to Ignacio I. Wistuba, MD.

In a presentation at the 23rd Annual International Lung Cancer Congress^®, Wistuba examined a pathologist’s approach to interpreting these data and their role as clinical end points.¹

“Neoadjuvant and adjuvant therapies including chemotherapy, targeted therapy, and immunotherapy [have been studied] in lung cancer and NSCLC and [some] clinical trials, as you have seen, have used MPR and some are showing data now on pCR. These are new terms for pathologists, and we [must] adapt and learn [these terms] and work as members of the multidisciplinary team to provide clarity on these results,” he said. Wistuba is division head ad interim and codirector of the Division of Pathology/Lab Medicine, and a professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

The central issue, Wistuba noted, is that there is no standardized and validated pathology methodology for neoadjuvant-treated specimens to evaluate MPR and pCR.

The Growing Use of MPR and pCR

Several phase 3 studies have leveraged MPR or pCR as the primary end point for efficacy of neoadjuvant therapy for patients with nonmetastatic NSCLC. For example, the dual primary end points of the phase 3 AEGEAN trial (NCT03800134) are pCR and event-free survival (EFS).2 The trial is evaluating the efficacy of neoadjuvant durvalumab (Imfinzi) plus standard-of-care platinum-based chemotherapy doublet vs standard of care alone. Recently, it was announced that the combination elicited a statistically significant and meaningful improvement in pCR as well as MPR. Analysis of data for the EFS is ongoing and will be reported at an upcoming medical meeting.²

In the phase 3 CheckMate 816 trial (NCT02998528), data published in the New England Journal of Medicine, showed that patients with stage IB-IIIA resectable NSCLC who received nivolumab (Opdivo) plus platinum-based chemotherapy had a median EFS of 31.6 months (95% CI, 30.2-not reached) vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 97.38% CI, 0.43-0.91; P = .005).³ In terms of pCR, 24.0% of patients who received the combination had a pCR vs 2.2% who received standard of care (odds ratio, 13.94; 99% CI, 3.49-55.75; P < .001).

Other immunotherapy studies leveraging pCR and MPR as primary and/or secondary end points include the phase 3 IMpower030 trial (NCT03456063); the phase 3 KEYNOTE-671 trial (NCT03425643); and the phase 3 NeoADAURA trial (NCT04351555). Wistuba noted that neoadjuvant approaches using targeted therapies are also underway and called attention to the Lung Cancer Mutation Consortium screening trial— LCRF LEADER (NCT04712877)—which aims to enroll 1000 patients with lung cancer who are candidates for neoadjuvant therapy to receive targeted agents for specific genetic mutations.⁴

“For pathologists, we now [must] be more careful on the assessment of these specimens,” Wistuba said.

Establishing Definitions for Pathologists

Wistuba said that the integration of a new concept, the tumor bed, which is a microscopic finding of a tumor and what was potentially tumor that has been modified by therapy. To establish the tumor bed, he noted that tumor grossing must include radiographic/pathologic correlation.

“We need to use more correlation with the images to better assess the area, we need to have a systematic [tissue] sample throughout the tumor and the tumor bed that sometimes can be confused with inflammatory processes that are going on adjacent to a tumor that is growing,” he said. “We need to be able to with this rise sampling and observation the microscope to identify residual tumor cells that are viable, sometimes [that is] not easy.”

Wistuba cautioned that pathologists need to take caution when it comes to using terms as definitions may vary. Viable tumor should be used to describe the percentage of viable malignant cells in a specimen. Tumor regression, or tumor bed, should be used to describe the percentage of area of a tumor that has responded to therapy. This includes necrosis, cavitation, fibrosis, and areas with inflammatory or immune cell infiltration.

“Recently, we have fortunately seen pCR, [which] requires finding no viable malignant cells, but the sampling has to be complete of the specimen,” Wistuba said.

The definition for MPR—the presence of 10% or less percent of viable malignant cells—is based on observations from retrospective analyses from clinical trials which examined the efficacy of chemotherapy in the neoadjuvant setting. The definition is being used in trials for immunotherapy. “These retrospective studies showed that this percentage of 10% was critical to differentiate disease-free survival, and overall survival at 5 years in the chemotherapy-treated setting, [but] we haven't seen any of these data in the monotherapy to the setting.”

Steps for Assessing pCR and MPR

For NSCLC, Wistuba said that there are 4 steps for assessing resected specimens for pCR and MPR. The first step is gross analysis that includes correlation with imaging. The second step includes taking stained slides of the specimen. “A good analysis of a specimen includes cavitation across it, that needs to be reported carefully,” Wistuba said. “[For] appropriate sampling of the tumor we use this principle: 3 cm or less, you put it all [on the slide], more than 3 cm diameter, you can [create] 1 slide per cm.”

Step 3 is to measure the percentage of viable tumor cells in each slide and step 4 is to calculate the percentages to determine the mean residual viable tumor percentage. “Some slides have a small piece of tissue [and] some have a larger piece of tissue, [and therefore there is some] suggestion to correct for the size of the specimens that you are analyzing. Then the percentage is based on the representation of tumors in a slide.”

Wistuba noted that pathologists are using these protocols in the academic and institution settings, but the challenge is to bring these to the community pathologists who are diagnosing lung cancer. He added that, unlike with breast or sarcoma samples, pathologists in lung cancer not used to sampling an entire tumor and more resources are needed to make a diagnostic because these pathologists may be looking at 30 slides rather than 5.

“I think that the future of this is computational pathology using digital approaches,” Wistuba said. “There are several studies ongoing that are showing [digital approaches have] good correlation assessing MPR and pCR compared with observations of an experienced pathologist.”

One such study is the phase 2 LCMC3 trial (NCT02927301), which is evaluating atezolizumab (Tecentriq) as neoadjuvant therapy in NSCLC. Investigators evaluated computer vision machine learning and digital assessment of pCR using an artificial intelligence tool developed in accordance with consensus recommendations.⁵ The tool was trained to predict areas of tumor bed, viable tumor, stroma, necrosis, and to label individual cells.

Cases were evaluated by local site pathologists as well as 3 central pathology experts using the definition of MPR of 10% or less viable tumor cells. This analysis demonstrated that manual reporting was comparable to the digital assessment for pCR (98%) and MPR (91%). Further, digital pathological response demonstrated an “outstanding predictability” for manual MPR (area under the receiver operating characteristic, 0.975).⁵

Wistuba concluded by noting that although the end points of MPR and pCR are important, improved outcomes for patients is what all clinicians are striving to achieve. He noted that these may represent appropriate end points for disease-free survival and overall survival and provide guidance for decision-making in the adjuvant setting.¹

References

1. Wistuba II. Determining MPR and pCR after neo-adjuvant immunotherapy: are these appropriate endpoints? Presented at: 23rd Annual International Lung Cancer Congress®. July 28-30, 2022; Huntington Beach, CA.
2. Imfinzi plus chemotherapy significantly improved pathologic complete response in AEGEAN phase III trial in resectable non-small cell lung cancer. News release. AstraZeneca. June 30, 2022. Accessed July 28, 2022. bit.ly/3OKQe10
3. Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170
4. Sepesi B, Jones DR, Meyers BF, et al. LCMC LEADER neoadjuvant screening trial: LCMC4 evaluation of actionable drivers in early-stage lung cancers. J Clin Oncol. 2022;40(suppl 16):TPS8596. doi:10.1200/JCO.2022.40.16_suppl.TPS8596
5. Dacic S, Travis WD, Giltnane JM, et al. Artificial intelligence (AI)–powered pathologic response (PathR) assessment of resection specimens after neoadjuvant atezolizumab in patients with non-small cell lung cancer: results from the LCMC3 study. J Clin Oncol. 2022;39(suppl 15):106. doi:10.1200/JCO.2021.39.15_suppl.106